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  1. PRL — EDRN Public Portal

    Cancer.gov

    There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis.

  2. Tissue-specific alterations of PRL-1 and PRL-2 expression in cancer.

    PubMed

    Dumaual, Carmen M; Sandusky, George E; Soo, Han Weng; Werner, Sean R; Crowell, Pamela L; Randall, Stephen K

    2012-01-01

    The PRL-1 and PRL-2 phosphatases have been implicated as oncogenic, however the involvement of these molecules in human neoplasms is not well understood. To increase understanding of the role PRL-1 and PRL-2 play in the neoplastic process, in situ hybridization was used to examine PRL-1 and PRL-2 mRNA expression in 285 normal, benign, and malignant human tissues of diverse origin. Immunohistochemical analysis was performed on a subset of these. PRL-1 and PRL-2 mRNA expression was also assessed in a small set of samples from a variety of diseases other than cancer. Where possible, associations with clinicopathological characteristics were evaluated. Alterations in PRL-1 or -2 expression were a frequent event, but the nature of those alterations was highly tumor type specific. PRL-1 was significantly overexpressed in 100% of hepatocellular and gastric carcinomas, but significantly under-expressed in 100% of ovarian, 80% of breast, and 75% of lung tumors. PRL-2 expression was significantly increased in 100% of hepatocellular carcinomas, yet significantly downregulated in 54% of kidney carcinomas. PRL-1 expression was correlated to patient gender in the bladder and to patient age in the brain and skeletal muscle. PRL-1 expression was also associated with tumor grade in the prostate, ovary, and uterus. These results suggest a pleiotropic role for PRL-1 and PRL-2 in the neoplastic process. These molecules may associate with tumor progression and serve as clinical markers of tumor aggressiveness in some tissues, but be involved in inhibition of tumor formation or growth in others.

  3. Unmodified prolactin (PRL) promotes PRL secretion and acidophil hypertrophy and is associated with pituitary hyperplasia in female rats.

    PubMed

    Johnson, Terence E; Vue, Mayza; Brekhus, Sharyn; Khong, Amy; Ho, Timothy W C; Walker, Ameae M

    2003-01-01

    In this study, we have tested the hypothesis that unmodified prolactin (U-PRL) and phosphorylated prolactin (P-PRL) have differential roles in the autoregulation of PRL secretion in vivo. Recombinant human U-PRL and a molecular mimic of P-PRL (S179D PRL) were administered to male rats and to female rats in different physiological states and the effect on rat PRL release was measured. Administration of U-PRL elevated rat PRL in all female animals, but was without effect in males. By contrast, S179D PRL was inactive in females, but inhibited PRL release in males. Morphometric and immunohistochemical analyses demonstrated acidophil hypertrophy and evidence of increased PRL secretion in the pituitaries of U-PRL-treated females. Analysis of the two forms of PRL during prolactinoma induction in two differentially susceptible strains of rats found a strong temporal correlation among increased ratios of U-PRL: P-PRL, increased circulating PRL, and increased cell proliferation. We conclude (1). that the autoregulatory mechanism(s) can distinguish between the two major forms of PRL and that higher proportions of U-PRL not only allow for higher circulating levels of PRL, but are also autostimulatory, (2). that the autoregulatory mechanism( s) are set differently in males and females such that females are more sensitive to autostimulation by U-PRL and less sensitive to inhibition by P-PRL, and (3). that U-PRL and P-PRL may also have differential roles in the regulation of pituitary cell proliferation.

  4. Purification of PRL receptors from toad kidney: Comparisons with rabbit mammary PRL receptors

    SciTech Connect

    Dunand, M.; Kraehenbuhl, J.P.; Rossier, B.C.; Aubert, M.L. Univ. of Lausanne School of Medicine )

    1988-03-01

    The binding characteristics of the prolactin (PRL) receptors present in toad (Bufo marinus) kidneys were investigated and compared to those of PRL receptors present in rabbit mammary glands. The molecular characteristics of the Triton X-100 solubilized renal and mammary PRL receptors were assessed by gel filtration and by migration analysis on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) after affinity labeling of the binding sites with {sup 125}I-human growth hormone. Similar results were obtained for both receptors. Partial purification of the toad PRL receptor could be achieved by affinity chromatography. The molecular weight of this purified receptor could be determined by analysis of SDS-PAGE. With the use of a polyclonal antiserum raised against a purified preparation of rabbit mammary PRL receptor, one or several antigenic epitope(s) could be identified on the core of the toad renal PRL receptor. In conclusion, although the structure and the biological role(s) of PRL have substantially changed during evolution, the receptor for this hormone has retained many of its structural features as could be assessed between an amphibian and a mammalian species on functionally different target tissues.

  5. Emodin inhibits migration and invasion of DLD-1 (PRL-3) cells via inhibition of PRL-3 phosphatase activity.

    PubMed

    Han, Young-Min; Lee, Su-Kyung; Jeong, Dae Gwin; Ryu, Seong Eon; Han, Dong Cho; Kim, Dae Keun; Kwon, Byoung-Mog

    2012-01-01

    Anthraquinones have been reported as phosphatase inhibitors. Therefore, anthraquinone derivatives were screened to identify a potent phosphatase inhibitor against the phosphatase of regenerating liver-3 (PRL-3). Emodin strongly inhibited phosphatase activity of PRL-3 with IC(50) values of 3.5μM and blocked PRL-3-induced tumor cell migration and invasion in a dose-dependent manner. Emodin rescued the phosphorylation of ezrin, which is a known PRL-3 substrate. The results of this study reveal that emodin is a PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor.

  6. Generation of conditional knockout alleles for PRL-3.

    PubMed

    Yan, Hong; Kong, Dong; Ge, Xiaomei; Gao, Xiang; Han, Xiao

    2011-11-01

    Phosphatase of regenerating liver-3 (PRL-3) is a member of the protein tyrosine phosphatase (PTP) superfamily and is highly expressed in cancer metastases. For better understanding of the role of PRL-3 in tumor metastasis, we applied a rapid and efficient method for generating PRL-3 floxed mice and investigated its phenotypes. A BAC retrieval strategy was applied to construct the PRL-3 conditional gene-targeting vector. Exon 4 was selected for deletion to generate a nonfunctional prematurely terminated short peptide as it will cause a frame-shift mutation. Conditional knockout PRL-3 mice were generated by using the Cre-loxP system and were validated by Southern blot and RT-PCR analysis. Further analysis revealed the phenotype characteristics of PRL-3 knockout mice and wildtype mice. In this study, we successfully constructed the PRL-3 conditional knockout mice, which will be helpful to clarify the roles of PRL-3 and the mechanisms in tumor metastasis.

  7. Hyperprolactinemia after neonatal prolactin (PRL) deficiency in rats: evidence for altered anterior pituitary regulation of PRL secretion.

    PubMed

    Shah, G V; Shyr, S W; Grosvenor, C E; Crowley, W R

    1988-05-01

    Previous findings from this laboratory suggest a role for milk-borne PRL in the development of the inhibitory neuroendocrine controls over PRL secretion. Thus, rats that consumed milk deficient in PRL on days 2-5 postpartum show reduced concentrations and turnover of DA in the median eminence and elevated serum levels of PRL at 30-35 days of age. The present experiments were undertaken to investigate whether these consequences of neonatal PRL deficiency persist beyond puberty, and whether alterations in pituitary responsiveness to hypothalamic hormones may be involved. Lactating rats received sc injections of either saline or the dopamine (DA) agonist bromocriptine (125 micrograms/rat.day) on each of days 2-5 postpartum, a treatment that reduces the amount of PRL in milk without abolishing lactation. Blood samples were obtained from male and female offspring at various postnatal ages, and PRL concentrations were determined by RIA. Serum PRL concentrations in offspring from both groups were low until after weaning, but the female offspring of bromocriptine-treated mothers showed significantly elevated serum PRL between days 30 and 90 postpartum. Male offspring of bromocriptine-treated mothers also had transiently increased serum PRL levels, which returned to control levels by day 40. The turnover rate of DA in the median eminence, calculated from the rate of decline after synthesis inhibition, was reduced on day 35 in neonatally PRL-deficient offspring, as shown previously. However, no differences in DA turnover between the two groups were apparent on day 60, indicating a recovery of normal dopaminergic activity. Anterior pituitary cells of 100-day-old control and neonatally PRL-deficient animals were dispersed, cultured for 3 days, and then exposed to either TRH, to stimulate PRL release, or to the DA agonist bromocriptine, which inhibits PRL release. Pituitary cells of neonatally PRL-deficient offspring were almost completely unresponsive to bromocriptine with

  8. Both prolactin (PRL) and a molecular mimic of phosphorylated PRL, S179D-PRL, protect the hippocampus of female rats against excitotoxicity.

    PubMed

    Morales, T; Lorenson, M; Walker, A M; Ramos, E

    2014-01-31

    Prolactin (PRL) has many functions in the CNS, including neuroprotection. During lactation, the dorsal hippocampus is protected from excitotoxic kainic acid (KA)-induced cellular damage. We have previously reported that systemic pre-treatment with ovine PRL had similar protective effects in female rats. Here, we asked (1) whether intracerebral human PRL (hPRL) would have the same action, (2) because phosphorylated PRL is high in lactation, whether a mimic of phosphorylated hPRL, human prolactin in which the normally phosphorylated serine at position 179 is replaced with an aspartate (S179D-PRL), had similar activity, and (3) what signaling pathways mediated the protective effect. Female ovariectomized (OVX, 1 month) rats were implanted with micro-osmotic pumps connected to unilateral icv cannulae directed at the right lateral ventricle. The pumps delivered 0.10 ng/h of hPRL, S179D-PRL, a combination of hPRL+S179D-PRL, or saline vehicle for 7 days prior to a systemic dose of 7.5mg/kg of KA. Rats were sacrificed 48 h after KA injection. Immunostaining for neuronal nuclei (Neu-N) revealed a significant KA-induced decrease in cell number in the CA1, CA3, and CA4 hippocampal areas of rats (∼55% of control). Treatment with either hPRL or S179D-PRL or the combination prevented the damaging effect of KA in these hippocampal regions (∼95% of corresponding control), but was not completely effective at preventing early seizure-related behaviors such as staring and wet dog shakes. Analysis of signals generated by hPRL and S179D-PRL showed no activation of signal transducer and activation of transcription 5 (Stat5) or other signaling molecules in the hippocampus, but activation of extracellular-regulated kinase (ERK)1/2 in the amygdala. These results support a central protective effect of both PRL forms and suggest that PRL could be exerting its protective action by indirectly modulating input signals to the hippocampus and thus regulating excitability.

  9. Cysteamine depletes prolactin (PRL) but does not alter the structure of PRL-containing granules in the anterior pituitary

    SciTech Connect

    Weinstein, L.A.; Landis, D.M.; Sagar, S.M.; Millard, W.J.; Martin, J.B.

    1984-10-01

    Cysteamine causes a profound depletion of PRL in the anterior pituitary and in the systemic circulation, as measured by RIA and bioassay. However, electron microscopic study of PRL-containing cells in rat anterior pituitary does not reveal changes in secretory granule or cytoplasmic structure during the interval of depressed PRL content and of subsequent recovery to normal levels. In contrast to the results obtained by RIA, PRL-like immunoreactivity as detected by immunocyto-chemistry is present and similar to that of control preparations after cysteamine administration. We suggest that cysteamine alters PRL structure in secretory granules, probably by interacting with the disulfide bonds of PRL, thereby altering bioactivity and immunoreactivity. The presence of cysteamine-altered PRL in secretory granules does not seem to trigger degradation of granules by the lysosomal system.

  10. Prolactin (PRL) in adipose tissue: regulation and functions.

    PubMed

    Ben-Jonathan, Nira; Hugo, Eric

    2015-01-01

    New information concerning the effects of prolactin (PRL) on metabolic processes warrants reevaluation of its overall metabolic actions. PRL affects metabolic homeostasis by regulating key enzymes and transporters associated with glucose and lipid metabolism in several target organs. In the lactating mammary gland, PRL increases the production of milk proteins, lactose, and lipids. In adipose tissue, PRL generally suppresses lipid storage and adipokine release and affect adipogenesis. A specific case is made for PRL in the human breast and adipose tissues, where it acts as a circulating hormone and an autocrine/paracrine factor. Although its overall effects on body composition are both modest and species-specific, PRL may be involved in the manifestation of insulin resistance.

  11. Characterization of the protein tyrosine phosphatase PRL from Entamoeba histolytica.

    PubMed

    Ramírez-Tapia, Ana Lilia; Baylón-Pacheco, Lidia; Espíritu-Gordillo, Patricia; Rosales-Encina, José Luis

    2015-12-01

    Protein tyrosine phosphatase of regenerating liver (PRL) is a group of phosphatases that has not been broadly studied in protozoan parasites. In humans, PRLs are involved in metastatic cancer, the promotion of cell migration and invasion. PTPs have been increasingly recognized as important effectors of host-pathogen interactions. We characterized the only putative protein tyrosine phosphatase PRL (PTP EhPRL) in the eukaryotic human intestinal parasite Entamoeba histolytica. Here, we reported that the EhPRL protein possessed the classical HCX5R catalytic motif of PTPs and the CAAX box characteristic of the PRL family and exhibited 31-32% homology with the three human PRL isoforms. In amebae, the protein was expressed at low but detectable levels. The recombinant protein (rEhPRL) had enzymatic activity with the 3-o-methyl fluorescein phosphate (OMFP) substrate; this enzymatic activity was inhibited by the PTP inhibitor o-vanadate. Using immunofluorescence we showed that native EhPRL was localized to the cytoplasm and plasma membrane. When the trophozoites interacted with collagen, EhPRL relocalized over time to vesicle-like structures. Interaction with fibronectin increased the presence of the enzyme in the cytoplasm. Using RT-PCR, we demonstrated that EhPRL mRNA expression was upregulated when the trophozoites interacted with collagen but not with fibronectin. Trophozoites recovered from amoebic liver abscesses showed higher EhPRL mRNA expression levels than normal trophozoites. These results strongly suggest that EhPRL may play an important role in the biology and adaptive response of the parasite to the host environment during amoebic liver abscess development, thereby participating in the pathogenic mechanism.

  12. PRL-3 activates mTORC1 in Cancer Progression.

    PubMed

    Ye, Zu; Al-Aidaroos, Abdul Qader Omer; Park, Jung Eun; Yuen, Hiu Fung; Zhang, Shu Dong; Gupta, Abhishek; Lin, Youbin; Shen, Han-Ming; Zeng, Qi

    2015-11-24

    PRL-3, a metastasis-associated phosphatase, is known to exert its oncogenic functions through activation of PI3K/Akt, which is a key regulator of the rapamycin-sensitive mTOR complex 1 (mTORC1), but a coherent link between PRL-3 and activation of mTOR has not yet been formally demonstrated. We report a positive correlation between PRL-3 expression and mTOR phospho-activation in clinical tumour samples and mouse models of cancer and demonstrate that PRL-3 increased downstream signalling to the mTOR substrates, p70S6K and 4E-BP1, by increasing PI3K/Akt-mediated activation of Rheb-GTP via TSC2 suppression. We also show that PRL-3 increases mTOR translocation to lysosomes via increased mTOR binding affinity to Rag GTPases in an Akt-independent manner, demonstrating a previously undescribed mechanism of action for PRL-3. PRL-3 also enhanced matrix metalloproteinase-2 secretion and cellular invasiveness via activation of mTOR, attributes which were sensitive to rapamycin treatment. The downstream effects of PRL-3 were maintained even under conditions of environmental stress, suggesting that PRL-3 provides a strategic survival advantage to tumour cells via its effects on mTOR.

  13. Extra-pituitary prolactin (PRL) and prolactin-like protein (PRL-L) in chickens and zebrafish.

    PubMed

    Bu, Guixian; Liang, Xiaomeng; Li, Juan; Wang, Yajun

    2015-09-01

    It is generally believed that in vertebrates, prolactin (PRL) is predominantly synthesized and released by pituitary lactotrophs and plays important roles in many physiological processes via activation of PRL receptor (PRLR), including water and electrolyte balance, reproduction, growth and development, metabolism, immuno-modulation, and behavior. However, there is increasing evidence showing that PRL and the newly identified 'prolactin-like protein (PRL-L)', a novel ligand of PRL receptor, are also expressed in a variety of extra-pituitary tissues, such as the brain, skin, ovary, and testes in non-mammalian vertebrates. In this brief review, we summarize the recent research progress on the structure, biological activities, and extra-pituitary expression of PRL and PRL-L in chickens (Gallus gallus) and zebrafish (Danio rerio) from our and other laboratories and briefly discuss their potential paracrine/autocrine roles in non-mammalian vertebrates, which may promote us to rethink the broad spectrum of PRL actions previously attributed to pituitary PRL only.

  14. Discovery and Evaluation of PRL Trimer Disruptors for Novel Anticancer Agents.

    PubMed

    Bai, Yunpeng; Yu, Zhi-Hong; Zhang, Zhong-Yin

    2016-01-01

    Overexpression of PRL phosphatases (PRL1, PRL2, and PRL3) has been found in a variety of late-stage tumors and their distant metastatic sites. Therefore, the oncogenic PRL phosphatases represent intriguing targets for cancer therapy. There is considerable interest in identifying small molecule inhibitors targeting PRLs as novel anticancer agents. However, it has been difficult to acquire phosphatase activity-based PRL inhibitors due to the unusual wide and shallow catalytic pockets of PRLs revealed by crystal structure studies. Here, we present a novel method to identify PRL1 inhibitors by targeting the PRL1 trimer interface and the procedure to characterize their biochemical and cellular activity.

  15. Expression and clinical role of protein of regenerating liver (PRL) phosphatases in ovarian carcinoma.

    PubMed

    Reich, Reuven; Hadar, Shany; Davidson, Ben

    2011-02-11

    The present study analyzed the expression and clinical role of the protein of regenerating liver (PRL) phosphatase family in ovarian carcinoma. PRL1-3 mRNA expression was studied in 184 tumors (100 effusions, 57 primary carcinomas, 27 solid metastases) using RT-PCR. PRL-3 protein expression was analyzed in 157 tumors by Western blotting. PRL-1 mRNA levels were significantly higher in effusions compared to solid tumors (p < 0.001), and both PRL-1 and PRL-2 were overexpressed in pleural compared to peritoneal effusions (p = 0.001). PRL-3 protein expression was significantly higher in primary diagnosis pre-chemotherapy compared to post-chemotherapy disease recurrence effusions (p = 0.003). PRL-1 mRNA expression in effusions correlated with longer overall survival (p = 0.032), and higher levels of both PRL-1 and PRL-2 mRNA correlated with longer overall survival for patients with pre-chemotherapy effusions (p = 0.022 and p = 0.02, respectively). Analysis of the effect of laminin on PRL-3 expression in ovarian carcinoma cells in vitro showed dose-dependent PRL-3 expression in response to exogenous laminin, mediated by Phospholipase D. In contrast to previous studies associating PRL-3 with poor outcome, our data show that PRL-3 expression has no clinical role in ovarian carcinoma, whereas PRL-1 and PRL-2 expression is associated with longer survival, suggesting that PRL phosphatases may be markers of improved outcome in this cancer.

  16. Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis

    PubMed Central

    Bai, Yunpeng; Zhou, Hong-Ming; Zhang, Lujuan; Dong, Yuanshu; Zeng, Qi; Shou, Weinian; Zhang, Zhong-Yin

    2016-01-01

    The PRL phosphatases are oncogenic when overexpressed but their in vivo biological function is less well understood. Previous gene deletion study revealed a role for PRL2 in spermatogenesis. We report here the first knockout mice lacking PRL1, the most related homolog of PRL2. We found that loss of PRL1 does not affect spermatogenesis and reproductive ability of male mice, likely due to functional compensation by the relatively higher expression of PRL2 in the testes. However, PRL1−/−/PRL2+/− male mice show testicular atrophy phenotype similar to PRL2−/− mice. More strikingly, deletion of one PRL1 allele in PRL2−/− male mice causes complete infertility. Mechanistically, the total level of PRL1 and PRL2 is negatively correlated with the PTEN protein level in the testis and PRL1+/−/PRL2−/− mice have the highest level of PTEN, leading to attenuated Akt activation and increased germ cell apoptosis, effectively halting spermatozoa production. These results provide the first evidence that in addition to PRL2, PRL1 is also required for spermatogenesis by downregulating PTEN and promoting Akt signaling. The ability of the PRLs to suppress PTEN expression underscores the biochemical basis for their oncogenic potential. PMID:27666520

  17. Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

    PubMed Central

    Turroni, Francesca; Taverniti, Valentina; Ruas-Madiedo, Patricia; Duranti, Sabrina; Guglielmetti, Simone; Lugli, Gabriele Andrea; Gioiosa, Laura; Palanza, Paola; Margolles, Abelardo; van Sinderen, Douwe

    2014-01-01

    Here, we describe data obtained from transcriptome profiling of human cell lines and intestinal cells of a murine model upon exposure and colonization, respectively, with Bifidobacterium bifidum PRL2010. Significant changes were detected in the transcription of genes that are known to be involved in innate immunity. Furthermore, results from enzyme-linked immunosorbent assays (ELISAs) showed that exposure to B. bifidum PRL2010 causes enhanced production of interleukin 6 (IL-6) and IL-8 cytokines, presumably through NF-κB activation. The obtained global transcription profiles strongly suggest that Bifidobacterium bifidum PRL2010 modulates the innate immune response of the host. PMID:24242237

  18. Thioredoxin-related protein 32 (TRP32) specifically reduces oxidized phosphatase of regenerating liver (PRL).

    PubMed

    Ishii, Tasuku; Funato, Yosuke; Miki, Hiroaki

    2013-03-08

    PRL family constitutes a unique class of phosphatases associated with metastasis. The phosphatase activity of PRL has been reported to be important for promoting metastasis, and it is inactivated by reversible oxidation of its catalytic cysteine. Here, we show that TRP32 specifically reduces PRL. Reduction of oxidized PRL in cells is inhibited by 2,4-dinitro-1-chlorobenzene, an inhibitor of TRX reductase. In vitro assays for the reduction of PRL show that only TRP32 can potently reduce oxidized PRL, whereas other TRX-related proteins linked to TRX reductase show little or no reducing activity. Indeed, TRP32 knockdown significantly prolongs the H2O2-induced oxidation of PRL. Binding analyses reveal that the unique C-terminal domain of TRP32 is required and sufficient for its direct interaction with PRL. These results suggest that TRP32 maintains the reduced state of PRL and thus regulates the biological function of PRL.

  19. Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.

    PubMed

    Gulerez, Irina; Funato, Yosuke; Wu, Howie; Yang, Meng; Kozlov, Guennadi; Miki, Hiroaki; Gehring, Kalle

    2016-12-01

    PRLs (phosphatases of regenerating liver) are frequently overexpressed in human cancers and are prognostic markers of poor survival. Despite their potential as therapeutic targets, their mechanism of action is not understood in part due to their weak enzymatic activity. Previous studies revealed that PRLs interact with CNNM ion transporters and prevent CNNM4-dependent Mg(2+) transport, which is important for energy metabolism and tumor progression. Here, we report that PRL-CNNM complex formation is regulated by the formation of phosphocysteine. We show that cysteine in the PRL catalytic site is endogenously phosphorylated as part of the catalytic cycle and that phosphocysteine levels change in response to Mg(2+) levels. Phosphorylation blocks PRL binding to CNNM Mg(2+) transporters, and mutations that block the PRL-CNNM interaction prevent regulation of Mg(2+) efflux in cultured cells. The crystal structure of the complex of PRL2 and the CBS-pair domain of the Mg(2+) transporter CNNM3 reveals the molecular basis for the interaction. The identification of phosphocysteine as a regulatory modification opens new perspectives for signaling by protein phosphatases.

  20. Src-Mediated Phosphorylation of the Tyrosine Phosphatase PRL-3 Is Required for PRL-3 Promotion of Rho Activation, Motility and Invasion

    PubMed Central

    Fiordalisi, James J.; Dewar, Brian J.; Graves, Lee M.; Madigan, James P.; Cox, Adrienne D.

    2013-01-01

    The metastasis-associated tyrosine phosphatase PRL-3/PTP4A is upregulated in numerous cancers, but the mechanisms modulating PRL-3 activity other than its expression levels have not been investigated. Here we report evidence for both Src-dependent tyrosine phosphorylation of PRL-3 and Src-mediated regulation of PRL-3 biological activities. We used structural mutants, pharmacological inhibitors and siRNA to demonstrate Src-dependent phosphorylation of endogenous PRL-3 in SW480 colon cancer cells. We also demonstrated that PRL-3 was not tyrosine phosphorylated in SYF mouse embryo fibroblasts deficient in Src, Yes and Fyn unless Src was re-expressed. Further, we show that platelet-derived growth factor (PDGF) can stimulate PRL-3 phosphorylation in a Src-dependent manner. Finally, we show that PRL-3-induced cell motility, Matrigel invasion and activation of the cytoskeleton-regulating small GTPase RhoC were abrogated in the presence of the phosphodeficient PRL-3 mutant Y53F, or by use of a Src inhibitor. Thus, PRL-3 requires the activity of a Src kinase, likely Src itself, to promote these cancer-associated phenotypes. Our data establish a model for the regulation of PRL-3 by Src that supports the possibility of their coordinate roles in signaling pathways promoting invasion and metastasis, and supports simultaneous use of novel molecularly targeted therapeutics directed at these proteins. PMID:23691193

  1. Src-mediated phosphorylation of the tyrosine phosphatase PRL-3 is required for PRL-3 promotion of Rho activation, motility and invasion.

    PubMed

    Fiordalisi, James J; Dewar, Brian J; Graves, Lee M; Madigan, James P; Cox, Adrienne D

    2013-01-01

    The metastasis-associated tyrosine phosphatase PRL-3/PTP4A is upregulated in numerous cancers, but the mechanisms modulating PRL-3 activity other than its expression levels have not been investigated. Here we report evidence for both Src-dependent tyrosine phosphorylation of PRL-3 and Src-mediated regulation of PRL-3 biological activities. We used structural mutants, pharmacological inhibitors and siRNA to demonstrate Src-dependent phosphorylation of endogenous PRL-3 in SW480 colon cancer cells. We also demonstrated that PRL-3 was not tyrosine phosphorylated in SYF mouse embryo fibroblasts deficient in Src, Yes and Fyn unless Src was re-expressed. Further, we show that platelet-derived growth factor (PDGF) can stimulate PRL-3 phosphorylation in a Src-dependent manner. Finally, we show that PRL-3-induced cell motility, Matrigel invasion and activation of the cytoskeleton-regulating small GTPase RhoC were abrogated in the presence of the phosphodeficient PRL-3 mutant Y53F, or by use of a Src inhibitor. Thus, PRL-3 requires the activity of a Src kinase, likely Src itself, to promote these cancer-associated phenotypes. Our data establish a model for the regulation of PRL-3 by Src that supports the possibility of their coordinate roles in signaling pathways promoting invasion and metastasis, and supports simultaneous use of novel molecularly targeted therapeutics directed at these proteins.

  2. Metastasis-associated phosphatase PRL-2 regulates tumor cell migration and invasion.

    PubMed

    Wang, Y; Lazo, J S

    2012-02-16

    The phosphatase of regenerating liver (PRL) family, comprising PRL-1, PRL-2 and PRL-3, is a group of prenylated phosphatases that are candidate cancer biomarkers and therapeutic targets. Although several studies have documented that altered expression of PRL-1 or PRL-3 can influence cell proliferation, migration and invasion, there is a dearth of knowledge about the biological functions of PRL-2. Thus, in the current study we have evaluated the role of PRL-2 in cell migration and invasion in human cancer cells. We found that four human lung cancer cells, including A549 cells, overexpress PRL-2 when compared with normal lung cells. PRL-2 knockdown by RNA interference markedly inhibited cell migration and invasion, and this inhibition can be restored by overexpressing the short interference RNA (siRNA)-resistant vector HA-PRL-2m. PRL-2 suppression by siRNA decreased p130Cas and vinculin expression, and decreased extracellular signal-regulated kinase (ERK) phosphorylation, while increasing the phosphorylation of ezrin on tyrosine 146. We found no significant changes in total p53, Akt and c-Src expression levels or their phosphorylation status, suggesting that PRL-2 knockdown could inhibit tumor cell migration and invasion through a Src-independent p130Cas signaling pathway. Ectopic expression of wild-type PRL-2, a catalytic inactive C101S mutant and a C-terminal CAAX deletion revealed a requirement for both the PRL-2 catalytic functionality and prenylation site. Expression of wild-type but not mutant forms of PRL-2 caused ERK phosphorylation and nuclear translocation. These results support a model in which PRL-2 promotes cell migration and invasion through an ERK-dependent signaling pathway.

  3. PRL3-zumab, a first-in-class humanized antibody for cancer therapy

    PubMed Central

    Thura, Min; Al-Aidaroos, Abdul Qader Omer; Yong, Wei Peng; Kono, Koji; Gupta, Abhishek; Lin, You Bin; Mimura, Kousaku; Thiery, Jean Paul; Goh, Boon Cher; Tan, Patrick; Soo, Ross; Hong, Cheng William; Wang, Lingzhi; Lin, Suling Joyce; Chen, Elya; Rha, Sun Young; Chung, Hyun Cheol; Li, Jie; Nandi, Sayantani; Yuen, Hiu Fung; Zhang, Shu-Dong; Guan, Yeoh Khay; So, Jimmy

    2016-01-01

    Novel, tumor-specific drugs are urgently needed for a breakthrough in cancer therapy. Herein, we generated a first-in-class humanized antibody (PRL3-zumab) against PRL-3, an intracellular tumor-associated phosphatase upregulated in multiple human cancers, for unconventional cancer immunotherapies. We focused on gastric cancer (GC), wherein elevated PRL-3 mRNA levels significantly correlated with shortened overall survival of GC patients. PRL-3 protein was overexpressed in 85% of fresh-frozen clinical gastric tumor samples examined but not in patient-matched normal gastric tissues. Using human GC cell lines, we demonstrated that PRL3-zumab specifically blocked PRL-3+, but not PRL-3–, orthotopic gastric tumors. In this setting, PRL3-zumab had better therapeutic efficacy as a monotherapy, rather than simultaneous combination with 5-fluorouracil or 5-fluorouracil alone. PRL3-zumab could also prevent PRL-3+ tumor recurrence. Mechanistically, we found that intracellular PRL-3 antigens could be externalized to become “extracellular oncotargets” that serve as bait for PRL3-zumab binding to potentially bridge and recruit immunocytes into tumor microenvironments for killing effects on cancer cells. In summary, our results document a comprehensive cancer therapeutic approach to specific antibody-targeted therapy against the PRL-3 oncotarget as a case study for developing antibodies against other intracellular targets in drug discovery. PMID:27699276

  4. PRL-3 activates NF-κB signaling pathway by interacting with RAP1.

    PubMed

    Lian, Shenyi; Meng, Lin; Liu, Caiyun; Xing, Xiaofang; Song, Qian; Dong, Bin; Han, Yong; Yang, Yongyong; Peng, Lirong; Qu, Like; Shou, Chengchao

    2013-01-04

    Phosphatase of regenerating liver (PRL-3) promotes cancer metastasis through enhanced cell motility and invasiveness, however its role in tumorigenesis remains unclear. Herein, we reported that PRL-3 interacts with telomere-related protein RAP1. PRL-3 promotes the cytosolic localization of RAP1, which is counteracted by silencing of PRL-3. Immunohistochemical staining of colon cancer tissue array (n=170) revealed that high level of PRL-3 associates with cytosolic localization of RAP1 (p=0.01). Microarray analysis showed that PRL-3 regulates expression of diverse genes and enhances phosphorylation of p65 subunit of NF-κB in a RAP1-dependent manner. Furthermore, PRL-3 transcriptionally activates RAP1 expression, which is counteracted by ablating p65. Therefore, our results demonstrate PRL-3 as a novel regulator of NF-κB signaling pathway through RAP1.

  5. Rhodanine-based PRL-3 inhibitors blocked the migration and invasion of metastatic cancer cells.

    PubMed

    Min, Garam; Lee, Su-Kyung; Kim, Hye-Nan; Han, Young-Min; Lee, Rhan-Hee; Jeong, Dae Gwin; Han, Dong Cho; Kwon, Byoung-Mog

    2013-07-01

    PRL-3, phosphatase of regenerating liver-3, plays a role in cancer progression through its involvement in invasion, migration, metastasis, and angiogenesis. We synthesized rhodanine derivatives, CG-707 and BR-1, which inhibited PRL-3 enzymatic activity with IC50 values of 0.8 μM and 1.1 μM, respectively. CG-707 and BR-1 strongly inhibited the migration and invasion of PRL-3 overexpressing colon cancer cells without exhibiting cytotoxicity. The specificity of the inhibitors on PRL-3 phosphatase activity was confirmed by the phosphorylation recovery of known PRL-3 substrates such as ezrin and cytokeratin 8. The compounds selectively inhibited PRL-3 in comparison with other phosphatases, and CG-707 regulated epithelial-to-mesenchymal transition (EMT) marker proteins. The results of the present study reveal that rhodanine is a specific PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor.

  6. The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis.

    PubMed

    Hardy, S; Uetani, N; Wong, N; Kostantin, E; Labbé, D P; Bégin, L R; Mes-Masson, A; Miranda-Saavedra, D; Tremblay, M L

    2015-02-19

    The three PRL (phosphatases of regenerating liver) protein tyrosine phosphatases (PRL-1, -2 and -3) have been identified as key contributors to metastasis in several human cancers, yet the molecular basis of their pro-oncogenic property is unclear. Among the subfamily of PRL phosphatases, overexpression of PRL-2 in breast cancer cells has been shown to promote tumor growth by a mechanism that remains to be uncovered. Here we show that PRL-2 regulates intracellular magnesium levels by forming a functional heterodimer with the magnesium transporter CNNM3. We further reveal that CNNM3 is not a phosphorylated substrate of PRL-2, and that the interaction occurs through a loop unique to the CBS pair domains of CNNM3 that exists only in organisms having PRL orthologs. Supporting the role of PRL-2 in cellular magnesium transport is the observation that PRL-2 knockdown results in a substantial decrease of cellular magnesium influx. Furthermore, in PRL-2 knockout mice, serum magnesium levels were significantly elevated as compared with control animals, indicating a pivotal role for PRL-2 in regulating cellular magnesium homeostasis. Although the expression levels of CNNM3 remained unchanged after magnesium depletion of various cancer cell lines, the interaction between endogenous PRL-2 and CNNM3 was markedly increased. Importantly, xenograft tumor assays with CNNM3 and a mutant form that does not associate with PRL-2 confirm that CNNM3 is itself pro-oncogenic, and that the PRL-2/CNNM3 association is important for conferring transforming activities. This finding is further confirmed from data in human breast cancer tissues showing that CNNM3 levels correlate positively with both PRL-2 expression and the tumor proliferative index. In summary, we demonstrate that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.

  7. Oncogenic function and prognostic significance of protein tyrosine phosphatase PRL-1 in hepatocellular carcinoma

    PubMed Central

    Jin, Shaowen; Wang, Kaimei; Xu, Kang; Xu, Junyao; Sun, Jian; Chu, Zhonghua; Lin, Dechen; Koeffler, Phillip H.; Wang, Jie; Yin, Dong

    2014-01-01

    Our SNP-Chip data demonstrated 7/60 (12%) hepatocellular carcinoma (HCC) patients had PRL-1 copy number amplification. However, its biological functions and signaling pathways in HCC are deficient. Here, we investigated its oncogenic function and prognostic significance in HCC. PRL-1 protein levels were examined in 167 HCC samples by immunohistochemisty (IHC). The relationship of PRL-1 expression and clinicopathological features was assessed by correlation, Kaplan-Meier and Cox regression analyses. The oncogenic function of PRL-1 in HCC cells and its underlying mechanism were investigated by ectopic overexpression and knockdown model. PRL-1 levels in primary HCC and metastatic intravascular cancer thrombus were also determined by IHC. PRL-1 levels were frequently elevated in HCC tissues (81%), and elevated expression of PRL-1 was significantly associated with more aggressive phenotype and poorer prognosis in HCC patients (p<0.05). Ectopic overexpression of PRL-1 markedly enhanced HCC cells migration and invasion. Furthermore, the oncogenic functions of PRL-1 were mediated by PI3K/AKT/GSK3β signaling pathway through inhibiting E-cadherin expression. Finally, PRL-1 protein levels in metastatic cancer thrombus were higher than that in primary HCC tissues (p<0.05). These data highlight the oncogenic function of PRL-1 in HCC invasion and metastasis implicating PRL-1 as a potential prognostic marker as well as therapeutic target in HCC. PMID:25003523

  8. Oncogenic function and prognostic significance of protein tyrosine phosphatase PRL-1 in hepatocellular carcinoma.

    PubMed

    Jin, Shaowen; Wang, Kaimei; Xu, Kang; Xu, Junyao; Sun, Jian; Chu, Zhonghua; Lin, Dechen; Koeffler, Phillip H; Wang, Jie; Yin, Dong

    2014-06-15

    Our SNP-Chip data demonstrated 7/60 (12%) hepatocellular carcinoma (HCC) patients had PRL-1 copy number amplification. However, its biological functions and signaling pathways in HCC are deficient. Here, we investigated its oncogenic function and prognostic significance in HCC. PRL-1 protein levels were examined in 167 HCC samples by immunohistochemisty (IHC). The relationship of PRL-1 expression and clinicopathological features was assessed by correlation, Kaplan-Meier and Cox regression analyses. The oncogenic function of PRL-1 in HCC cells and its underlying mechanism were investigated by ectopic overexpression and knockdown model. PRL-1 levels in primary HCC and metastatic intravascular cancer thrombus were also determined by IHC. PRL-1 levels were frequently elevated in HCC tissues (81%), and elevated expression of PRL-1 was significantly associated with more aggressive phenotype and poorer prognosis in HCC patients (p<0.05). Ectopic overexpression of PRL-1 markedly enhanced HCC cells migration and invasion. Furthermore, the oncogenic functions of PRL-1 were mediated by PI3K/AKT/GSK3β signaling pathway through inhibiting E-cadherin expression. Finally, PRL-1 protein levels in metastatic cancer thrombus were higher than that in primary HCC tissues (p<0.05). These data highlight the oncogenic function of PRL-1 in HCC invasion and metastasis implicating PRL-1 as a potential prognostic marker as well as therapeutic target in HCC.

  9. Drosophila PRL-1 is a growth inhibitor that counteracts the function of the Src oncogene.

    PubMed

    Pagarigan, Krystle T; Bunn, Bryce W; Goodchild, Jake; Rahe, Travis K; Weis, Julie F; Saucedo, Leslie J

    2013-01-01

    Phosphatase of Regenerating Liver (PRL) family members have emerged as molecular markers that significantly correlate to the ability of many cancers to metastasize. However, contradictory cellular responses to PRL expression have been reported, including the inhibition of cell cycle progression. An obvious culprit for the discrepancy is the use of dozens of different cell lines, including many isolated from tumors or cultured cells selected for immortalization which may have missing or mutated modulators of PRL function. We created transgenic Drosophila to study the effects of PRL overexpression in a genetically controlled, organismal model. Our data support the paradigm that the normal cellular response to high levels of PRL is growth suppression and furthermore, that PRL can counter oncogenic activity of Src. The ability of PRL to inhibit growth under normal conditions is dependent on a CAAX motif that is required to localize PRL to the apical edge of the lateral membrane. However, PRL lacking the CAAX motif can still associate indiscriminately with the plasma membrane and retains its ability to inhibit Src function. We propose that PRL binds to other membrane-localized proteins that are effectors of Src or to Src itself. This first examination of PRL in a model organism demonstrates that PRL performs as a tumor suppressor and underscores the necessity of identifying the conditions that enable it to transform into an oncogene in cancer.

  10. Increased expression of the PRL-3 gene in human oral squamous cell carcinoma and dysplasia tissues.

    PubMed

    Hassan, Nur Mohammad Monsur; Hamada, Jun-ichi; Kameyama, Takeshi; Tada, Mitsuhiro; Nakagawa, Koji; Yoshida, Shoko; Kashiwazaki, Haruhiko; Yamazaki, Yutaka; Suzuki, Yukiko; Sasaki, Akira; Nagatsuka, Hitoshi; Inoue, Nobuo; Moriuchi, Tetsuya

    2011-01-01

    Phosphatase of regenerating liver (PRL) belongs to a class of the protein tyrosine phosphatase family, which is known so far to consist of 3 members, PRL-1, PRL-2, and PRL-3. The aim of this study was to uncover the role of PRL genes in development of oral malignancy. We analyzed expression levels of the 3 PRL genes in 50 human oral squamous cell carcinomas (OSCCs), 11 dysplasia and 12 normal mucosa tissues by a real-time RT-PCR method. PRL-3 but not PRL-1 or PRL-2 expressions were significantly higher in OSCC and dysplasia than in normal mucosa tissues. Additionally, PRL-3 expressions were significantly higher in OSCC tissues harboring dominant-negative p53 or recessive p53 mutation than in those harboring wild-type p53. These results suggest that PRL-3 plays a role in oral cancer development and can be useful as a marker of pre-malignant and malignant lesion of oral mucosa.

  11. Plasticity of the prolactin (PRL) axis: mechanisms underlying regulation of output in female mice.

    PubMed

    Le Tissier, P R; Hodson, D J; Martin, A O; Romanò, N; Mollard, P

    2015-01-01

    The output of prolactin (PRL) is highly dynamic with dramatic changes in its secretion from the anterior pituitary gland depending on prevailing physiological status. In adult female mice, there are three distinct phases of output and each of these is related to the functions of PRL at specific stages of reproduction. Recent studies of the changes in the regulation of PRL during its period of maximum output, lactation, have shown alterations at both the level of the anterior pituitary and hypothalamus. The PRL-secreting cells of the anterior pituitary are organised into a homotypic network in virgin animals, facilitating coordinated bouts of activity between interconnected PRL cells. During lactation, coordinated activity increases due to the changes in structural connectivity, and this drives large elevations in PRL secretion. Surprisingly, these changes in connectivity are maintained after weaning, despite reversion of PRL output to that of virgin animals, and result in an augmented output of hormone during a second lactation. At the level of the hypothalamus, tuberoinfundibular dopamine (TIDA) neurons, the major inhibitors of PRL secretion, have unexpectedly been shown to remain responsive to PRL during lactation. However, there is an uncoupling between TIDA neuron firing and dopamine secretion, with a potential switch to enkephalin release. Such a process may reinforce hormone secretion through dual disinhibition and stimulation of PRL cell activity. Thus, integration of signalling along the hypothalamo-pituitary axis is responsible for increased secretory output of PRL cells during lactation, as well as allowing the system to anticipate future demands.

  12. Phosphatase PRL-3 is a direct regulatory target of TGFbeta in colon cancer metastasis.

    PubMed

    Jiang, Yanjun; Liu, Xiao-Qiong; Rajput, Ashwani; Geng, Liying; Ongchin, Melanie; Zeng, Qi; Taylor, Gregory S; Wang, Jing

    2011-01-01

    Metastasis causes most deaths from cancer yet mechanistic understanding and therapeutic options remain limited. Overexpression of the phosphatase PRL-3 (phosphatase of regenerating liver) is associated with metastasis of colon cancer. Here, we show that PRL-3 is a direct target of signaling by TGFβ, which is broadly implicated in progression and metastasis. We found that suppression of PRL-3 expression by TGFβ was mediated by Smad-dependent inhibition of PRL-3 transcription at the level of promoter activity. PRL-3 activation stimulated PI3K/AKT signaling that caused resistance to stress-induced apoptosis. PRL-3 overexpression promoted metastatic colonization in an orthotopic mouse model of colon cancer, whereas PRL-3 knockdown reduced metastatic potential. Altered metastatic phenotypes were not derivative of primary tumor development or local invasion but could be attributed to PRL-3-mediated cell survival. Our findings suggest that inhibiting PRL-3 expression might be an important mechanism through which TGFβ suppresses metastasis in colon cancer. In addition, our findings suggest that loss of TGFβ signaling, which occurs commonly during colon cancer progression, is sufficient to activate a PRL-3-mediated cell survival pathway that can selectively promote metastasis. Therefore, a major implication of our findings is that PRL-3 antagonists may offer significant value for antimetastatic therapy in patients with colon cancer.

  13. Anti-cytomegalovirus activity of the anthraquinone atanyl blue PRL.

    PubMed

    Alam, Zohaib; Al-Mahdi, Zainab; Zhu, Yali; McKee, Zachary; Parris, Deborah S; Parikh, Hardik I; Kellogg, Glen E; Kuchta, Alison; McVoy, Michael A

    2015-02-01

    Human cytomegalovirus (CMV) causes significant disease in immunocompromised patients and serious birth defects if acquired in utero. Available CMV antivirals target the viral DNA polymerase, have significant toxicities, and suffer from resistance. New drugs targeting different pathways would be beneficial. The anthraquinone emodin is proposed to inhibit herpes simplex virus by blocking the viral nuclease. Emodin and related anthraquinones are also reported to inhibit CMV. In the present study, emodin reduced CMV infectious yield with an EC50 of 4.9μM but was cytotoxic at concentrations only twofold higher. Related anthraquinones acid blue 40 and alizarin violet R inhibited CMV at only high concentrations (238-265μM) that were also cytotoxic. However, atanyl blue PRL inhibited infectious yield of CMV with an EC50 of 6.3μM, significantly below its 50% cytotoxic concentration of 216μM. Atanyl blue PRL reduced CMV infectivity and inhibited spread. When added up to 1h after infection, it dramatically reduced CMV immediate early protein expression and blocked viral DNA synthesis. However, it had no antiviral activity when added 24h after infection. Interestingly, atanyl blue PRL inhibited nuclease activities of purified CMV UL98 protein with IC50 of 4.5 and 9.3μM. These results indicate that atanyl blue PRL targets very early post-entry events in CMV replication and suggest it may act through inhibition of UL98, making it a novel CMV inhibitor. This compound may provide valuable insights into molecular events that occur at the earliest times post-infection and serve as a lead structure for antiviral development.

  14. Exploring Amino Acid Auxotrophy in Bifidobacterium bifidum PRL2010

    PubMed Central

    Ferrario, Chiara; Duranti, Sabrina; Milani, Christian; Mancabelli, Leonardo; Lugli, Gabriele A.; Turroni, Francesca; Mangifesta, Marta; Viappiani, Alice; Ossiprandi, Maria C.; van Sinderen, Douwe; Ventura, Marco

    2015-01-01

    The acquisition and assimilation strategies followed by members of the infant gut microbiota to retrieve nitrogen from the gut lumen are still largely unknown. In particular, no information on these metabolic processes is available regarding bifidobacteria, which are among the first microbial colonizers of the human intestine. Here, evaluation of amino acid auxotrophy and prototrophy of Bifidobacterium bifidum, with particular emphasis on B. bifidum strain PRL2010 (LMG S-28692), revealed a putative auxotrophy for cysteine. In addition, we hypothesized that cysteine plays a role in the oxidative stress response in B. bifidum. The use of glutathione as an alternative reduced sulfur compound did not alleviate cysteine auxotrophy of this strain, though it was shown to stimulate expression of the genes involved in cysteine biosynthesis, reminiscent of oxidative stress response. When PRL2010 was grown on a medium containing complex substrates, such as whey proteins or casein hydrolysate, we noticed a distinct growth-promoting effect of these compounds. Transcriptional analysis involving B. bifidum PRL2010 cultivated on whey proteins or casein hydrolysate revealed that the biosynthetic pathways for cysteine and methionine are modulated by the presence of casein hydrolysate. Such findings support the notion that certain complex substrates may act as potential prebiotics for bifidobacteria in their ecological niche. PMID:26635786

  15. Novel Anticancer Agents Based on Targeting the Trimer Interface of the PRL Phosphatase.

    PubMed

    Bai, Yunpeng; Yu, Zhi-Hong; Liu, Sijiu; Zhang, Lujuan; Zhang, Ruo-Yu; Zeng, Li-Fan; Zhang, Sheng; Zhang, Zhong-Yin

    2016-08-15

    Phosphatase of regenerating liver (PRL) oncoproteins are phosphatases overexpressed in numerous types of human cancer. Elevated levels of PRL associate with metastasis and poor clinical outcomes. In principle, PRL phosphatases offer appealing therapeutic targets, but they remain underexplored due to the lack of specific chemical probes. In this study, we address this issue by exploiting a unique property of PRL phosphatases, namely, that they may function as homotrimers. Starting from a sequential structure-based virtual screening and medicinal chemistry strategy, we identified Cmpd-43 and several analogs that disrupt PRL1 trimerization. Biochemical and structural analyses demonstrate that Cmpd-43 and its close analogs directly bind the PRL1 trimer interface and obstruct PRL1 trimerization. Cmpd-43 also specifically blocks the PRL1-induced cell proliferation and migration through attenuation of both ERK1/2 and Akt activity. Importantly, Cmpd-43 exerted potent anticancer activity both in vitro and in vivo in a murine xenograft model of melanoma. Our results validate a trimerization-dependent signaling mechanism for PRL and offer proof of concept for trimerization inhibitors as candidate therapeutics to treat PRL-driven cancers. Cancer Res; 76(16); 4805-15. ©2016 AACR.

  16. Metastasis-associated PRL-3 induces EGFR activation and addiction in cancer cells.

    PubMed

    Al-Aidaroos, Abdul Qader Omer; Yuen, Hiu Fung; Guo, Ke; Zhang, Shu Dong; Chung, Tae-Hoon; Chng, Wee Joo; Zeng, Qi

    2013-08-01

    Metastasis-associated phosphatase of regenerating liver-3 (PRL-3) has pleiotropic effects in driving cancer progression, yet the signaling mechanisms of PRL-3 are still not fully understood. Here, we provide evidence for PRL-3-induced hyperactivation of EGFR and its downstream signaling cascades in multiple human cancer cell lines. Mechanistically, PRL-3-induced activation of EGFR was attributed primarily to transcriptional downregulation of protein tyrosine phosphatase 1B (PTP1B), an inhibitory phosphatase for EGFR. Functionally, PRL-3-induced hyperactivation of EGFR correlated with increased cell growth, promigratory characteristics, and tumorigenicity. Moreover, PRL-3 induced cellular addiction to EGFR signaling, as evidenced by the pronounced reversion of these oncogenic attributes upon EGFR-specific inhibition. Of clinical significance, we verified elevated PRL-3 expression as a predictive marker for favorable therapeutic response in a heterogeneous colorectal cancer (CRC) patient cohort treated with the clinically approved anti-EGFR antibody cetuximab. The identification of PRL-3-driven EGFR hyperactivation and consequential addiction to EGFR signaling opens new avenues for inhibiting PRL-3-driven cancer progression. We propose that elevated PRL-3 expression is an important clinical predictive biomarker for favorable anti-EGFR cancer therapy.

  17. LEO1 is regulated by PRL-3 and mediates its oncogenic properties in acute myelogenous leukemia.

    PubMed

    Chong, Phyllis S Y; Zhou, Jianbiao; Cheong, Lip-Lee; Liu, Shaw-Cheng; Qian, Jingru; Guo, Tiannan; Sze, Siu Kwan; Zeng, Qi; Chng, Wee Joo

    2014-06-01

    PRL-3, an oncogenic dual-specificity phosphatase, is overexpressed in 50% of acute myelogenous leukemia (AML) and associated with poor survival. We found that stable expression of PRL-3 confers cytokine independence and growth advantage of AML cells. However, how PRL-3 mediates these functions in AML is not known. To comprehensively screen for PRL3-regulated proteins in AML, we performed SILAC-based quantitative proteomics analysis and discovered 398 significantly perturbed proteins after PRL-3 overexpression. We show that Leo1, a component of RNA polymerase II-associated factor (PAF) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. We described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Furthermore, PRL-3 and Leo1 levels were positively associated in AML patient samples (N=24; P<0.01). On the other hand, inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of the PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation. In conclusion, we identify an important and novel mechanism by which PRL-3 mediates its oncogenic function in AML.

  18. Overexpression of the protein tyrosine phosphatase PRL-2 correlates with breast tumor formation and progression.

    PubMed

    Hardy, Serge; Wong, Nau Nau; Muller, William J; Park, Morag; Tremblay, Michel L

    2010-11-01

    The PRL-1, PRL-2, and PRL-3 phosphatases are prenylated protein tyrosine phosphatases with oncogenic activity that are proposed to drive tumor metastasis. We found that PRL-2 mRNA is elevated in primary breast tumors relative to matched normal tissue, and also dramatically elevated in metastatic lymph nodes compared with primary tumors. PRL-2 knockdown in metastatic MDA-MB-231 breast cancer cells decreased anchorage-independent growth and cell migration, suggesting that the malignant phenotype of these cells is mediated at least in part through PRL-2 signaling. In different mouse mammary tumor-derived cell lines overexpressing PRL-2, we confirmed its role in anchorage-independent growth and cell migration. Furthermore, injection of PRL-2-overexpressing cells into the mouse mammary fat pad promoted extracellular signal-regulated kinase 1/2 activation and tumor formation. MMTV-PRL-2 transgenic mice engineered to overexpress the enzyme in mammary tissue did not exhibit spontaneous tumorigenesis, but they exhibited an accelerated development of mammary tumors initiated by introduction of an MMTV-ErbB2 transgene. Together, our results argue that PRL-2 plays a role in breast cancer progression.

  19. Direct effect of PGF2α pulses on PRL pulses, based on inhibition of PRL or PGF2α secretion in heifers.

    PubMed

    Pinaffi, F L V; Pugliesi, G; Hannan, M A; Silva, L A; Beg, M A; Ginther, O J

    2012-08-01

    The relationships between PRL and PGF(2α) and their effect on luteolysis were studied. Heifers were treated with a dopamine-receptor agonist (bromocriptine; Bc) and a Cox-1 and -2 inhibitor (flunixin meglumine [FM]) to inhibit PRL and PGF(2α), respectively. The Bc was given (Hour 0) when ongoing luteolysis was indicated by a 12.5% reduction in CL area (cm(2)) from the area on Day 14 postovulation, and FM was given at Hours 0, 4, and 8. Blood samples were collected every 8-h beginning on Day 14 until Hour 48 and hourly for Hours 0 to 12. Three groups of heifers in ongoing luteolysis were used: control (n = 7), Bc (n = 7), and FM (n = 4). Treatment with Bc decreased (P < 0.003) the PRL concentrations averaged over Hours 1 to 12. During the greatest decrease in PRL (Hours 2-6), LH concentrations were increased. Progesterone concentrations averaged over hours were greater (P < 0.05) in the Bc group than in the controls. In the FM group, no PGFM pulses were detected, and PRL concentrations were reduced. Concentrations of PGFM were not reduced in the Bc group, despite the reduction in PRL. Results supported the hypothesis that a decrease (12.5%) in CL area (cm(2)) is more efficient in targeting ongoing luteolysis (63%) than using any day from Days 14 to ≥ 19 (efficiency/day, 10-24%). The hypothesis that PRL has a role in luteolysis was supported but was confounded by the known positive effect of LH on progesterone. The hypothesis was supported that the synchrony of PGFM and PRL pulses represents a positive effect of PGF(2α) on PRL, rather than an effect of PRL on PGF(2α).

  20. Assessment of lactotroph axis functionality in mice: longitudinal monitoring of PRL secretion by ultrasensitive-ELISA.

    PubMed

    Guillou, Anne; Romanò, Nicola; Steyn, Frederik; Abitbol, Karine; Le Tissier, Paul; Bonnefont, Xavier; Chen, Chen; Mollard, Patrice; Martin, Agnès O

    2015-05-01

    The pattern of prolactin (PRL) secretion depends on the physiological state. Due to insufficient detection sensitivity of existing assays, the precise description of these patterns in mice is lacking. We described an ultrasensitive ELISA assay that can detect mouse PRL in small fractions of whole blood, allowing longitudinal studies of PRL secretion profiles in freely moving mice. Over a 24-hour period, males displayed no oscillation in PRL levels, whereas virgin and lactating females showed large pulses. Peaks of PRL secretion reached 30-40 ng/mL in lactating female mice and rarely exceeded 10 ng/mL in virgin females. These pulses of PRL in lactating females were associated with suckling. The return of pups after an experimental 12-hour weaning induced a pulse of PRL release, reaching 100 ng/mL. This approach also enabled us to assess the inhibitory tone from hypothalamic dopamine neurons on PRL secretion. We used a dopamine D2 receptor antagonist to relieve pituitary lactotrophs from the tuberoinfundibular dopaminergic inhibitory tone and demonstrate a D2-induced PRL rise that can be used to evaluate both the secretory capacity of lactotrophs and the magnitude of the inhibitory tone on pituitary PRL release. We demonstrate that, although lactotroph function is altered to enhance chronic PRL output, their secretory response to acute stimulus is not modified during lactation and that chronic hyperprolactinemia is linked to a lower inhibitory tone. The combination of a sensitive PRL ELISA and administration of D2 receptor antagonist provide a unique opportunity to investigate the function and plasticity of the lactotroph axis in freely moving mice.

  1. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

    PubMed Central

    Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

    2013-01-01

    FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan–Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients. PMID:23929599

  2. PRL-3 promotes cell adhesion by interacting with JAM2 in colon cancer

    PubMed Central

    Lian, Shenyi; Meng, Lin; Xing, Xiaofang; Yang, Yongyong; Qu, Like; Shou, Chengchao

    2016-01-01

    Phosphatase of regenerating liver-3 (PRL-3), also termed PTP4A3, is a metastasis-related protein tyrosine phosphatase. Its expression levels are significantly correlated with the progression and survival of a wide range of malignant tumors. However, the mechanism by which PRL-3 promotes tumor invasion and metastasis is not clear. In the present study, the functions of PRL-3 were systemically analyzed in the key events of metastasis including, motility and adhesion. A cell wounding assay, cell spread assay and cell-matrix adhesion assay were carried out to analyze the cell movement and cell adhesion ability of colon cancer, immunoprecipitation and immunofluorescence assay was confirmed the interaction of PRL-3 and JAM2. It was demonstrated that PRL-3 promoted the motility of Flp-In-293 and LoVo colon cancer cells and increased the distribution of cell skeleton proteins on the cell protrusions. In addition, stably expressing PRL-3 reduced the spreading speed of colon cancer cells and cell adhesion on uncoated, fibronectin-coated and collagen I-coated plates. Mechanistically, junction adhesion molecular 2 (JAM2) was identified as a novel interacting protein of PRL-3. The findings of the present study revealed the roles of PRL-3 in cancer cell motility and adhesion process, and provided information on the possibility of PRL-3 increase cell-cell adhesion by associating with JAM2. PMID:27588115

  3. Snail as a key regulator of PRL-3 gene in colorectal cancer.

    PubMed

    Zheng, Ping; Meng, Hui-Min; Gao, Wei-Zhe; Chen, Lin; Liu, Xun-Hua; Xiao, Zheng-Quan; Liu, Yong-Xia; Sui, Hong-Mei; Zhou, Jun; Liu, Yu-Hong; Li, Jian-Ming

    2011-10-15

    The regulators of a key metastasis gene PRL-3 in colorectal cancer (CRC) are still largely unknown. We found three potential binding sites of Snail, a key transcriptional factor involved in the epithelial-mesenchymal transition (EMT), in the region of PRL-3 promoter (located at -642 to -383). Moreover, our results showed that one of the Snail binding sites (located at -624 to -619) was the key element to maintain promoter activity of human PRL-3 gene. The transcriptional activity of PRL-3 promoter was abolished after the Snail binding site (located at -624 to -619) was mutated. Both promoter activity and protein expression of PRL-3 in CRC cell lines could be regulated by Snail. In clinical samples of CRC and metastatic lymph node of CRC, expression of PRL-3 protein was correlated with expression of Snail protein. Functional studies using gene over-expression and knockdown methods indicated that Snail promoted proliferation, cell adhesion and migration of human CRC cells. In SW480 cells with PRL-3 stable knockdown, cell proliferation increased after Snail was up-regulated. Our data first reveal transcriptional factor Snail as a key regulator of PRL-3 in CRC. The link between Snail and PRL-3 suggests a new potential mechanism of Snail contributing to progression and metastasis of CRC.

  4. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia.

    PubMed

    Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-Aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

    2013-09-01

    FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan-Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients.

  5. Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion.

    PubMed

    Yang, Yongyong; Lian, Shenyi; Meng, Lin; Qu, Like; Shou, Chengchao

    2017-01-01

    Phosphatase of regenerating liver 3 (PRL-3) promotes cancer metastasis and progression via increasing cell motility and invasiveness, however the mechanism is still not fully understood. Previous reports showed that PRL-3 increases the phosphorylation of many important proteins and suspected that PRL-3-enhanced protein phosphorylation may be due to its regulation on cytokines. To investigate PRL-3's impact on protein phosphorylation and cytokine secretion, we performed antibody arrays against protein phosphorylation and cytokines separately. The data showed that PRL-3 could enhance tyrosine phosphorylation and serine/threonine phosphorylation of diverse signaling proteins. Meanwhile, PRL-3 could affect the secretion of a subset of cytokines. Furthermore, we discovered the PRL-3-increased IL-1α secretion was regulated by NF-κB and Jak2-Stat3 pathways and inhibiting IL-1α could reduce PRL-3-enhanced cell migration. Therefore, our result indicated that PRL-3 promotes protein phosphorylation by acting as an 'activator kinase' and consequently regulates cytokine secretion.

  6. Localizing PRL-2 expression and determining the effects of dietary Mg(2+) on expression levels.

    PubMed

    Gungabeesoon, Jeremy; Tremblay, Michel L; Uetani, Noriko

    2016-07-01

    The phosphatase of regenerating liver (PRL) is a group of protein tyrosine phosphatases that play a key role in cancer progression and metastasis. We previously showed that PRL-2 modulates intracellular Mg(2+) levels and sustains cancer phenotypes by binding to the Mg(2+) transporter CNNM3. However, the physiological functions of PRL-2 in animals remain largely unknown. To better understand which cell types are associated with PRL-2 function, we characterized its expression in mouse tissues using a PRL-2 β-galactosidase reporter mouse model. Our results demonstrated that PRL-2 was ubiquitously expressed, with the highest expression levels observed in the hippocampal pyramidal neurons, ependymal cells, cone and rod photoreceptor cells, endocardium, vascular and bronchial smooth muscle, and collecting ducts in the kidney. On the other hand, PRL-2 expression was undetectable or very low in the parenchymal cells of the liver and pancreas. Our results also indicated that PRL-2 is involved in cell-type-specific Mg(2+) homeostasis and that PRL-2 expression is potentially inversely regulated by dietary Mg(2+) levels.

  7. PRL-3 promotes cell adhesion by interacting with JAM2 in colon cancer.

    PubMed

    Lian, Shenyi; Meng, Lin; Xing, Xiaofang; Yang, Yongyong; Qu, Like; Shou, Chengchao

    2016-09-01

    Phosphatase of regenerating liver-3 (PRL-3), also termed PTP4A3, is a metastasis-related protein tyrosine phosphatase. Its expression levels are significantly correlated with the progression and survival of a wide range of malignant tumors. However, the mechanism by which PRL-3 promotes tumor invasion and metastasis is not clear. In the present study, the functions of PRL-3 were systemically analyzed in the key events of metastasis including, motility and adhesion. A cell wounding assay, cell spread assay and cell-matrix adhesion assay were carried out to analyze the cell movement and cell adhesion ability of colon cancer, immunoprecipitation and immunofluorescence assay was confirmed the interaction of PRL-3 and JAM2. It was demonstrated that PRL-3 promoted the motility of Flp-In-293 and LoVo colon cancer cells and increased the distribution of cell skeleton proteins on the cell protrusions. In addition, stably expressing PRL-3 reduced the spreading speed of colon cancer cells and cell adhesion on uncoated, fibronectin-coated and collagen I-coated plates. Mechanistically, junction adhesion molecular 2 (JAM2) was identified as a novel interacting protein of PRL-3. The findings of the present study revealed the roles of PRL-3 in cancer cell motility and adhesion process, and provided information on the possibility of PRL-3 increase cell-cell adhesion by associating with JAM2.

  8. Upregulation of metastasis-associated PRL-3 initiates chordoma in zebrafish.

    PubMed

    Li, Li; Shi, Hongshun; Zhang, Mingming; Guo, Xiaoling; Tong, Fang; Zhang, Wenliang; Zhou, Junyi; Wang, Haihe; Yang, Shulan

    2016-04-01

    The metastasis-associated phosphatase of regenerating liver-3 (PRL-3) plays multiple roles in progression of various human cancers; however, significance of its role during development has not been addressed. Here we cloned and characterized the expression pattern of zebrafish prl-3 transcript and showed that it is ubiquitiously expressed in the first 24 h of development with both maternal and zygotic expressions. The transcripts become progressively restricted to the notochord, vessels and the intestine by 96 h post-fertilization. Notably, overexpression of zebrafish Prl-3 (zPrl-3) and human PRL-3 induces notochord malformation in zebrafish. This phenotype resembles chordoma and is confirmed by associated misexpression of notochord-specific markers. Clinical significance of the PRL-3 in chordoma is strongly suggested by detection of PRL-3 antigen in clinical chordoma specimens. Collectively, our results uncovered that aberrant overexpression of PRL-3 could initiate chordoma in early development and suggest the use of PRL-3 could be used as a predictor and a therapeutic target for chordoma.

  9. Antibody Array Revealed PRL-3 Affects Protein Phosphorylation and Cytokine Secretion

    PubMed Central

    Meng, Lin; Qu, Like; Shou, Chengchao

    2017-01-01

    Phosphatase of regenerating liver 3 (PRL-3) promotes cancer metastasis and progression via increasing cell motility and invasiveness, however the mechanism is still not fully understood. Previous reports showed that PRL-3 increases the phosphorylation of many important proteins and suspected that PRL-3-enhanced protein phosphorylation may be due to its regulation on cytokines. To investigate PRL-3’s impact on protein phosphorylation and cytokine secretion, we performed antibody arrays against protein phosphorylation and cytokines separately. The data showed that PRL-3 could enhance tyrosine phosphorylation and serine/threonine phosphorylation of diverse signaling proteins. Meanwhile, PRL-3 could affect the secretion of a subset of cytokines. Furthermore, we discovered the PRL-3-increased IL-1α secretion was regulated by NF-κB and Jak2-Stat3 pathways and inhibiting IL-1α could reduce PRL-3-enhanced cell migration. Therefore, our result indicated that PRL-3 promotes protein phosphorylation by acting as an ‘activator kinase’ and consequently regulates cytokine secretion. PMID:28068414

  10. Cloning of PRL and VIP cDNAs of the Java sparrow (Padda oryzivora).

    PubMed

    Hiyama, Gen; Sato, Tsukasa; Zadworny, David; Kansaku, Norio

    2009-04-01

    Complementary DNA (cDNA) of prolactin (PRL) and vasoactive intestinal polypeptide (VIP) of the Java sparrow were cloned and sequenced. The proximal region of the PRL promoter was also identified. Java sparrow PRL was found to have 88.3, 88.3, and 89.1% sequence identity at the cDNA level to PRL of chicken, turkey, and duck, respectively. The predicted amino acid sequence had an overall similarity with a comparable region of chicken (91.4%), turkey (88.9%) and duck (92.0%) PRL. Based on the cDNA sequence and genomic structure of the chicken PRL gene, the proximal promoter was characterized. Sequence analysis of the proximal region of Java sparrow PRL promoter revealed a high degree of similarity to that of chicken, turkey and duck PRL promoters. Moreover, cDNA of prepro-VIP was also cloned and sequenced. Java sparrow prepro-VIP shows high similarity to chicken and turkey prepro-VIP. However, the region upstream of the 5' untranslated region of Java sparrow prepro-VIP did not show similarity to that of chicken. These results suggest that the mechanisms, which regulate expression of the VIP gene, may be different between precocial and altricial birds, but expression of the PRL gene may be widely conserved in avian species.

  11. Structure and backbone dynamics of vanadate-bound PRL-3: comparison of 15N nuclear magnetic resonance relaxation profiles of free and vanadate-bound PRL-3.

    PubMed

    Jeong, Ki-Woong; Kang, Dong-Il; Lee, Eunjung; Shin, Areum; Jin, Bonghwan; Park, Young-Guen; Lee, Chung-Kyoung; Kim, Eun-Hee; Jeon, Young Ho; Kim, Eunice Eunkyeong; Kim, Yangmee

    2014-07-29

    Phosphatases of regenerating liver (PRLs) constitute a novel class of small, prenylated phosphatases with oncogenic activity. PRL-3 is particularly important in cancer metastasis and represents a potential therapeutic target. The flexibility of the WPD loop as well as the P-loop of protein tyrosine phosphatases is closely related to their catalytic activity. Using nuclear magnetic resonance spectroscopy, we studied the structure of vanadate-bound PRL-3, which was generated by addition of sodium orthovanadate to PRL-3. The WPD loop of free PRL-3 extended outside of the active site, forming an open conformation, whereas that of vanadate-bound PRL-3 was directed into the active site by a large movement, resulting in a closed conformation. We suggest that vanadate binding induced structural changes in the WPD loop, P-loop, helices α4-α6, and the polybasic region. Compared to free PRL-3, vanadate-bound PRL-3 has a longer α4 helix, where the catalytic R110 residue coordinates with vanadate in the active site. In addition, the hydrophobic cavity formed by helices α4-α6 with a depth of 14-15 Å can accommodate a farnesyl chain at the truncated prenylation motif of PRL-3, i.e., from R169 to M173. Conformational exchange data suggested that the WPD loop moves between open and closed conformations with a closing rate constant k(close) of 7 s(-1). This intrinsic loop flexibility of PRL-3 may be related to their catalytic rate and may play a role in substrate recognition.

  12. Analysis of Predicted Carbohydrate Transport Systems Encoded by Bifidobacterium bifidum PRL2010

    PubMed Central

    Turroni, Francesca; Strati, Francesco; Foroni, Elena; Serafini, Fausta; Duranti, Sabrina; van Sinderen, Douwe

    2012-01-01

    The Bifidobacterium bifidum PRL2010 genome encodes a relatively small set of predicted carbohydrate transporters. Growth experiments and transcriptome analyses of B. bifidum PRL2010 revealed that carbohydrate utilization in this microorganism appears to be restricted to a relatively low number of carbohydrates. PMID:22562993

  13. Prolactin (PRL) and prolactin receptor (PRLR) genes and their role in poultry production traits.

    PubMed

    Wilkanowska, Anna; Mazurowski, Artur; Mroczkowski, Sławomir; Kokoszyński, Dariusz

    2014-01-01

    Prolactin (PRL), secreted from the anterior pituitary, plays extensive roles in osmoregulation, corpus luteum formation, mammogenesis, lactogenesis, lactopoiesis, and production of crop milk. In birds, prolactin (PRL) is generally accepted as crucial to the onset and maintenance of broodiness. All the actions of prolactin (PRL) hormone are mediated by its receptor (PRLR), which plays an important role in the PRL signal transduction cascade. It has been well established that the PRL gene is closely associated to the onset and maintenance of broody behavior, and could be a genetic marker in breeding against broodiness in chickens. Meanwhile, the prolactin receptor (PRLR) gene is regarded as a candidate genetic marker for reproductive traits. PRLR is also an important regulator gene for cell growth and differentiation. The identified polymorphism of this gene is mainly viewed in terms of egg production traits. Due to different biological activities attributed to PRL and PRLR, they can be used as major candidate genes in molecular animal breeding programs. Characterization of PRL and PRLR genes helps to elucidate their roles in birds and provides insights into the regulatory mechanisms of PRL and PRLR expression conserved in birds and mammals.

  14. Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

    PubMed

    Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng; Yoshimoto, Momoko; Gao, Rui; Chen, Sisi; Yao, Chonghua; Dong, Yuanshu; Zhang, Lujuan; Rodriguez, Sonia; Yashiro-Ohtani, Yumi; Pear, Warren S; Carlesso, Nadia; Yoder, Mervin C; Kapur, Reuben; Kaplan, Mark H; Daniel Lacorazza, Hugo; Zhang, Zhong-Yin; Liu, Yan

    2017-04-01

    The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064.

  15. PRL-3, an emerging marker of carcinogenesis, is strongly associated with poor prognosis.

    PubMed

    Guzińska-Ustymowicz, Katarzyna; Pryczynicz, Anna

    2011-01-01

    PRL-3 protein belongs to the family of protein tyrosine phosphatases with unique COOH-terminal prenylation motif, which determines the functions of this protein and its location in the cell. Numerous research studies revealed that apart from performing the poorly investigated physiological role, PRL-3 takes part in the process of carcinogenesis. Specifically, it is involved in reconstructing of the cytoskeleton, regulating adhesion and cell cycle of the cancer cells, and in epithelial-mesenchymal transition. Through these mechanisms PRL-3 protein participates in invasion, migration, metastasis and angiogenesis. Numerous studies indicate that PRL-3 expression is particularly important in colorectal, as well as in gastric, ovarian and breast carcinomas. Recently, several studies on PRL-3 protein in other types of cancer have been published. They reveal a significant role of this protein in the process of angiogenesis and metastasis. It has been proven that a higher expression of PRL-3 correlates with tumor progression and its severity. While the degree of overexpression of PRL-3 varies in different types of tumors, most research shows that in the metastases of these tumors, whether to the lymph nodes or to other organs, the level of expression is extremely high. Overexpression of PRL-3 protein was repeatedly confirmed in metastases, but not with primary tumors. PRL-3 seems to be an adequate marker in diagnosing the stage of tumor advancement for various types of carcinomas, especially for colorectal carcinoma investigated thoroughly in this study. PRL-3 overexpression predicts poor prognosis in patients with various carcinomas and is a promising target in the cancer treatment.

  16. Phosphatase of Regenerating Liver 3 (PRL3) Provokes a Tyrosine Phosphoproteome to Drive Prometastatic Signal Transduction*

    PubMed Central

    Walls, Chad D.; Iliuk, Anton; Bai, Yunpeng; Wang, Mu; Tao, W. Andy; Zhang, Zhong-Yin

    2013-01-01

    Phosphatase of regenerating liver 3 (PRL3) is suspected to be a causative factor toward cellular metastasis when in excess. To date, the molecular basis for PRL3 function remains an enigma, making efforts at distilling a concerted mechanism for PRL3-mediated metastatic dissemination very difficult. We previously discovered that PRL3 expressing cells exhibit a pronounced increase in protein tyrosine phosphorylation. Here we take an unbiased mass spectrometry-based approach toward identifying the phosphoproteins exhibiting enhanced levels of tyrosine phosphorylation with a goal to define the “PRL3-mediated signaling network.” Phosphoproteomic data support intracellular activation of an extensive signaling network normally governed by extracellular ligand-activated transmembrane growth factor, cytokine, and integrin receptors in the PRL3 cells. Additionally, data implicate the Src tyrosine kinase as the major intracellular kinase responsible for “hijacking” this network and provide strong evidence that aberrant Src activation is a major consequence of PRL3 overexpression. Importantly, the data support a PDGF(α/β)-, Eph (A2/B3/B4)-, and Integrin (β1/β5)-receptor array as being the predominant network coordinator in the PRL3 cells, corroborating a PRL3-induced mesenchymal-state. Within this network, we find that tyrosine phosphorylation is increased on a multitude of signaling effectors responsible for Rho-family GTPase, PI3K-Akt, STAT, and ERK activation, linking observations made by the field as a whole under Src as a primary signal transducer. Our phosphoproteomic data paint the most comprehensive picture to date of how PRL3 drives prometastatic molecular events through Src activation. PMID:24030100

  17. Effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in male goats.

    PubMed

    Jin, Jin; Hara, Sayaka; Sawai, Ken; Fülöp, Ferenc; Nagy, György Miklos; Hashizume, Tsutomu

    2014-04-01

    The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) release in goats. The PRL-releasing response to an intravenous (i.v.) injection of SAL was examined after treatment with augmentation of central DA using carbidopa (carbi) and L-dopa in male goats under 8-h (8 h light, 16 h dark) or 16-h (16 h light, 8 h dark) photoperiod conditions. The carbi and L-dopa treatments reduced basal PRL concentrations in the 16-h photoperiod group (P < 0.05), while a reduction was not observed in the 8-h photoperiod group. The mean basal plasma PRL concentration in the control group for the 8-h photoperiod was lower than that for the 16-h photoperiod (P < 0.05). SAL significantly stimulated the release of PRL promptly after the injection in both the 8- and 16-h photoperiod groups (P < 0.05). PRL-releasing responses for the 16-h photoperiod were greater than those for the 8-h photoperiod (P < 0.05). The carbi and L-dopa treatments blunted SAL-induced PRL release in both the 8- and 16-h photoperiods (P < 0.05). These results indicate that hypothalamic DA blunts the SAL-induced release of PRL in male goats, regardless of the photoperiod, which suggests that both SAL and DA are involved in regulating the secretion of PRL in goats.

  18. The essential role of FKBP38 in regulating phosphatase of regenerating liver 3 (PRL-3) protein stability.

    PubMed

    Choi, Myung-Suk; Min, Sang-Hyun; Jung, Haiyoung; Lee, Ju Dong; Lee, Tae Ho; Lee, Heung Kyu; Yoo, Ook-Joon

    2011-03-11

    The phosphatase of regenerating liver-3 (PRL-3) is a member of protein tyrosine phosphatases and whose deregulation is implicated in tumorigenesis and metastasis of many cancers. However, the underlying mechanism by which PRL-3 is regulated is not known. In this study, we identified the peptidyl prolyl cis/trans isomerase FK506-binding protein 38 (FKBP38) as an interacting protein of PRL-3 using a yeast two-hybrid system. FKBP38 specifically binds to PRL-3 in vivo, and that the N-terminal region of FKBP38 is crucial for binding with PRL-3. FKBP38 overexpression reduces endogenous PRL-3 expression levels, whereas the depletion of FKBP38 by siRNA increases the level of PRL-3 protein. Moreover, FKBP38 promotes degradation of endogenous PRL-3 protein via protein-proteasome pathway. Furthermore, FKBP38 suppresses PRL-3-mediated p53 activity and cell proliferation. These results demonstrate that FKBP38 is a novel regulator of the oncogenic protein PRL-3 abundance and that alteration in the stability of PRL-3 can have a dramatic impact on cell proliferation. Thus, FKBP38 may play a critical role in tumorigenesis.

  19. VEGF promotes the transcription of the human PRL-3 gene in HUVEC through transcription factor MEF2C.

    PubMed

    Xu, Jianliang; Cao, Shaoxian; Wang, Lu; Xu, Rui; Chen, Gong; Xu, Qiang

    2011-01-01

    Phosphatase of regenerating liver 3 (PRL-3) is known to be overexpressed in many tumors, and its transcript level is high in the vasculature and endothelial cells of malignant tumor tissue. However, the mechanism(s) underlying its enhanced expression and its function in endothelial cells remain unknown. Here, we report that vascular endothelial growth factor (VEGF) can induce PRL-3 transcription in human umbilical vein endothelial cells (HUVEC). An analysis of its 5'UTR revealed that PRL-3 transcription is initiated from two distinct sites, which results in the formation of the two transcripts, PRL-3-iso1 and PRL-3-iso2, but only the latter is up-regulated in HUVEC by VEGF. The PRL-3-iso2 promoter region includes two functional MEF2 (myocyte enhancer factor2) binding sites. The over-expression of the constitutively active form of MEF2C promotes the abundance of the PRL-3-iso2 transcript in a number of human cell lines. The siRNA-induced knockdown of MEF2C abolished the stimulative effect of VEGF on PRL-3 transcript in HUVEC, indicating that the VEGF-induced promotion of PRL-3 expression requires the presence of MEF2C. Finally, blocking PRL-3 activity or expression suppresses tube formation by HUVEC. We suggest that PRL-3 functions downstream of the VEGF/MEF2C pathway in endothelial cells and may play an important role in tumor angiogenesis.

  20. KCNN4 channels participate in the EMT induced by PRL-3 in colorectal cancer.

    PubMed

    Lai, Wei; Liu, Lu; Zeng, Yujie; Wu, Heng; Xu, Heyang; Chen, Shuang; Chu, Zhonghua

    2013-01-01

    Studies have shown that phosphatase of regenerating liver-3 (PRL-3) promotes the invasion, migration, and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition (EMT). However, the mechanism by which PRL-3 induces tumor cell EMT is unknown. Our previous research revealed that PRL-3 promotes LoVo cell proliferation by up-regulating KCNN4 channels. In the current study, we explored the mechanism by which PRL-3 mediates EMT. We demonstrated that PRL-3 induced the expression of KCNN4 channels, leading to EMT and the down-regulation of E-cadherin. Further studies revealed that KCNN4 channels increased intracellular calcium levels and activated components of cell signaling downstream of calcium, including CaM-kinase II and glycogen synthase kinase-3 beta (GSK-3 beta), which increased Snail expression. Inhibiting KCNN4 with siRNA and TRAM-34, a specific inhibitor, restored E-cadherin expression and inhibited Snail expression. These results implicated the up-regulation of KCNN4 channels in the PRL-3-mediated induction of EMT and promotion of cancer metastasis.

  1. PRL-3 disrupts epithelial architecture by altering the post-mitotic midbody position.

    PubMed

    Luján, Pablo; Varsano, Giulia; Rubio, Teresa; Hennrich, Marco L; Sachsenheimer, Timo; Gálvez-Santisteban, Manuel; Martín-Belmonte, Fernando; Gavin, Anne-Claude; Brügger, Britta; Köhn, Maja

    2016-11-01

    Disruption of epithelial architecture is a fundamental event during epithelial tumorigenesis. We show that the expression of the cancer-promoting phosphatase PRL-3 (PTP4A3), which is overexpressed in several epithelial cancers, in polarized epithelial MDCK and Caco2 cells leads to invasion and the formation of multiple ectopic, fully polarized lumens in cysts. Both processes disrupt epithelial architecture and are hallmarks of cancer. The pathological relevance of these findings is supported by the knockdown of endogenous PRL-3 in MCF-7 breast cancer cells grown in three-dimensional branched structures, showing the rescue from multiple-lumen- to single-lumen-containing branch ends. Mechanistically, it has been previously shown that ectopic lumens can arise from midbodies that have been mislocalized through the loss of mitotic spindle orientation or through the loss of asymmetric abscission. Here, we show that PRL-3 triggers ectopic lumen formation through midbody mispositioning without altering the spindle orientation or asymmetric abscission, instead, PRL-3 accelerates cytokinesis, suggesting that this process is an alternative new mechanism for ectopic lumen formation in MDCK cysts. The disruption of epithelial architecture by PRL-3 revealed here is a newly recognized mechanism for PRL-3-promoted cancer progression.

  2. Expression of PRL proteins at invasive margin of rectal cancers in relation to preoperative radiotherapy

    SciTech Connect

    Wallin, Asa R.; Svanvik, Joar; Adell, Gunnar; Sun Xiaofeng . E-mail: xiasu@ibk.liu.se

    2006-06-01

    Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients. Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT. Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes' stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01). Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT.

  3. PRL-3 disrupts epithelial architecture by altering the post-mitotic midbody position

    PubMed Central

    Varsano, Giulia; Sachsenheimer, Timo; Brügger, Britta

    2016-01-01

    ABSTRACT Disruption of epithelial architecture is a fundamental event during epithelial tumorigenesis. We show that the expression of the cancer-promoting phosphatase PRL-3 (PTP4A3), which is overexpressed in several epithelial cancers, in polarized epithelial MDCK and Caco2 cells leads to invasion and the formation of multiple ectopic, fully polarized lumens in cysts. Both processes disrupt epithelial architecture and are hallmarks of cancer. The pathological relevance of these findings is supported by the knockdown of endogenous PRL-3 in MCF-7 breast cancer cells grown in three-dimensional branched structures, showing the rescue from multiple-lumen- to single-lumen-containing branch ends. Mechanistically, it has been previously shown that ectopic lumens can arise from midbodies that have been mislocalized through the loss of mitotic spindle orientation or through the loss of asymmetric abscission. Here, we show that PRL-3 triggers ectopic lumen formation through midbody mispositioning without altering the spindle orientation or asymmetric abscission, instead, PRL-3 accelerates cytokinesis, suggesting that this process is an alternative new mechanism for ectopic lumen formation in MDCK cysts. The disruption of epithelial architecture by PRL-3 revealed here is a newly recognized mechanism for PRL-3-promoted cancer progression. PMID:27656108

  4. Effects of extracerebral dopamine on salsolinol- or thyrotropin-releasing hormone-induced prolactin (PRL) secretion in goats.

    PubMed

    Inaba, Yuki; Kato, Yuki; Itou, Azumi; Chiba, Aoi; Sawai, Ken; Fülöp, Ferenc; Nagy, György Miklos; Hashizume, Tsutomu

    2016-12-01

    The aim of the present study was to clarify the effect of extracerebral dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in goats. An intravenous injection of SAL or thyrotropin-releasing hormone (TRH) was given to female goats before and after treatment with an extracerebral DA receptor antagonist, domperidone (DOM), and the PRL-releasing response to SAL was compared with that to TRH. DOM alone increased plasma PRL concentrations and the PRL-releasing response to DOM alone was greater than that to either SAL alone or TRH alone. The PRL-releasing response to DOM plus SAL was similar to that to DOM alone, and no additive effect of DOM and SAL on the secretion of PRL was observed. In contrast, the PRL-releasing response to DOM plus TRH was greater than that to either TRH alone or DOM alone and DOM synergistically increased TRH-induced PRL secretion. The present results demonstrate that the mechanism involved in PRL secretion by SAL differs from that by TRH, and suggest that the extracerebral DA might be associated in part with the modulation of SAL-induced PRL secretion in goats.

  5. Genomic gain of the PRL-3 gene may represent poor prognosis of primary colorectal cancer, and associate with liver metastasis.

    PubMed

    Nakayama, N; Yamashita, K; Tanaka, T; Kawamata, H; Ooki, A; Sato, T; Nakamura, T; Watanabe, M

    2016-01-01

    PRL-3 genomic copy number is increased in colorectal cancer (CRC), and PRL-3 expression is closely associated with lymph node and liver metastasis of CRC. However, the clinical significance of PRL-3 genomic gain for CRC remains obscure. Here, PRL-3 genomic status in 109 primary CRC tumors and in 44 CRC tumors that had metastasized to the liver, was quantified using real time PCR. Association of PRL-3 genomic status with clinicopathological factors and prognosis was assessed in detail. PRL-3 genomic gain was identified in 31 primary CRC (27.4 %) and was more frequently seen in stage III than in stage II (p = 0.025). Among the clinicopathological factors assessed, PRL-3 genomic gain was significantly associated with poorly differentiated histology (p = 0.0039). Moreover, CRC patients with PRL-3 genomic gain exhibited poorer prognosis than those with no gain in stage II-IV CRC (p = 0.017). PRL-3 genomic gain was identified in 18 (41 %) of the liver metastasis tumors, and this frequency of gain was significantly increased as compared to that of the corresponding primary CRCs (11 %) (p = 0.001). Our findings suggested that PRL-3 genomic gain may represent an aggressive phenotype of primary CRC, and may associate with liver metastasis.

  6. The metastasis-promoting phosphatase PRL-3 shows activity toward phosphoinositides.

    PubMed

    McParland, Victoria; Varsano, Giulia; Li, Xun; Thornton, Janet; Baby, Jancy; Aravind, Ajay; Meyer, Christoph; Pavic, Karolina; Rios, Pablo; Köhn, Maja

    2011-09-06

    Phosphatase of regenerating liver 3 (PRL-3) is suggested as a biomarker and therapeutic target in several cancers. It has a well-established causative role in cancer metastasis. However, little is known about its natural substrates, pathways, and biological functions, and only a few protein substrates have been suggested so far. To improve our understanding of the substrate specificity and molecular determinants of PRL-3 activity, the wild-type (WT) protein, two supposedly catalytically inactive mutants D72A and C104S, and the reported hyperactive mutant A111S were tested in vitro for substrate specificity and activity toward phosphopeptides and phosphoinositides (PIPs), their structural stability, and their ability to promote cell migration using stable HEK293 cell lines. We discovered that WT PRL-3 does not dephosphorylate the tested phosphopeptides in vitro. However, as shown by two complementary biochemical assays, PRL-3 is active toward the phosphoinositide PI(4,5)P(2). Our experimental results substantiated by molecular docking studies suggest that PRL-3 is a phosphatidylinositol 5-phosphatase. The C104S variant was shown to be not only catalytically inactive but also structurally destabilized and unable to promote cell migration, whereas WT PRL-3 promotes cell migration. The D72A mutant is structurally stable and does not dephosphorylate the unnatural substrate 3-O-methylfluorescein phosphate (OMFP). However, we observed residual in vitro activity of D72A against PI(4,5)P(2), and in accordance with this, it exhibits the same cellular phenotype as WT PRL-3. Our analysis of the A111S variant shows that the hyperactivity toward the unnatural OMFP substrate is not apparent in dephosphorylation assays with phosphoinositides: the mutant is completely inactive against PIPs. We observed significant structural destabilization of this variant. The cellular phenotype of this mutant equals that of the catalytically inactive C104S mutant. These results provide a possible

  7. Somatomammotrophic cells in GH-secreting and PRL-secreting human pituitary adenomas.

    PubMed

    Bassetti, M; Brina, M; Spada, A; Giannattasio, G

    1989-11-01

    A morphological study has been carried out on 20 GH-secreting adenomas removed from acromegalic normoprolactinemic patients, on 29 PRL-secreting adenomas removed from hyperprolactinemic patients without signs of acromegaly and on one normal human anterior pituitary gland collected at autopsy. The protein A-gold immunoelectron microscopic technique has been utilized in order to verify the presence of mixed cells producing both GH and PRL (somatomammotrophs) in these pituitary tissues. In the normal pituitary a considerable number of somatomammotrophs (15-20%) was found, thus supporting the idea that these cells are normal components of the human anterior pituitary gland. In 10 GH-secreting adenomas and in 10 PRL-secreting adenomas somatomammotrophs were present in a variable number (from 4 to 20% of the whole cell population in GH adenomas and from 1 to 47% in PRL tumors). It can be concluded therefore that these cells, largely present in all GH/PRL-secreting adenomas, can also be found in GH-secreting and PRL-secreting tumors without clinical evidence of a mixed secretion. Adenomatous somatomammotrophs displayed ultrastructural features of adenomatous somatotrophs and mammotrophs (prominent Golgi complexes, abundant rough endoplasmic reticulum, irregular nuclei). The size and the number of granules were variable. In some cells GH and PRL were stored in distinct secretory granules, in others in mixed granules or both in mixed and distinct granules, thus suggesting that in adenomatous somatomammotrophs the efficiency of the mechanisms of sorting of the two hormones varies from one cell to another.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Escherichia coli prlC encodes an endopeptidase and is homologous to the Salmonella typhimurium opdA gene.

    PubMed Central

    Conlin, C A; Trun, N J; Silhavy, T J; Miller, C G

    1992-01-01

    Mutations at the Escherichia coli prlC locus suppress the export defect of certain lamB signal sequence mutations. The Salmonella typhimurium opdA gene encodes an endoprotease that can participate in the catabolism of certain peptides and is required for normal development of phage P22. Plasmids carrying either the wild-type (pTC100 prlC+) or suppressor alleles of prlC complemented all phenotypes associated with an S. typhimurium opdA mutation. A plasmid carrying an amber mutation in prlC [prlC31(AM)] was unable to complement except in an amber suppressor background. Tn1000 insertions which eliminated the ability of pTC100 (prlC+) to complement opdA mapped to the region of the plasmid shown by deletion analysis and subcloning to contain prlC. The nucleotide sequence of a 2.7-kb fragment including this region was determined, revealing an open reading frame encoding a 77-kDa protein. The sequences of this open reading frame and its putative promoter region were very similar (84% nucleotide sequence identity and 95% amino acid identity) to those of S. typhimurium opdA, showing that these genes are homologs. The nucleotide sequence of the prlC1 suppressor allele was determined and predicts an in-frame duplication of seven amino acids, providing further confirmation that the prlC suppressor phenotype results from changes in the endopeptidase OpdA. PMID:1325967

  9. Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2.

    PubMed

    Giménez-Mascarell, Paula; Oyenarte, Iker; Hardy, Serge; Breiderhoff, Tilman; Stuiver, Marchel; Kostantin, Elie; Diercks, Tammo; Pey, Angel L; Ereño-Orbea, June; Martínez-Chantar, María Luz; Khalaf-Nazzal, Reham; Claverie-Martin, Felix; Müller, Dominik; Tremblay, Michel L; Martínez-Cruz, Luis Alfonso

    2017-01-20

    Phosphatases of regenerating liver (PRLs), the most oncogenic of all protein-tyrosine phosphatases (PTPs), play a critical role in metastatic progression of cancers. Recent findings established a new paradigm by uncovering that their association with magnesium transporters of the cyclin M (CNNM) family causes a rise in intracellular magnesium levels that promote oncogenic transformation. Recently, however, essential roles for regulation of the circadian rhythm and reproduction of the CNNM family have been highlighted. Here, we describe the crystal structure of PRL-1 in complex with the Bateman module of CNNM2 (CNNM2BAT), which consists of two cystathionine β-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disc-like homodimer of CNNM2BAT bound to two independent PRL-1 molecules, each one located at opposite tips of the disc. The structure highlights the key role played by Asp-558 at the extended loop of the CBS2 motif of CNNM2 in maintaining the association between the two proteins and proves that the interaction between CNNM2 and PRL-1 occurs via the catalytic domain of the phosphatase. Our data shed new light on the structural basis underlying the interaction between PRL phosphatases and CNNM transporters and provides a hypothesis about the molecular mechanism by which PRL-1, upon binding to CNNM2, might increase the intracellular concentration of Mg(2+) thereby contributing to tumor progression and metastasis. The availability of this structure sets the basis for the rational design of compounds modulating PRL-1 and CNNM2 activities.

  10. Ovarian and PGF2α responses to stimulation of endogenous PRL pulses during the estrous cycle in mares.

    PubMed

    Pinaffi, F L V; Khan, F A; Silva, L A; Beg, M A; Ginther, O J

    2012-10-01

    The effects of a PRL-stimulating substance (sulpiride) on PRL and PGF2α secretion and on luteal and ovarian follicular dynamics were studied during the estrous cycle in mares. A control group (n = 9) and a sulpiride group (Sp; n = 10) were used. Sulpiride (25 mg) was given every 8 h from Day 13 postovulation to the next ovulation. Repeated sulpiride treatment did not appear to maintain PRL concentrations at 12-h intervals beyond Day 14. Therefore, the hypothesis that a long-term increase in PRL altered luteal and follicular end points was not testable. Hourly samples were collected from the hour of a treatment (Hour 0) to Hour 8 on Day 14. Concentrations of PRL increased to maximum at Hour 4 in the Sp group. The PRL pulses were more prominent (P < 0.008) in the sulpiride group (peak, 19.4 ± 1.9 ng/mL; mean ± SEM) than in the controls (11.5 ± 1.8 ng/mL). Concentrations of a metabolite of PGF2α (PGFM), number, and characteristics of PGFM pulses, and concentrations of progesterone during Hours 0 to 8 were not affected by the increased PRL. A novel observation was that the peak of a PRL pulse occurred at the same hour or 1 h later than the peak of a PGFM pulse in 8 of 8 PGFM pulses in the controls and in 6 of 10 pulses in the Sp group (P < 0.04), indicating that sulpiride interfered with the synchrony between PGFM and PRL pulses. The hypothesis that sulpiride treatment during the equine estrous cycle increases concentrations of PRL and the prominence of PRL pulses was supported.

  11. Enzyme Activity of Phosphatase of Regenerating Liver (PRL-1) Is Controlled by Redox Environment and Its C-terminal Residues†

    PubMed Central

    Skinner, Andria L.; Vartia, Anthony A.; Williams, Todd D.; Laurence, Jennifer S.

    2009-01-01

    Phosphatase of regenerating liver-1 (PRL-1) belongs to a unique subfamily of protein tyrosine phosphatases (PTPases) associated with oncogenic and metastatic phenotypes. While considerable evidence exists to supports a role for PRL-1 in promoting proliferation, the biological regulators and effectors of PRL-1 activity remain unknown. PRL-1 activity is inhibited by disulfide bond formation at the active site in vitro, suggesting PRL-1 may be susceptible to redox regulation in vivo. Because PRL-1 has been observed to localize to several different subcellular locations and cellular redox conditions vary with tissue type, age, stage of cell cycle and subcellular location, we determined the reduction potential of the active site disulfide bond that controls phosphatase activity to better understand the function of PRL-1 in various cellular environments. We used high-resolution solution NMR spectroscopy to measure the potential and found it to be −364.3 ± 1.5 mV. Because normal cellular environments range from −170 to −320 mV, we concluded that nascent PRL-1 would be primarily oxidized inside cells. Our studies show that a significant conformational change accompanies activation, suggesting a post-translational modification may alter the reduction potential, conferring activity. We further demonstrate that alteration of the C-terminus renders the protein reduced and active in vitro, implying the C-terminus is an important regulator of PRL-1 function. These data provide a basis for understanding how subcellular localization regulates the activity of PRL-1 and, with further investigation, may help reveal how PRL-1 promotes unique outcomes in different cellular systems, including proliferation in both normal and diseased states. PMID:19341304

  12. The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells

    PubMed Central

    Slørdahl, Tobias S.; Abdollahi, Pegah; Vandsemb, Esten N.; Rampa, Christoph; Misund, Kristine; Baranowska, Katarzyna A.; Westhrin, Marita; Waage, Anders; Rø, Torstein B.; Børset, Magne

    2016-01-01

    Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells. PRL-3 is a phosphatase induced by interleukin (IL)-6 and other growth factors in MM cells and promotes MM-cell migration. PRL-3 has also been identified as a marker gene for a subgroup of patients with MM. In this study we found that forced expression of PRL-3 in the MM cell line INA-6 led to increased survival of cells that were depleted of IL-6. It also caused redistribution of cells in cell cycle, with an increased number of cells in G2M-phase. Furthermore, forced PRL-3 expression significantly increased phosphorylation of Signal transducer and activator of transcription (STAT) 3 both in the presence and the absence of IL-6. Knockdown of PRL-3 with shRNA reduced survival in MM cell line INA-6. A pharmacological inhibitor of PRL-3 reduced survival in the MM cell lines INA-6, ANBL-6, IH-1, OH-2 and RPMI8226. The inhibitor also reduced survival in 9 of 9 consecutive samples of purified primary myeloma cells. Treatment with the inhibitor down-regulated the anti-apoptotic protein Mcl-1 and led to activation of the intrinsic apoptotic pathway. Inhibition of PRL-3 also reduced IL-6-induced phosphorylation of STAT3. In conclusion, our study shows that PRL-3 is an important mediator of growth factor signaling in MM cells and hence possibly a good target for treatment of MM. PMID:27036022

  13. PRL-3 and E-cadherin show mutual interactions and participate in lymph node metastasis formation in gastric cancer.

    PubMed

    Pryczynicz, Anna; Guzińska-Ustymowicz, Katarzyna; Niewiarowska, Katarzyna; Cepowicz, Dariusz; Kemona, Andrzej

    2014-07-01

    E-cadherin, a transmembrane adhesion molecule, and phosphatase of regenerating liver 3 (PRL-3) protein, a member of the family of tyrosine phosphatases, seem to be responsible for cancer cell migration. Therefore, the study objective was to determine a correlation between PRL-3 and E-cadherin, to assess their expression in neoplastic tissue and normal mucosa of the stomach, to analyze their effect on cancer advancement, and to evaluate their potential as prognostic markers in gastric cancer. The expressions of PRL-3 and E-cadherin were assessed immunohistochemically in 71 patients with gastric cancer. Positive expression of PRL-3 was observed in 42.2 % of gastric cancer cases, whereas E-cadherin expression was abnormal in 38 % of cases. The study revealed that the positive PRL-3 expression and abnormal E-cadherin expression were associated with mucinous gastric carcinoma and lymph node involvement. The former was also related to the infiltrating type of tumor and abnormal E-cadherin expression. The expression of PRL-3, but not of E-cadherin, was associated with shorter survival of patients. PRL-3 and E-cadherin exhibit interactions in gastric cancer and are involved in the formation of lymph node metastases. The PRL-3 protein can be an independent predictive factor of overall survival in gastric cancer patients.

  14. The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells.

    PubMed

    Slørdahl, Tobias S; Abdollahi, Pegah; Vandsemb, Esten N; Rampa, Christoph; Misund, Kristine; Baranowska, Katarzyna A; Westhrin, Marita; Waage, Anders; Rø, Torstein B; Børset, Magne

    2016-05-10

    Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells. PRL-3 is a phosphatase induced by interleukin (IL)-6 and other growth factors in MM cells and promotes MM-cell migration. PRL-3 has also been identified as a marker gene for a subgroup of patients with MM. In this study we found that forced expression of PRL-3 in the MM cell line INA-6 led to increased survival of cells that were depleted of IL-6. It also caused redistribution of cells in cell cycle, with an increased number of cells in G2M-phase. Furthermore, forced PRL-3 expression significantly increased phosphorylation of Signal transducer and activator of transcription (STAT) 3 both in the presence and the absence of IL-6. Knockdown of PRL-3 with shRNA reduced survival in MM cell line INA-6. A pharmacological inhibitor of PRL-3 reduced survival in the MM cell lines INA-6, ANBL-6, IH-1, OH-2 and RPMI8226. The inhibitor also reduced survival in 9 of 9 consecutive samples of purified primary myeloma cells. Treatment with the inhibitor down-regulated the anti-apoptotic protein Mcl-1 and led to activation of the intrinsic apoptotic pathway. Inhibition of PRL-3 also reduced IL-6-induced phosphorylation of STAT3. In conclusion, our study shows that PRL-3 is an important mediator of growth factor signaling in MM cells and hence possibly a good target for treatment of MM.

  15. Temporal relationships of a pulse of prolactin (PRL) to a pulse of a metabolite of PGF2α in mares.

    PubMed

    Ginther, O J; Pinaffi, F L V; Silva, L A; Beg, M A

    2012-01-01

    Hourly blood samples were collected from 10 mares during 24 h of each of the preluteolytic, luteolytic, and postluteolytic periods. The autocorrelation function of the R program was used to detect pulse rhythmicity, and the intra-assay CV was used to locate and characterize pulses of prolactin (PRL) and a metabolite of prostaglandin F2α (PGFM). Rhythmicity of PRL and PGFM concentrations was detected in 67% and 89% of mares, respectively. Combined for the three periods (no difference among periods), the PRL pulses were 5.2±0.4 h (mean±SEM) at the base, 7.5±1.5 h between nadirs of adjacent pulses, and 12.3±1.5 h from peak to peak. The peaks of PRL pulses were greater (P<0.05) during the luteolytic period (46±14 ng/mL) and postluteolytic period (52±15 ng/mL) than during the preluteolytic period (17±3 ng/mL). Concentrations of PRL during hours of a PGFM pulse were different (P<0.003) within the luteolytic period and postluteolytic period and were greatest at the PGFM peak; PRL concentrations during a PGFM pulse were not different during the preluteolytic period. The frequency of the peak of PRL and PGFM pulses occurring at the same hour (synchrony) was greater for the luteolytic period (65%, P<0.01) and postluteolytic period (50%, P<0.001) than for the preluteolytic period (17%). This is the first report in mares on characterization and rhythmicity of PRL pulses, synchrony between PRL and PGFM pulses, and greater PRL activity during the luteolytic and postluteolytic periods than during the preluteolytic period.

  16. PRL-3 promotes the proliferation of LoVo cells via the upregulation of KCNN4 channels.

    PubMed

    Lai, Wei; Chen, Shuang; Wu, Heng; Guan, Yufeng; Liu, Lu; Zeng, Yujie; Zhao, Haiyan; Jiang, Jianmin; Chu, Zhonghua

    2011-10-01

    Previous studies have shown that phosphatase of regenerating liver-3 (PRL-3) plays an important role in the metastasis and proliferation of tumor cells. However, the mechanism by which PRL-3 controls the cell cycle of tumor cells remains unknown. In the present study, considering that the K+ channels strictly control cell proliferation, we examined whether K+ channels participate in the proliferation of tumor cells induced by PRL-3. Interestingly, the expression of intermediate-conductance Ca2+-activated K+ channels (KCNN4) was upregulated in an NF-κB-dependent manner when PRL-3 was transfected into LoVo cells. Also, we identified two NF-κB binding sites in the promoter region of KCNN4. Use of the specific inhibitor 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) significantly inhibited the proliferation induced by PRL-3 and blocked the cell cycle at the G2/M phase. Meanwhile, the level of phosphorylation of Cdc2 was increased in a dose-dependent manner. Furthermore, TRAM-34 also inhibited tumor formation of PRL-3 cell xenografts implanted by injection in nude mice. In conclusion, PRL-3 promoted the proliferation of LoVo cells through upregulation of KCNN4 channels which facilitated the G2/M transition.

  17. Prolactin (PRL) induction of cyclooxygenase 2 (COX2) expression and prostaglandin (PG) production in hamster Leydig cells.

    PubMed

    Matzkin, María Eugenia; Ambao, Verónica; Carino, Mónica Herminia; Rossi, Soledad Paola; González, Lorena; Turyn, Daniel; Campo, Stella; Calandra, Ricardo Saúl; Frungieri, Mónica Beatriz

    2012-01-02

    Serum prolactin (PRL) variations play a crucial role in the photoperiodic-induced testicular regression-recrudescence transition in hamsters. We have previously shown that cyclooxygenase 2 (COX2), a key enzyme in the biosynthesis of prostaglandins (PGs), is expressed mostly in Leydig cells of reproductively active hamsters with considerable circulating and pituitary levels of PRL. In this study, we describe a stimulatory effect of PRL on COX2/PGs in hamster Leydig cells, which is mediated by IL-1β and prevented by P38-MAPK and JAK2 inhibitors. Furthermore, by preparative isoelectric focusing (IEF), we isolated PRL charge analogues from pituitaries of active [isoelectric points (pI): 5.16, 4.61, and 4.34] and regressed (pI: 5.44) hamsters. More acidic PRL charge analogues strongly induced COX2 expression, while less acidic ones had no effect. Our studies suggest that PRL induces COX2/PGs in hamster Leydig cells through IL-1β and activation of P38-MAPK and JAK2. PRL microheterogeneity detected in active/inactive hamsters may be responsible for the photoperiodic variations of COX2 expression in Leydig cells.

  18. Feedback regulation of PRL secretion is mediated by the transcription factor, signal transducer, and activator of transcription 5b.

    PubMed

    Grattan, D R; Xu, J; McLachlan, M J; Kokay, I C; Bunn, S J; Hovey, R C; Davey, H W

    2001-09-01

    PRL secretion from the anterior pituitary gland is inhibited by dopamine produced in the tuberoinfundibular dopamine neurons of the hypothalamus. The activity of tuberoinfundibular dopamine neurons is stimulated by PRL; thus, PRL regulates its own secretion by a negative feedback mechanism. PRL receptors are expressed on tuberoinfundibular dopamine neurons, but the intracellular signaling pathway is not known. We have observed that mice with a disrupted signal transducer and activator of transcription 5b gene have grossly elevated serum PRL concentrations. Despite this hyperprolactinemia, mRNA levels and immunoreactivity of tyrosine hydroxylase, the key enzyme in dopamine synthesis, were significantly lower in the tuberoinfundibular dopamine neurons of these signal transducer and activator of transcription 5b-deficient mice. Concentrations of the dopamine metabolite dihydroxyphenylacetic acid in the median eminence were also significantly lower in signal transducer and activator of transcription 5b-deficient mice than in wild-type mice. No changes were observed in nonhypothalamic dopaminergic neuronal populations, indicating that the effects were selective to tuberoinfundibular dopamine neurons. These data indicate that in the absence of signal transducer and activator of transcription 5b, PRL signal transduction in tuberoinfundibular dopamine neurons is impaired, and they demonstrate that this transcription factor plays an obligatory and nonredundant role in mediating the negative feedback action of PRL on tuberoinfundibular dopamine neurons.

  19. Bifidobacterium asteroides PRL2011 Genome Analysis Reveals Clues for Colonization of the Insect Gut

    PubMed Central

    Bottacini, Francesca; Milani, Christian; Turroni, Francesca; Sánchez, Borja; Foroni, Elena; Duranti, Sabrina; Serafini, Fausta; Viappiani, Alice; Strati, Francesco; Ferrarini, Alberto; Delledonne, Massimo; Henrissat, Bernard; Coutinho, Pedro; Fitzgerald, Gerald F.; Margolles, Abelardo; van Sinderen, Douwe; Ventura, Marco

    2012-01-01

    Bifidobacteria are known as anaerobic/microaerophilic and fermentative microorganisms, which commonly inhabit the gastrointestinal tract of various animals and insects. Analysis of the 2,167,301 bp genome of Bifidobacterium asteroides PRL2011, a strain isolated from the hindgut of Apis mellifera var. ligustica, commonly known as the honey bee, revealed its predicted capability for respiratory metabolism. Conservation of the latter gene clusters in various B. asteroides strains enforces the notion that respiration is a common metabolic feature of this ancient bifidobacterial species, which has been lost in currently known mammal-derived Bifidobacterium species. In fact, phylogenomic based analyses suggested an ancient origin of B. asteroides and indicates it as an ancestor of the genus Bifidobacterium. Furthermore, the B. asteroides PRL2011 genome encodes various enzymes for coping with toxic products that arise as a result of oxygen-mediated respiration. PMID:23028506

  20. Inhibition of PRL-2·CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth.

    PubMed

    Kostantin, Elie; Hardy, Serge; Valinsky, William C; Kompatscher, Andreas; de Baaij, Jeroen H F; Zolotarov, Yevgen; Landry, Melissa; Uetani, Noriko; Martínez-Cruz, Luis Alfonso; Hoenderop, Joost G J; Shrier, Alvin; Tremblay, Michel L

    2016-05-13

    The oncogenic phosphatase of regenerating liver 2 (PRL-2) has been shown to regulate intracellular magnesium levels by forming a complex through an extended amino acid loop present in the Bateman module of the CNNM3 magnesium transporter. Here we identified highly conserved residues located on this amino acid loop critical for the binding with PRL-2. A single point mutation (D426A) of one of those critical amino acids was found to completely disrupt PRL-2·human Cyclin M 3 (CNNM3) complex formation. Whole-cell voltage clamping revealed that expression of CNNM3 influenced the surface current, whereas overexpression of the binding mutant had no effect, indicating that the binding of PRL-2 to CNNM3 is important for the activity of the complex. Interestingly, overexpression of the CNNM3 D426A-binding mutant in cancer cells decreased their ability to proliferate under magnesium-deprived situations and under anchorage-independent growth conditions, demonstrating a PRL-2·CNNM3 complex-dependent oncogenic advantage in a more stringent environment. We further confirmed the importance of this complex in vivo using an orthotopic xenograft breast cancer model. Finally, because molecular modeling showed that the Asp-426 side chain in CNNM3 buries into the catalytic cavity of PRL-2, we showed that a PRL inhibitor could abrogate complex formation, resulting in a decrease in proliferation of human breast cancer cells. In summary, we provide evidence that this fundamental regulatory aspect of PRL-2 in cancer cells could potentially lead to broadly applicable and innovative therapeutic avenues.

  1. Stimulatory effect of PGF2α on PRL based on experimental inhibition of each hormone in mares.

    PubMed

    Ginther, O J; Pinaffi, F L V; Rodriguez, M B; Duarte, L F; Beg, M A

    2012-12-01

    During the luteolytic period in mares, the peak of 65% of pulses of a PGF2α metabolite (PGFM) and the peak of a pulse of PRL have been reported to occur at the same hour. It is unknown whether the synchrony reflects an effect of PGF2α on PRL or vice versa. Controls, a flunixin meglumine (FM)-treated group (to inhibit PGF2α), and a bromocriptine-treated group (to inhibit PRL), were used at 14 days postovulation in June and in September (n = 6 mares/group/mo). Blood samples were collected hourly from just before treatment (Hour 0) to Hour 10. Concentrations of PGFM in the FM group were lower (P < 0.05) at Hours 4 to 6 than in the controls in each month, but bromocriptine had no detected effects on PGFM. Concentrations of PGFM averaged over all groups and within each group did not differ between June and September. Compared to the controls, concentrations of PRL in June were lower (P < 0.05) in the FM group at Hours 4 to 8 and in the bromocriptine group at Hours 4 to 10. Concentration of PRL averaged over groups was lower (P < 0.0001) in September (0.9 ± 0.05 ng/mL, mean ± SEM) than in June (3.0 ± 0.3 ng/mL). Results supported the hypothesis that the positive association between PGFM and PRL concentrations in mares represents an effect of PGF2α on PRL rather than an effect of PRL on PGF2α.

  2. PRL-3 Promotes the Malignant Progression of Melanoma via Triggering Dephosphorylation and Cytoplasmic Localization of NHERF1.

    PubMed

    Fang, Xian-Ying; Song, Ran; Chen, Wei; Yang, Yuan-Yuan; Gu, Yan-Hong; Shu, Yong-Qian; Wu, Xu-Dong; Wu, Xue-Feng; Sun, Yang; Shen, Yan; Xu, Qiang

    2015-09-01

    Phosphatase of regenerating liver-3 (PRL-3) has been reported to have a critical role in metastatic progression of cancers. Here, we investigate how PRL-3 increases the malignant degree of melanoma cells. The expression of PRL-3 increased gradually during the malignant progression of melanoma. The phosphorylation of Akt was elevated in highly malignant melanoma cells, which was accompanied by a decrease in nuclear phosphatase and tensin homolog (PTEN). The phosphorylation of NHERF1 in the serine site was regulated by PRL-3 and showed cytoplasmic translocation upon dephosphorylation, which resulted in a decrease in nuclear PTEN. The co-translocation of NHERF1 and PTEN from the nucleus to the cytoplasm was observed during the malignant progression of melanoma cells. Tumor growth was inhibited significantly, and the survival was prolonged upon knockdown of cytoplasmic NHERF1 in B16BL6 cells prior to the inoculation into mice. Taken together, to our knowledge previously unreported, we have identified NHERF1 as a potential substrate of PRL-3. Its phosphorylation status as well as its change in cellular localization and association with PTEN correlated with the malignant progression of melanoma. Our data provide an explanation for how PRL-3 promotes the malignant progression of melanoma, as well as a diagnostic marker or therapeutic target for malignant melanoma.

  3. PRL-3/PTP4A3 phosphatase regulates integrin β1 in adhesion structures during migration of human ocular melanoma cells.

    PubMed

    Foy, Malika; Anézo, Océane; Saule, Simon; Planque, Nathalie

    2017-03-08

    In a previous transcriptomic analysis of 63 ocular melanomas of the uvea, we found that expression of the PRL-3/PTP4A3 gene, encoding a phosphatase that is anchored to the plasma membrane, was associated with the risk of metastasis, and a poor prognosis. We also showed that PRL-3 overexpression in OCM-1 ocular melanoma cells significantly increased cell migration in vitro and invasiveness in vivo, suggesting a direct role for PRL-3 in the metastatic spreading of uveal melanoma. Here, we aimed to identify PRL-3 substrates at the plasma membrane involved in adhesion to the extracellular matrix. We focused on integrin β1, which is the most highly expressed integrin in our cohort of uveal melanomas. We show that preventing PRL-3 anchorage to the plasma membrane i) abolishes PRL-3-induced migration in OCM-1 cells, ii) specifically enhances the spreading of OCM-1 cells overexpressing PRL-3, and iii) favors the maturation of large focal adhesions (FAs) containing integrin β1 on collagen I. Knockdown experiments confirmed integrin β1 involvement in PRL3-induced migration. We identified interactions between PRL-3 and integrin β1, as well as with FAK P-Y397, an auto-activated form of Focal Adhesion Kinase found in FAs. We also show that integrin β1 may be dephosphorylated by PRL-3 in its intracytoplasmic S/T region, an important motif for integrin-mediated cell adhesion. Finally, we observed that PRL-3 regulated the clustering of integrin β1 in FAs on collagen I but not on fibronectin. This work identifies PRL-3 as a new regulator of cell adhesion structures to the extracellular matrix, and further supports PRL-3 as a key actor of metastasis in uveal melanoma, of which molecular mechanisms are still poorly understood.

  4. Effect of hyperprolactinemia on PRL-receptor expression and activation of Stat and Mapk cell signaling in the prostate of long-term sexually-active rats.

    PubMed

    Pascual-Mathey, Luz I; Rojas-Duran, Fausto; Aranda-Abreu, Gonzalo E; Manzo, Jorge; Herrera-Covarrubias, Deissy; Muñoz-Zavaleta, David A; Garcia, Luis I; Hernandez, Ma Elena

    2016-04-01

    The abnormal elevation of serum PRL, referred to as hyperprolactinemia (HyperPRL), produces alterations in several reproductive parameters of male rats such as penile erection or decreased tendency to reach ejaculation. Additionally, this situation produces a significant modification of prostate histology, as observed in the epithelial structure and alveolar area, which could reach a level of hyperplasia in the long-term. In this tissue, HyperPRL produces an increase in expression of PRL receptors and activation of the Stat3 signaling pathway that is correlated with the evolution of prostate pathologies. However, the impact of HyperPRL in long-term sexually active male rats is unknown. In this work, using constantly copulating Wistar male rats with induced HyperPRL, we analyzed the level of serum PRL, the effect on prostate PRL receptors, and activation of pStat3, pStat5 and Mapk signaling pathways. Two procedures to induce HyperPRL were employed, comprising daily IP administration or adenohypophysis transplant, and although neither affected the execution of sexual behavior, the serum PRL profile following successive ejaculations was affected. Messenger RNA expression of the short and long isoforms of the PRL receptor at the ventral prostate was affected in different ways depending on the procedure to induce HyperPRL. The ventral prostate did not show any modification in terms of activation of the pStat5 signaling pathway in subjects with daily administration of PRL, although this was significantly increased in ADH transplanted subjects in the second and fourth consecutive ejaculation. A similar profile was found for the pStat3 pathway which additionally showed a significant increase in the third and fourth ejaculation of daily-injected subjects. The Mapk signaling pathway did not show any modifications in subjects with daily administration of PRL, but showed a significant increase in the second and third ejaculations of subjects with ADH transplants. Thus

  5. Increased serum interleukin-22 levels in patients with PRL-secreting and non-functioning pituitary macroadenomas.

    PubMed

    Cannavo, S; Ferrau, F; Cotta, O R; Saitta, S; Barresi, V; Cristani, M T; Saija, A; Ruggeri, R M; Trimarchi, F; Gangemi, S

    2014-02-01

    Cytokines' involvement in tumorigenesis has been hypothesized. Interleukin-22 (IL-22) is implicated in proliferative and anti-apoptotic pathways via its receptor IL-22R. Its role in pituitary adenomas has never been investigated. Twenty-seven patients with pituitary macroadenomas (PA, 21 males, mean age 53.8 ± 14.4 years) and 30 healthy controls (19 males, mean age 50.4 ± 8.4 years) were enrolled. Out of 27 PA patients, 17 had a non-functioning tumour (NFPA) and 10 a PRL-secreting adenoma (PRL-oma). Serum IL-22 levels were measured in both patients and controls. Immunohistochemical (IHC) tumoral IL-22R expression was evaluated in 10 patients with NFPA and 4 with PRL-oma. IL-22 levels were significantly higher in PA patients than in controls [32.47 (11.29-70.12) vs. 5.58 (0.19-21.46) pg/mL, p < 0.0001] but did not correlate with tumor maximum diameter and were not associated to pituitary function impairment. PRL-oma patients had significantly higher IL-22 levels than NFPA patients [37.18 (14.82-70.12) vs. 21.29 (11.29-56) pg/mL, p = 0.039]. IHC revealed a strong IL-22R staining in 100 % of PRL-omas and 60 % of NFPAs. We provide the first evidence of increased serum IL-22 levels in patients with pituitary macroadenoma, especially in PRL-omas, regardless of tumor size and/or degree of pituitary function impairment. We also demonstrated the expression of IL22R in all PRL-omas and in 60 % of NFPAs.

  6. Modeling Prolactin Actions in Breast Cancer in vivo: Insights from the NRL-PRL Mouse

    PubMed Central

    O'Leary, Kathleen A.; Shea, Michael P.; Schuler, Linda A.

    2016-01-01

    Elevated exposure to prolactin is epidemiologically associated with an increased risk of aggressive ER+ breast cancer. To understand the underlying mechanisms and crosstalk with other oncogenic factors, we developed the NRL-PRL mouse. In this model, mammary expression of a rat prolactin transgene raises local exposure to prolactin without altering estrous cycling. Nulliparous females develop metastatic, histotypically diverse mammary carcinomas independent from ovarian steroids, and most are ER+. These characteristics resemble the human clinical disease, facilitating study of tumorigenesis, and identification of novel preventive and therapeutic approaches. PMID:25472540

  7. Stathmin, a new target of PRL-3 identified by proteomic methods, plays a key role in progression and metastasis of colorectal cancer.

    PubMed

    Zheng, Ping; Liu, Yong-Xia; Chen, Lin; Liu, Xun-Hua; Xiao, Zheng-Quan; Zhao, Liang; Li, Guang-Qiu; Zhou, Jun; Ding, Yan-Qing; Li, Jian-Ming

    2010-10-01

    To better understand the role of PRL-3 in progression and metastasis of colorectal cancer (CRC), we searched for PRL-3 associated proteins using proteomic methods. We identified 39 PRL-3 associated proteins based on proteomic strategy. Stathmin, a key oncoprotein, was proved to be a new PRL-3 associated protein. Notably, co-immunoprecipitation assays in both endogenous CRC cell lines and CRC tissues indicated that PRL-3 could interact with stathmin. And, both stathmin and PRL-3 contributed to microtubule (MT) destabilization of CRC cells. Moreover, gain-of-function and loss-of-function analyses revealed that stathmin promoted proliferation, cell adhesion, and migration of human CRC cells. Immunohistochemical analysis of 149 colorectal tumor samples showed that overexpression of stathmin was strongly correlated with tumor differentiation (P = 0.035), tumor invasion (P = 0.024), lymph node status (P < 0.001), Dukes classification (P < 0.001), and TNM staging (P < 0.001) of CRC patients. Univariate and multivariate survival analyses further supported that overexpression of stathmin protein was a potential independent poor prognostic factor for CRC. Our results reveal many PRL-3 associated proteins for the first time. The oncoprotein stathmin plays a key role in CRC as a new target of PRL-3. Interaction between PRL-3 and stathmin leads to MT destabilization of CRC cells, which contributes to progression and metastasis of CRC.

  8. LIN28B Activation by PRL-3 Promotes Leukemogenesis and a Stem Cell-like Transcriptional Program in AML.

    PubMed

    Zhou, Jianbiao; Chan, Zit-Liang; Bi, Chonglei; Lu, Xiao; Chong, Phyllis S Y; Chooi, Jing-Yuan; Cheong, Lip-Lee; Liu, Shaw-Cheng; Ching, Ying Qing; Zhou, Yafeng; Osato, Motomi; Tan, Tuan Zea; Ng, Chin Hin; Ng, Siok-Bian; Wang, Shi; Zeng, Qi; Chng, Wee-Joo

    2017-03-01

    PRL-3 (PTP4A3), a metastasis-associated phosphatase, is also upregulated in patients with acute myeloid leukemia (AML) and is associated with poor prognosis, but the underlying molecular mechanism is unknown. Here, constitutive expression of PRL-3 in human AML cells sustains leukemogenesis in vitro and in vivo Furthermore, PRL-3 phosphatase activity dependently upregulates LIN28B, a stem cell reprogramming factor, which in turn represses the let-7 mRNA family, inducing a stem cell-like transcriptional program. Notably, elevated levels of LIN28B protein independently associate with worse survival in AML patients. Thus, these results establish a novel signaling axis involving PRL-3/LIN28B/let-7, which confers stem cell-like properties to leukemia cells that is important for leukemogenesis.Implications: The current study offers a rationale for targeting PRL-3 as a therapeutic approach for a subset of AML patients with poor prognosis. Mol Cancer Res; 15(3); 294-303. ©2016 AACR.

  9. Identification and characterization of novel membrane-bound PRL protein tyrosine phosphatases from Setaria cervi, a bovine filarial parasite.

    PubMed

    Singh, Neetu; Yadav, Smita; Rathaur, Sushma

    2015-11-01

    A significant amount of protein tyrosine phosphatase (PTP) activity was detected in the detergent-soluble membrane-bound fraction of Setaria cervi, a bovine filarial parasite. The membrane-bound PTP activity was significantly inhibited when the adult parasites were exposed to compounds having antifilarial activity like aspirin and SK7 as well as phenylarsine oxide, a specific PTP inhibitor suggesting that this activity is stress regulated. Further, this enzyme was purified as a single protein of apparently 21 kDa using two different chromatographic techniques. The MALDI-MS/MS analysis of its peptides showed closest match with protein tyrosine phosphatase PRL (Aedes aegypti). This purified enzyme (named as PRL) showed maximum activity at pH 5.5/37 °C and hydrolysed para nitro phenyl phosphate (pNPP) at the highest rate followed by O-P-L-tyrosine and O-P-L-threonine. It showed significant inhibition by specific inhibitors of PTP such as sodium orthovanadate, phenylarsine oxide and ammonium molybdate and was activated by dithiothreitol (DTT). The active site modification studies suggested involvement of cysteine, arginine, histidine and aspartic acid in the catalytic activity of PRL. The activity of S. cervi PRL was also found to be resistant towards the external oxidative stress. Thus, S. cervi PRL could be taken as a potential target for the management of human lymphatic filariasis.

  10. Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2*♦

    PubMed Central

    Giménez-Mascarell, Paula; Oyenarte, Iker; Hardy, Serge; Breiderhoff, Tilman; Stuiver, Marchel; Kostantin, Elie; Diercks, Tammo; Pey, Angel L.; Ereño-Orbea, June; Martínez-Chantar, María Luz; Khalaf-Nazzal, Reham; Claverie-Martin, Felix; Müller, Dominik; Tremblay, Michel L.

    2017-01-01

    Phosphatases of regenerating liver (PRLs), the most oncogenic of all protein-tyrosine phosphatases (PTPs), play a critical role in metastatic progression of cancers. Recent findings established a new paradigm by uncovering that their association with magnesium transporters of the cyclin M (CNNM) family causes a rise in intracellular magnesium levels that promote oncogenic transformation. Recently, however, essential roles for regulation of the circadian rhythm and reproduction of the CNNM family have been highlighted. Here, we describe the crystal structure of PRL-1 in complex with the Bateman module of CNNM2 (CNNM2BAT), which consists of two cystathionine β-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disc-like homodimer of CNNM2BAT bound to two independent PRL-1 molecules, each one located at opposite tips of the disc. The structure highlights the key role played by Asp-558 at the extended loop of the CBS2 motif of CNNM2 in maintaining the association between the two proteins and proves that the interaction between CNNM2 and PRL-1 occurs via the catalytic domain of the phosphatase. Our data shed new light on the structural basis underlying the interaction between PRL phosphatases and CNNM transporters and provides a hypothesis about the molecular mechanism by which PRL-1, upon binding to CNNM2, might increase the intracellular concentration of Mg2+ thereby contributing to tumor progression and metastasis. The availability of this structure sets the basis for the rational design of compounds modulating PRL-1 and CNNM2 activities. PMID:27899452

  11. PRL-3 promotes the peritoneal metastasis of gastric cancer through the PI3K/Akt signaling pathway by regulating PTEN.

    PubMed

    Xiong, Jianbo; Li, Zhengrong; Zhang, Yang; Li, Daojiang; Zhang, Guoyang; Luo, Xianshi; Jie, Zhigang; Liu, Yi; Cao, Yi; Le, Zhibiao; Tan, Shengxing; Zou, Wenyu; Gong, Peitao; Qiu, Lingyu; Li, Yuanyuan; Wang, Huan; Chen, Heping

    2016-10-01

    Peritoneal metastasis is the most frequent cause of death in patients with advanced gastric carcinoma (GC). The phosphatase of regenerating liver-3 (PRL-3) is recognized as an oncogene and plays an important role in GC peritoneal metastasis. However, the mechanism of how PRL-3 regulates GC invasion and metastasis is unknown. In the present study, we found that PRL-3 presented with high expression in GC with peritoneal metastasis, but phosphatase and tensin homologue (PTEN) was weakly expressed. The p-PTEN/PTEN ratio was also higher in GC with peritoneal metastasis than that in the normal gastric tissues. We also found the same phenomenon when comparing the gastric mucosa cell line with the GC cell lines. After constructing a wild-type and a mutant-type plasmid without enzyme activity and transfecting them into GC SGC7901 cells, we showed that only PRL-3 had enzyme activity to downregulate PTEN and cause PTEN phosphorylation. The results also showed that PRL-3 increased the expression levels of MMP-2/MMP-9 and promoted the migration and invasion of the SGC7901 cells. Knockdown of PRL-3 decreased the expression levels of MMP-2/MMP-9 significantly, which further inhibited the migration and invasion of the GC cells. PRL-3 also increased the expression ratio of p-Akt/Akt, which indicated that PRL-3 may mediate the PI3K/Akt pathway to promote GC metastasis. When we transfected the PTEN siRNA plasmid into the PRL-3 stable low expression GC cells, the expression of p-Akt, MMP-2 and MMP-9 was reversed. In conclusion, our results provide a bridge between PRL-3 and PTEN; PRL-3 decreased the expression of PTEN as well as increased the level of PTEN phosphorylation and inactivated it, consequently activating the PI3K/Akt signaling pathway, and upregulating MMP-2/MMP-9 expression to promote GC cell peritoneal metastasis.

  12. A novel method for detection of preferred retinal locus (PRL) through simple retinal image processing using MATLAB

    NASA Astrophysics Data System (ADS)

    Kalikivayi, V.; Pal, Sudip; Ganesan, A. R.

    2013-09-01

    simple and new technique for detection of `Preferred Retinal Locus' (PRL) in human eye is proposed in this paper. Simple MATLAB algorithms for estimating RGB pixel intensity values of retinal images were used. The technique proved non-existence of `S' cones in Fovea Centralis and also proposes that rods are involved in blue color perception. Retinal images of central vision loss and normal retina were taken for image processing. Blue minimum, Red maximum and Red+Green maximum were the three methods used in detecting PRL. Comparative analyses were also performed for these methods with patient's age and visual acuity.

  13. Inhibition of PRL-3 gene expression in gastric cancer cell line SGC7901 via microRNA suppressed reduces peritoneal metastasis

    SciTech Connect

    Li Zhengrong; Zhan Wenhua . E-mail: wcywk@hotmail.com; Wang Zhao; Zhu Baohe; He Yulong; Peng Junsheng; Cai Shirong; Ma Jinping

    2006-09-15

    High expression of PRL-3, a protein tyrosine phosphatase, is proved to be associated with lymph node metastasis in gastric carcinoma from previous studies. In this paper, we examined the relationship between PRL-3 expression and peritoneal metastasis in gastric carcinoma. We applied the artificial miRNA (pCMV-PRL3miRNA), which is based on the murine miR-155 sequence, to efficiently silence the target gene expression of PRL-3 in SGC7901 gastric cancer cells at both mRNA and protein levels. Then we observed that, in vitro, pCMV-PRL3miRNA significantly depressed the SGC7901 cell invasion and migration independent of cellular proliferation. In vivo, PRL-3 knockdown effectively suppressed the growth of peritoneal metastases and improved the prognosis in nude mice. Therefore, we concluded that artificial miRNA can depress the expression of PRL-3, and that PRL-3 might be a potential therapeutic target for gastric cancer peritoneal metastasis.

  14. The phosphatase of regenerating liver 3 (PRL-3) promotes cell migration through Arf-activity-dependent stimulation of integrin α5 recycling.

    PubMed

    Krndija, Denis; Münzberg, Christin; Maass, Ulrike; Hafner, Margit; Adler, Guido; Kestler, Hans A; Seufferlein, Thomas; Oswald, Franz; von Wichert, Götz

    2012-08-15

    The formation of metastasis is one of the most critical problems in oncology. The phosphatase of regenerating liver 3 (PRL-3) is a new target in colorectal cancer, mediating metastatic behavior through a promigratory function. However, detailed explanations for this effect have remained elusive. Here we show that PRL-3 interacts with the ADP-ribosylation factor 1 (Arf1). PRL-3 colocalizes with Arf1 in an endosomal compartment and associates with transmembrane proteins such as the transferrin receptor and α5 integrins. PRL-3 interacts with Arf1 through a distinct motif and regulates activation of Arf1. PRL-3-mediated migration depends on expression and activation of Arf1 and is sensitive to treatment with Brefeldin A. We also demonstrate that PRL-3 modulates recycling of α5 integrins and that its phosphatase activity as well as Arf activation and compartmentalization with Arf1 are required for this effect. In summary our data identify a new function for PRL-3 and show that Arf1 is a new PRL-3-dependent mediator of enhanced migration of cancer cells through enhanced recycling of matrix receptors.

  15. Central infusions of the recombinant human prolactin receptor antagonist, S179D-PRL, delay the onset of maternal behavior in steroid-primed, nulliparous female rats.

    PubMed

    Bridges, R; Rigero, B; Byrnes, E; Yang, L; Walker, A

    2001-02-01

    The expression of maternal behavior in the newly parturient rat is under endocrine regulation. Blocking endogenous PRL secretion with bromocriptine delays the normal rapid expression of maternal care shown toward foster young in steroid-primed virgin female rats. The recent development of the PRL receptor antagonist S179D-PRL, a mutant of human PRL in which the serine residue at the 179 position is replaced with aspartate, provides a potentially useful tool to examine the role of PRL in neural processing. In the present report, three experiments were conducted that examined the effects of this PRL antagonist on the induction of maternal behavior. In each experiment, ovariectomized, nulliparous rats were treated sequentially with SILASTIC capsules implanted sc with progesterone (days 1-11) and estradiol (days 11-17), a treatment that stimulates a rapid onset of maternal behavior in virgin rats. On day 11, females were implanted with Alzet miniosmotic pumps connected to cannulae directed unilaterally at the lateral ventricle (Exp 1) or bilaterally at the medial preoptic area (MPOA; Exp 2 and 3). Pumps contained either doses of S179D-PRL (0.115 or 1.15 mg/ml; Exp 1 and 2), wild-type human PRL (1.15 mg/ml; Exp 3), or the saline vehicle (Exp 1-3). Testing for maternal behavior began on day 12, a day after pump insertion, and animals were tested daily for 6 days. Latencies to contact, retrieve, and group foster test young were recorded. Administration of both the high and low doses of S179D-PRL infused into the lateral ventricle (Exp 1) or MPOA (Exp 2) significantly delayed the onset of maternal behavior. In contrast, MPOA infusions of the control hormone, wild-type human PRL, in Exp 3 did not delay the onset of maternal behavior. These findings support the concept that the effects of S179D-PRL are caused by its actions as a PRL receptor antagonist rather than by a nonspecific effect of the protein. Overall, these results demonstrate the effectiveness of S179D-PRL acting

  16. Correlation of prolactin levels and PRL-receptor expression with Stat and Mapk cell signaling in the prostate of long-term sexually active rats.

    PubMed

    Rojas-Durán, Fausto; Pascual-Mathey, Luz I; Serrano, Karina; Aranda-Abreu, Gonzalo E; Manzo, Jorge; Soto-Cid, Abraham H; Hernandez, Ma Elena

    2015-01-01

    Prolactin (PRL) is a key hormone for prostate function, with a basal level in serum and associated with two characteristic circadian peaks. In the male rat, the execution of one bout of sexual behavior with consecutive ejaculations produces a significant transient increase in PRL. However, the impact of a constant sexual life on both PRL levels and prostate function is unknown. Thus, by using constantly copulating males we analyzed the levels of serum PRL, the effect on prostate PRL receptors, and activation of pStat3, pStat5 and Mapk signaling pathways. Sexually experienced Wistar male rats were used, which underwent periodic sessions of sexual behavior tests. Males were subjected to a session of sexual behavior to achieve at least one and up to four ejaculations. Of these, a blood sample was collected from randomly selected males and the ventral prostate was removed for analysis. Serum PRL was quantified, the mRNA for PRL receptors was determined, and signaling pathways were analyzed. Data show that a constant sexual life produced a constant elevation of PRL in serum during four consecutive ejaculations. The ventral prostate showed a different mRNA expression profile for the long and short isoform of the PRL receptor, and both mRNA levels increased. Although the gland did not show modification of the activation of the pStat5 signaling pathway, the levels of pStat3 increased, and the Mapk pathway showed one significant elevation after the third ejaculation. Thus, we showed that an active and constant sexual life produces a sustained increase in serum PRL, its receptors, and the pStat3 signaling pathway. These responses seem to underlie the required physiological need to produce the quantity and quality of prostatic semen to ensure the appropriate environment for sperm to reach and fertilize the ovum.

  17. prlF and yhaV encode a new toxin-antitoxin system in Escherichia coli.

    PubMed

    Schmidt, Oliver; Schuenemann, Verena J; Hand, Nicholas J; Silhavy, Thomas J; Martin, Jörg; Lupas, Andrei N; Djuranovic, Sergej

    2007-09-28

    Toxin-antitoxin systems consist of a stable toxin, frequently with endonuclease activity, and a small, labile antitoxin, which sequesters the toxin into an inactive complex. Under unfavorable conditions, the antitoxin is degraded, leading to activation of the toxin and resulting in growth arrest, possibly also in bacterial programmed cell death. Correspondingly, these systems are generally viewed as agents of the stress response in prokaryotes. Here we show that prlF and yhaV encode a novel toxin-antitoxin system in Escherichia coli. YhaV, a ribonuclease of the RelE superfamily, causes reversible bacteriostasis that is counteracted by PrlF, a swapped-hairpin transcription factor homologous to MazE. The two proteins form a tight, hexameric complex, which binds with high specificity to a conserved sequence in the promoter region of the prlF-yhaV operon. As homologs of MazE and RelE, respectively, PrlF and YhaV provide an evolutionary connection between the two best-characterized toxin-antitoxin systems in E. coli, mazEF and relEB.

  18. Endoscopic transsphenoidal excision of a GH-PRL-secreting pituitary macroadenoma in a patient with McCune-Albright syndrome.

    PubMed

    Natarajan, Manikandan S; Prabhu, Krishna; Chacko, Geeta; Rajaratnam, Simon; Chacko, Ari G

    2012-02-01

    We describe an endoscopic transsphenoidal excision of a GH-PRL-secreting pituitary adenoma and remodeling of frontotemporal fibrous dysplasia in a patient with McCune-Albright syndrome. Sphenoid dysplasia rendered transsphenoidal surgery challenging, but a study of the radiological anatomy and good surgical planning made this feasible. Medical therapy and radiation was required for persistent acromegaly after surgery.

  19. Modulation of rat testes lipid composition by hormones: Effect of PRL (prolactin) and hCG (human chorionic gonadotropin)

    SciTech Connect

    Sebokova, E.; Wierzbicki, A.; Clandinin, M.T. )

    1988-10-01

    The effect of prolactin (PRL) and human chorionic gonadotropin (hCG) administration for 7 days on the composition and function of rat testicular plasma membrane was investigated. Refractory state in Leydig cells desensitized by hCG decreased the binding capacity for {sup 125}I-labeled hCG and also luteinizing hormone (LH)-induced adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) and testosterone production. In testicular membranes of hCG-treated animals, a depletion of cholesterol and an increase in total phospholipid content was observed after gonadotropin injection, thereby decreasing the cholesterol-to-phospholipid ratio. Injection of high doses of PRL had no effect on the binding capacity or affinity of the LH-hCG receptor but decreased the response of Leydig cells to LH in terms of cAMP and testosterone synthesis. PRL also increased total and esterified cholesterol and decreased free cholesterol and membrane phospholipid content. The fatty acid composition of testicular lipids was significantly and selectively influenced by both hormonal treatments. These observations suggest that metabolism of cholesterol and long-chain polyunsaturated fatty acids in testicular tissue is affected by chorionic gonadotropin and PRL and may provide the mechanism for regulating steroidogenic functions.

  20. PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy.

    PubMed

    Zhou, Jianbiao; Bi, Chonglei; Chng, Wee-Joo; Cheong, Lip-Lee; Liu, Shaw-Cheng; Mahara, Sylvia; Tay, Kian-Ghee; Zeng, Qi; Li, Jie; Guo, Ke; Tan, Cheng Peow Bobby; Yu, Hanry; Albert, Daniel H; Chen, Chien-Shing

    2011-05-12

    Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation.

  1. PRL and GH synthesis and release from the sea bream (Sparus auratus L.) pituitary gland in vitro in response to osmotic challenge.

    PubMed

    Fuentes, Juan; Brinca, Lilia; Guerreiro, Pedro M; Power, Deborah M

    2010-08-01

    The endocrine factors prolactin (PRL) and growth hormone (GH) are believed to have counteracting effects in the adaption of fish to changes in environmental salinity. In order to further investigate this interaction sea bream were challenged with full seawater (SW) or freshwater (FW) for 7 days and the response of pituitary glands cultured in vitro to an osmotic challenge (230, 275 and 320 mOsm/kg) was assessed. In vitro PRL secretion from pituitaries of SW-adapted fish was unaltered in response to an osmotic challenge, while GH secretion increased in the lowest osmolality (230 mOsm/kg). In contrast, both GH and PRL secretion by pituitaries from FW challenged fish was significantly increased (p<0.01) over that of pituitaries from SW fish at the highest osmolality (320 mOsm/kg). After FW challenge pituitary PRL content and de novo synthesised and released PRL were significantly increased (p<0.01), while total PRL secretion was not different from SW animals. GH pituitary content decreased in FW animals while total secretion and secretion of de novo synthesised protein were significantly increased (p<0.01). In addition, after transfer of fish to FW expression of PRL and GH increased 3- and 2-fold, respectively. Despite the increase in PRL expression, no increase in total PRL secretion occurred and although in gills a 2-fold increase in the osmoregulatory marker, Na(+)/K(+)-ATPase activity was detected, profound haemodilution and a cumulative mortality of 40% occurred in sea bream placed in FW. Taken together the results suggest that the sea bream pituitary gland fails to respond appropriately to the osmotic challenge caused by low salinity and the physiological response evoked in vivo is not enough to allow this species to withstand and adapt to FW.

  2. Identification of Apoptosis Genes Induced by the Human Prolactin Antagonist, hPRL-G129R, in Several Breast Cancer Cell Lines

    DTIC Science & Technology

    2002-05-01

    real - time PCR analysis was used to detect bcl-2 mRNA, in 11 human breast cancer cell lines after treatment with hPRL or its antagonist. Our data suggest that Bc 1-2 is upregulated in response to hPRL stimulation & is competively inhibited by the antagonist in the majority of the cell lines tested. We propose that the anti-apoptotic role of hPRL in breast cancer is mediated, at least in part, through regulation of

  3. Role of sortase-dependent pili of Bifidobacterium bifidum PRL2010 in modulating bacterium–host interactions

    PubMed Central

    Turroni, Francesca; Serafini, Fausta; Foroni, Elena; Duranti, Sabrina; O’Connell Motherway, Mary; Taverniti, Valentina; Mangifesta, Marta; Milani, Christian; Viappiani, Alice; Roversi, Tommaso; Sánchez, Borja; Santoni, Andrea; Gioiosa, Laura; Ferrarini, Alberto; Delledonne, Massimo; Margolles, Abelardo; Piazza, Laura; Palanza, Paola; Bolchi, Angelo; Guglielmetti, Simone; van Sinderen, Douwe; Ventura, Marco

    2013-01-01

    Bifidobacteria represent one of the dominant groups of microorganisms colonizing the human infant intestine. Commensal bacteria that interact with a eukaryotic host are believed to express adhesive molecules on their cell surface that bind to specific host cell receptors or soluble macromolecules. Whole-genome transcription profiling of Bifidobacterium bifidum PRL2010, a strain isolated from infant stool, revealed a small number of commonly expressed extracellular proteins, among which were genes that specify sortase-dependent pili. Expression of the coding sequences of these B. bifidum PRL2010 appendages in nonpiliated Lactococcus lactis enhanced adherence to human enterocytes through extracellular matrix protein and bacterial aggregation. Furthermore, such piliated L. lactis cells evoked a higher TNF-α response during murine colonization compared with their nonpiliated parent, suggesting that bifidobacterial sortase-dependent pili not only contribute to adherence but also display immunomodulatory activity. PMID:23776216

  4. Leptin, GH, PRL, insulin and metabolic parameters throughout the dry period and lactation in dairy cows.

    PubMed

    Accorsi, P A; Govoni, N; Gaiani, R; Pezzi, C; Seren, E; Tamanini, C

    2005-06-01

    Leptin may play a role in the endocrine-metabolic processes that guarantee the physiological course of lactation in dairy cattle. This study was aimed at determining the changes in plasma concentrations of leptin and some of the main hormones and metabolites involved in the lactogenetic process in high-yielding dairy cows throughout lactation; we also wanted to assess whether leptin secretion is subjected to seasonal influences. Blood samples were collected from 23 Italian Friesian dairy cows from the end of a lactation to the ninth month of the subsequent one; in addition, blood was sampled from 47 dairy cows in different phases of lactation during February and July. Plasma concentrations of leptin, growth hormone (GH), insulin, prolactin (PRL), glucose, non-esterified fatty acids (NEFA) and urea were quantified by either validated radioimmunoassay (RIA) or enzymatic colorimetric methods. At the beginning of lactation, GH concentrations significantly increased, while a significant reduction occurred in leptin and insulin. This endocrine condition, such as the significant increase in NEFA plasma concentrations, is indicative of a marked lipid mobilization. In the more advanced stages of lactation, when both energy and protein balances become positive, leptin plasma concentrations increased, whereas GH and NEFA concentrations declined. During the summer months, a significant increase in leptin plasma concentrations, irrespective of the phase of lactation, was observed. Collectively, our findings suggest that, in dairy cows, leptin may represent a 'metabolic signal' of animal's status of fattening and nutritional level; in addition, leptin seems to be influenced by photoperiod and environmental temperature.

  5. A prl Mutation in SecY Suppresses Secretion and Virulence Defects of Listeria monocytogenes secA2 Mutants

    PubMed Central

    Durack, Juliana; Burke, Thomas P.

    2014-01-01

    The bulk of bacterial protein secretion occurs through the conserved SecY translocation channel that is powered by SecA-dependent ATP hydrolysis. Many Gram-positive bacteria, including the human pathogen Listeria monocytogenes, possess an additional nonessential specialized ATPase, SecA2. SecA2-dependent secretion is required for normal cell morphology and virulence in L. monocytogenes; however, the mechanism of export via this pathway is poorly understood. L. monocytogenes secA2 mutants form rough colonies, have septation defects, are impaired for swarming motility, and form small plaques in tissue culture cells. In this study, 70 spontaneous mutants were isolated that restored swarming motility to L. monocytogenes secA2 mutants. Most of the mutants had smooth colony morphology and septated normally, but all were lysozyme sensitive. Five representative mutants were subjected to whole-genome sequencing. Four of the five had mutations in proteins encoded by the lmo2769 operon that conferred lysozyme sensitivity and increased swarming but did not rescue virulence defects. A point mutation in secY was identified that conferred smooth colony morphology to secA2 mutants, restored wild-type plaque formation, and increased virulence in mice. This secY mutation resembled a prl suppressor known to expand the repertoire of proteins secreted through the SecY translocation complex. Accordingly, the ΔsecA2prlA1 mutant showed wild-type secretion levels of P60, an established SecA2-dependent secreted autolysin. Although the prl mutation largely suppressed almost all of the measurable SecA2-dependent traits, the ΔsecA2prlA1 mutant was still less virulent in vivo than the wild-type strain, suggesting that SecA2 function was still required for pathogenesis. PMID:25535272

  6. Effects of perfluorooctane sulfuric acid on placental PRL-family hormone production and fetal growth retardation in mice.

    PubMed

    Lee, Chae Kwan; Kang, Sung Goo; Lee, Jong Tae; Lee, Soo-Woong; Kim, Jeong Ho; Kim, Dae Hwan; Son, Byung Chul; Kim, Kun Hyung; Suh, Chun Hui; Kim, Se Yeong; Park, Yeong Beom

    2015-02-05

    Perfluorooctane sulfuric acid (PFOS) is a persistent organic pollutant, causes fetal growth retardation but the mechanism is still unclear. This study focused on PFOS-induced toxicity such as placental trophoblast cell histopathological changes, endocrine function (i.e., prolactin (PRL)-family hormone production) and subsequent fetal growth retardation in mice. Maternal body weight gain, placental and fetal weights were significantly decreased in proportion to PFOS dosage. Placental efficiency (fetal weight/placental weight) was significantly reduced dose-dependently. Necrotic changes were observed in PFOS-treated placental tissues, and the area of injury increased dose-dependently. Finally, mRNA levels and maternal serum concentrations of the PRL-family hormones (mPL-II, mPLP-Cα, mPLP-K) were significantly reduced dose-dependently. In addition, the changing pattern between PRL-family hormone concentrations and fetal body weight was positively correlated. These results suggest that gestational PFOS treatment induces placental histopathological changes and disruption of endocrine function, finally may lead to fetal growth retardation in mice.

  7. A Pit-1 Binding Site Adjacent to E-box133 in the Rat PRL Promoter is Necessary for Pulsatile Gene Expression Activity.

    PubMed

    Bose, Sudeep; Ganguly, Surajit; Kumar, Sachin; Boockfor, Fredric R

    2016-06-01

    Recent evidence reveals that prolactin gene expression (PRL-GE) in mammotropes occurs in pulses, but the molecular process(es) underlying this phenomenon remains unclear. Earlier, we have identified an E-box (E-box133) in the rat PRL promoter that binds several circadian elements and is critical for this dynamic process. Preliminary analysis revealed a Pit-1 binding site (P2) located immediately adjacent to this E-box133 raising the possibility that some type of functional relationship may exist between these two promoter regions. In this study, using serum shocked GH3 cell culture system to synchronize PRL-GE activity, we determined that Pit-1 gene expression occurred in pulses with time phases similar to that for PRL. Interestingly, EMSA analysis not only confirmed Pit-1 binding to the P2 site, but also revealed an interaction with factor(s) binding to the adjacent E-box133 promoter element. Additionally, down-regulation of Pit-1 by siRNA reduced PRL levels during pulse periods. Thus, using multiple evidences, our results demonstrate clearly that the Pit-1 P2 site is necessary for PRL-GE elaboration. Furthermore, the proximity of this critical Pit-1 binding site (P2) and the E-box133 element coupled with the evidences of a site-to-site protein interactions suggest that the process of PRL-GE pulse activity might involve more dynamic and intricate cross-talks between promoter elements that may span some, or all, of the proximal region of the PRL promoter in driving its pulsatile expression.

  8. PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion.

    PubMed

    Gari, Hamid H; DeGala, Gregory D; Ray, Rahul; Lucia, M Scott; Lambert, James R

    2016-10-01

    Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells.

  9. miR-495 and miR-551a inhibit the migration and invasion of human gastric cancer cells by directly interacting with PRL-3.

    PubMed

    Li, Zhengrong; Cao, Yi; Jie, Zhigang; Liu, Yi; Li, Yingliang; Li, Junhe; Zhu, Guoming; Liu, Zhengren; Tu, Yi; Peng, Gen; Lee, Dong-woo; Park, Sung-soo

    2012-10-01

    The phosphatase of regenerating liver-3 (PRL-3) gene is associated with metastasis in gastric cancer, and is believed to play a causative role by promoting tumor cell motility, invasion, and metastasis, but little is known of the mechanisms involved. We previously reported that PRL-3 expression is significantly higher in the tissues of primary gastric carcinomas with peritoneal metastasis. In the present study, we found that two microRNAs (miRNAs), miR-495 and miR-551a, predicted to target PRL-3, are downregulated in gastric carcinoma samples. The validation of this interaction between those two miRNAs and PRL-3 was confirmed by western blotting and quantitative real-time PCR (qPCR) in GC cell lines transfected with miR-495 and miR-551a mimics. Furthermore, the migration and invasion of GC cells were significantly inhibited by transfection with miR-495 or -551a mimics, and the mRNA and protein levels of PRL-3 were reduced in cells overexpressing miR-495 or -551a. Collectively, our findings suggest that miR-495 and miR-551a both act as tumor suppressors by targeting the PRL-3 oncogene and inhibiting gastric cancer cell migration and invasion. The findings of this study contribute to current understanding of the functions of miRNA mimics in GC gene therapy.

  10. Combined expression of metastasis related markers Naa10p, SNCG and PRL-3 and its prognostic value in breast cancer patients.

    PubMed

    Min, Li; Ma, Ruo-Lan; Yuan, Hua; Liu, Cai-Yun; Dong, Bing; Zhang, Cheng; Zeng, Yan; Wang, Li; Guo, Jian-Ping; Qu, Li-Ke; Shou, Cheng-Chao

    2015-01-01

    Combinations of multiple biomarkers representing distinct aspects of metastasis may have better prognostic value for breast cancer patients, especially those in late stages. In this study, we evaluated the protein levels of N-α-acetyltransferase 10 protein (Naa10p), synuclein-γ (SNCG), and phosphatase of regenerating liver-3 (PRL-3) in 365 patients with breast cancer by immunohistochemistry. Distinct prognostic subgroups of breast cancer were identified by combination of the three biomarkers. The Naa10p+SNCG-PRL-3- subgroup showed best prognosis with a median distant metastasis-free survival (DMFS) of 140 months, while the Naa10p-SNCG+PRL-3+ subgroup had the worst prognosis with a median DMFS of 60.5 months. Multivariate analysis indicated Naa10p, SNCG, PRL-3, and the TNM classification were all independent prognostic factors for both DMFS and overall survival (OS). The three biomarker combination of Naa10p, SNCG and PRL-3 performed better in patients with lymph node metastasis, especially those with more advanced tumors than other subgroups. In conclusion, the combined expression profile of Naa10p, SNCG and PRL-3, alone or in combination with the TNM classification system, may provide a precise estimate of prognosis of breast cancer patients.

  11. Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers.

    PubMed

    Gari, Hamid H; Gearheart, Christy M; Fosmire, Susan; DeGala, Gregory D; Fan, Zeying; Torkko, Kathleen C; Edgerton, Susan M; Lucia, M Scott; Ray, Rahul; Thor, Ann D; Porter, Christopher C; Lambert, James R

    2016-03-29

    Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells.

  12. Genome-wide functional genetic screen with the anticancer agent AMPI-109 identifies PRL-3 as an oncogenic driver in triple-negative breast cancers

    PubMed Central

    Gari, Hamid H.; Gearheart, Christy M.; Fosmire, Susan; DeGala, Gregory D.; Fan, Zeying; Torkko, Kathleen C.; Edgerton, Susan M.; Lucia, M. Scott; Ray, Rahul; Thor, Ann D.; Porter, Christopher C.; Lambert, James R.

    2016-01-01

    Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells. PMID:26909599

  13. Congenital complete absence of GH, TSH and PRL in infants: a consequence of Pit-1 gene deletion.

    PubMed

    Preeyasombat, C; Suprasongsin, C; Chiranuphab, A; Mahachoklertwattana, P; Sriphrapradang, A; Choubtum, L

    1993-10-01

    The patient was the first child of a short mother (140 cm) born at term with a birthweight of 2,700 g. On arrival, she was 1 4/12-year-old, weighed 4,150 g and 47 cm long. Her bone age was at the 6 month-old level. Endocrine investigation revealed undetectable plasma growth hormone (GH), thyrotropin (TSH) and prolactin (PRL) levels. CT scan of ovaries revealed bilateral ovarian agenesis in spite of normal, 46 XX karyotype. MRI of the brain did not demonstrate intracranial tumor or congenital malformation. Peak plasma GH level after oral clonidine provocation, insulin induced hypoglycemia, and I.V. GH-RF stimulation were 0.6, 0, and 0 ng/ml respectively. Peak plasma TSH response after I.V. TRH stimulation was 0.04 microU/ml. The patient could not secrete PRL at any time after insulin induced hypoglycemia, TRH and metoclopramide stimulations. On the other hand the child had elevated basal plasma cortisol (38 micrograms/dl at 8.00 AM) and raised 24 hr urinary 17 OHCS excretion (50 mg/1 g Cr against normal value of 3 mg/1 g Cr) without evidence of Cushing syndrome probably indicate partial glucocorticoid resistance. Peak plasma cortisol responses after intravenous metoclopramide and insulin induced hypoglycemia were 46 and 42.9 micrograms/dl respectively. Dexamethasone administration reduced plasma cortisol to 2.9 micrograms/dl. The child had also elevated basal plasma FSH (36 microU/ml) and LH (5 microU/ml) with further elevation to the peak of 123 and 99 microU/ml respectively after LHRH stimulation. All evidence suggested the diagnosis of congenital complete absence of GH, TSH, and PRL which is characteristic of Pit-1-gene deletion.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Uptake Hydrogenase Activity Determined by Plasmid pRL6JI in Rhizobium leguminosarum Does Not Increase Symbiotic Nitrogen Fixation

    PubMed Central

    Cunningham, Scott D.; Kapulnik, Yoram; Brewin, Nicholas J.; Phillips, Donald A.

    1985-01-01

    Six mutants of Rhizobium leguminosarum 3855 lacking uptake hydrogenase activity (Hup− phenotype) as a result of Tn5-mob mutagenesis of the hup-containing plasmid pRL6JI were tested for symbiotic performance on Pisum sativum L. and Vicia benghalensis L. Three pea cultivars and one vetch line, which induce four different levels of Hup activity in strain 3855, were grown to flowering under microbiologically controlled conditions in the absence of combined N. Direct Kjeldahl N measurements showed that in every case at least one Hup− mutant fixed as much N2 as the isogenic Hup+ strain. Measures of C2H2 reduction, H2 evolution, 3H2 incorporation, and plant dry weight were consistent with the interpretation that the oxidation of H2 produced by the nitrogenase enzyme complex was not necessarily associated with increased N2 fixation in these symbiotic associations. Tests with a smaller subset of the Hup− strains under four different root environments ranging from pH 5.0 to 8.2 likewise showed no significant advantage for the isogenic Hup+ strain. It was concluded that the improvements in symbiotic N2 fixation produced by pRL6JI are associated with some trait other than the Hup+ phenotype. PMID:16346912

  15. Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth.

    PubMed

    Gari, H H; DeGala, G D; Lucia, M S; Lambert, J R

    2016-08-15

    Stimulating tumor cell senescence and apoptosis are proven methods for therapeutically combating cancer. However, senescence and apoptosis are conventionally viewed as parallel, not sequential, processes. We have discovered that the metastasis-promoting phosphatase, PRL-3, is transcriptionally regulated by the NF-ĸB pathway in triple-negative breast cancer (TNBC) cells, and that PRL-3 knockdown elicits an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop that results in TNBC cell senescence followed by apoptosis. Knockdown of PRL-3 leads to rapid G1 cell cycle arrest and induction of a strong TNFα cytokine response that promotes a period of cellular senescence through TNF-R1-mediated activation of NF-ĸB. Senescent PRL-3 knockdown cells subsequently underwent apoptosis as a result of increased TNF-R1 signaling through the TNFα-associated extrinsic death pathway, shunting signaling away from the NF-ĸB cascade. These data suggest that TNF-R1 signaling dynamically re-programs after PRL-3 knockdown, from sustaining cell senescence through NF-ĸB to promoting apoptosis through TNF-R1 internalization and caspase-8 activation. The molecular mechanisms that determine the survival-death balance of TNF-R1 signaling are poorly understood, despite the fact that TNF-R1 has been extensively studied. Our results describe PRL-3 knockdown as a novel survival-death balance modifier of the TNF-R1 pathway, and show that senescent TNBC tumor cells can be sensitized to undergo apoptosis in a sequential manner.

  16. Methylation-associated silencing of miR-495 inhibit the migration and invasion of human gastric cancer cells by directly targeting PRL-3.

    PubMed

    Li, Zhengrong; Zhang, Guoyang; Li, Daojiang; Jie, Zhigang; Chen, Heping; Xiong, Jianbo; Liu, Yi; Cao, Yi; Jiang, Mengmeng; Le, Zhibiao; Tan, Shengxing

    2015-01-02

    Phosphatase of regenerating liver-3 (PRL-3) is believed to be associated with cell motility, invasion, and metastasis. Our previous work found that PRL-3 is highly overexpressed in gastric cancer (GC) tissue with peritoneal metastasis and directly involved in the pathogenesis of GC peritoneal metastasis. Moreover, we further found that the down-regulation of endogenous miR-495 expression plays a causative role in over expression of PRL-3 in GC peritoneal metastasis. However, the molecular regulation mechanisms by which endogenous miR-495 expression is down-regulated and PRL-3 promotes GC peritoneal metastasis remain to be clearly elucidated. Some studies have shown that the promoter methylation is closely related to the miRNA gene expression. Therefore, in present study, based on our previous findings, we will analysis whether DNA methylation is a major cause of the down-expression of endogenous miR-495, which results in PRL-3 overexpression in GC peritoneal metastasis. Methylation specific PCR (MSP) and sodium bisulfite sequencing method (BSP) detected miR-495 gene promoter methylation status. We treated GC cell lines with 5-Aza-2'-deoxycytidine (5-Aza-dC) to make the gene promoter methylation inactivation. By treating with 5-Aza-dC the migration and invasion of GC cells were significantly inhibited. And the miR-495 was overexpressing, corresponds to the mRNA and protein levels of PRL-3 were reduced, the ability of invasion and metastasis was inhibited. This study suggest that miR-495 have tumor suppressor properties and are partially silenced by DNA hypermethylation in GC, will provide new strategies for prevention and treatment of GC peritoneal metastasis.

  17. Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth

    PubMed Central

    Gari, H H; DeGala, G D; Lucia, M S; Lambert, J R

    2016-01-01

    Stimulating tumor cell senescence and apoptosis are proven methods for therapeutically combating cancer. However, senescence and apoptosis are conventionally viewed as parallel, not sequential, processes. We have discovered that the metastasis-promoting phosphatase, PRL-3, is transcriptionally regulated by the NF-ĸB pathway in triple-negative breast cancer (TNBC) cells, and that PRL-3 knockdown elicits an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop that results in TNBC cell senescence followed by apoptosis. Knockdown of PRL-3 leads to rapid G1 cell cycle arrest and induction of a strong TNFα cytokine response that promotes a period of cellular senescence through TNF-R1-mediated activation of NF-ĸB. Senescent PRL-3 knockdown cells subsequently underwent apoptosis as a result of increased TNF-R1 signaling through the TNFα-associated extrinsic death pathway, shunting signaling away from the NF-ĸB cascade. These data suggest that TNF-R1 signaling dynamically re-programs after PRL-3 knockdown, from sustaining cell senescence through NF-ĸB to promoting apoptosis through TNF-R1 internalization and caspase-8 activation. The molecular mechanisms that determine the survival–death balance of TNF-R1 signaling are poorly understood, despite the fact that TNF-R1 has been extensively studied. Our results describe PRL-3 knockdown as a novel survival–death balance modifier of the TNF-R1 pathway, and show that senescent TNBC tumor cells can be sensitized to undergo apoptosis in a sequential manner. PMID:27526109

  18. PRL-1 protein promotes ERK1/2 and RhoA protein activation through a non-canonical interaction with the Src homology 3 domain of p115 Rho GTPase-activating protein.

    PubMed

    Bai, Yunpeng; Luo, Yong; Liu, Sijiu; Zhang, Lujuan; Shen, Kui; Dong, Yuanshu; Walls, Chad D; Quilliam, Lawrence A; Wells, Clark D; Cao, Youjia; Zhang, Zhong-Yin

    2011-12-09

    Phosphatases of the regenerating liver (PRL) play oncogenic roles in cancer development and metastasis. Although previous studies indicate that PRL-1 promotes cell growth and migration by activating both the ERK1/2 and RhoA pathways, the mechanism by which it activates these signaling events remains unclear. We have identified a PRL-1-binding peptide (Peptide 1) that shares high sequence identity with a conserved motif in the Src homology 3 (SH3) domain of p115 Rho GTPase-activating protein (GAP). p115 RhoGAP directly binds PRL-1 in vitro and in cells via its SH3 domain. Structural analyses of the PRL-1·Peptide 1 complex revealed a novel protein-protein interaction whereby a sequence motif within the PxxP ligand-binding site of the p115 RhoGAP SH3 domain occupies a folded groove within PRL-1. This prevents the canonical interaction between the SH3 domain of p115 RhoGAP and MEKK1 and results in activation of ERK1/2. Furthermore, PRL-1 binding activates RhoA signaling by inhibiting the catalytic activity of p115 RhoGAP. The results demonstrate that PRL-1 binding to p115 RhoGAP provides a coordinated mechanism underlying ERK1/2 and RhoA activation.

  19. Molecular performance of Prl and Gh/Igf1 axis in the Mediterranean meager, Argyrosomus regius, acclimated to different rearing salinities.

    PubMed

    Mohammed-Geba, Khaled; González, Antonio Astola; Suárez, Rubén Ayala; Galal-Khallaf, Asmaa; Martos-Sitcha, Juan Antonio; Ibrahim, Hany Mohammed; Martínez-Rodríguez, Gonzalo; Mancera, Juan Miguel

    2017-02-01

    Aquaculture industry in the Mediterranean region exhibits a growing interest for the Mediterranean meager Argyrosomus regius. Some preliminary works showed a good growth performance of the species in nearly isosmotic salinities. However, the patterns of alteration of prolactin (Prl) as well as growth hormone (Gh)/insulin growth factor-1 (Igf1) axis at the molecular level are not yet described in this species. Therefore, we cloned and sequenced partial cDNAs for pituitary prolactin (prl) and growth hormone (gh), hepatic insulin-like growth factor (igf1), and β-actin (actb). Expression patterns of these transcripts were tested in juveniles of A. regius acclimated to four different environmental salinities: (1) 5 ‰ (hyposmotic); (2) 12 ‰ (isosmotic); (3) 38 ‰ (hyperosmotic; seawater control); and (4) 55 ‰ (extremely hyperosmotic). All investigated transcripts shared high sequence identities with their counterparts in other perciformes. prl mRNA levels showed inverse pattern with increasing salinities. gh mRNA enhanced significantly in both 12 and 55 ‰ salinity groups in comparison with the control group, while igf1 showed its maximum expression levels under the nearly isosmotic environment. The results indicated clear sensitivity of prl, gh and igf1 to changes in environmental salinity, which can possibly control the euryhalinity capacity of this species.

  20. Polymorphisms in the 5'-flanking regions of the GH, PRL, and Pit-1 genes with Muscovy duck egg production.

    PubMed

    Xu, Z Q; He, J; Ji, C L; Zhang, Y; Nie, Q H; Zhang, D X; Zhang, X Q

    2015-01-01

    Somatotropic axis-related genes contribute to reproduction of ducks. Five SNP in the 5'-flanking regions of the growth hormone (GH), prolactin (PRL), and pituitary-specific transcription factor (Pit-1) genes were identified and genotyped in a female population of Muscovy ducks. Association analysis of these SNP with Muscovy duck egg production traits was performed. Results showed that SNP C-515G of GH was significantly associated with egg number in ducks at age 59 wk (E59W; P = 0.0009) and egg number in ducks at age 300 d (E300D; P = 0.0022). Single nucleotide polymorphism C-441T of GH was significantly associated with E59W (P = 0.0014). Significant associations of SNP T-884C and T-335C of PRL with the age at first egg (A1D), E59W, and E300D were detected in this population (P < 0.0001). It was concluded that these 4 SNP might be useful markers to use with the aim of increasing Muscovy duck E59W. On the basis of genetic parameter estimation, the heritability of A1D, E300D, E59W, and molting time were 0.43 ± 0.04, 0.45 ± 0.04, 0.36 ± 0.04, and 0.04 ± 0.03, respectively. Strong positive genetic correlation was noted between E59W and E300D (correlation coefficient = 0.80), whereas a negative association was noted between E59W and A1D (correlation coefficient = -0.80). Therefore, the selection for improved A1D should also increase E59W.

  1. Breeding period-associated changes in semen quality, concentrations of LH, PRL, gonadal steroid and thyroid hormones in domestic goose ganders (Anser anser f. domesticus).

    PubMed

    Gumułka, Małgorzata; Rozenboim, Israel

    2015-03-01

    In flocks of geese fertility decreases in the second half of the breeding season. The reasons for this reduction in reproduction ability are still unclear. This study measured changes in semen quality variables throughout the period of intensive breeding in relation to hormonal concentrations associated with the sexual activity of ganders. Semen was collected (2×/week) from 2-year-old ganders in the period February-June. Standard ejaculation parameters and spermatozoa (spz) membrane integrity after E/N and SYBR-14/PI staining were evaluated. The DNA Fragmentation Index was measured by flow cytometry and sperm quality factors (SQF). The plasma levels of T, E2, P4, LH, PRL, THs in relation to semen parameters were evaluated. In ejaculate collected at the onset of the second half of breeding (April - spring period), a reduction in sperm concentration and % of liveE/N and liveSYBR-14+/PI- spz was shown. At this time, decrease in concentrations of LH and T and increase in PRL were found as well as moderate changes in THs were observed. However, in May a second peak in T and sperm production occurred. The DFI-% was higher in the middle part of breeding. Gonadal steroids concentration were not good prognostic marker of the reproductive potential of ganders. We suggest that a marked decline in LH and T in the spring period indicated the onset of endocrine changes mediated by PRL and THs resulting in progressive regression of testis functions. The lowest SQF in the spring/summer period coincided with the highest PRL suggesting an anti-spermatogenic action of PRL in ganders.

  2. Changes in gene expression for GH/PRL/SL family hormones in the pituitaries of homing chum salmon during ocean migration through upstream migration.

    PubMed

    Onuma, Takeshi A; Ban, Masatoshi; Makino, Keita; Katsumata, Hiroshi; Hu, WeiWei; Ando, Hironori; Fukuwaka, Masa-aki; Azumaya, Tomonori; Urano, Akihisa

    2010-05-01

    Gene expression for growth hormone (GH)/prolactin (PRL)/somatolactin (SL) family hormones in the pituitaries of homing chum salmon were examined, because gene expression for these hormones during ocean-migrating phases remains unclear. Fish were collected in the winter Gulf of Alaska, the summer Bering Sea and along homing pathway in the Ishikari River-Ishikari Bay water system in Hokkaido, Japan in autumn. The oceanic fish included maturing adults, which had developing gonads and left the Bering Sea for the natal river by the end of summer. The absolute amounts of GH, PRL and SL mRNAs in the pituitaries of the maturing adults in the summer Bering Sea were 5- to 20-fold those in the winter Gulf of Alaska. The amount of GH mRNA in the homing adults at the coastal seawater (SW) areas was smaller than that in the Bering fish, while the amount of PRL mRNA remained at the higher level until fish arrived at the Ishikari River. The gill Na(+),K(+)-ATPase activity in the coastal SW fish and the plasma Na(+) levels in the brackish water fish at the estuary were lowered to the levels that were comparable to those in the fresh water (FW) fish. In conclusion, gene expression for GH, PRL and SL was elevated in the pituitaries of chum salmon before initiation of homing behavior from the summer Bering Sea. Gene expression for GH is thereafter lowered coincidently with malfunction of SW adaptability in the breeding season, while gene expression for PRL is maintained high until forthcoming FW adaptation.

  3. Targeted deletion of the metastasis-associated phosphatase Ptp4a3 (PRL-3) suppresses murine colon cancer.

    PubMed

    Zimmerman, Mark W; Homanics, Gregg E; Lazo, John S

    2013-01-01

    Ptp4a3 (commonly known as PRL-3) is an enigmatic member of the Ptp4a family of prenylated protein tyrosine phosphatases that are highly expressed in many human cancers. Despite strong correlations with tumor metastasis and poor patient prognosis, there is very limited understanding of this gene family's role in malignancy. Therefore, we created a gene-targeted murine knockout model for Ptp4a3, the most widely studied Ptp4a family member. Mice deficient for Ptp4a3 were grossly normal. Fewer homozygous-null males were observed at weaning, however, and they maintained a decreased body mass. Although Ptp4a3 is normally associated with late-stage cancer and metastasis, we observed increased Ptp4a3 expression in the colon of wildtype mice immediately following treatment with the carcinogen azoxymethane. To investigate the role of Ptp4a3 in malignancy, we used the most commonly studied murine colitis-associated colon cancer model. Wildtype mice treated with azoxymethane and dextran sodium sulfate developed approximately 7-10 tumors per mouse in the distal colon. The resulting tumor tissue had 4-fold more Ptp4a3 mRNA relative to normal colon epithelium and increased PTP4A3 protein. Ptp4a3-null mice developed 50% fewer colon tumors than wildtype mice after exposure to azoxymethane and dextran sodium sulfate. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with Ptp4a3, suggesting an enhanced cell signaling pathway engagement in the absence of the phosphatase. These results provide the first definitive evidence implicating Ptp4a3 in colon tumorigenesis and highlight the potential value of the phosphatase as a therapeutic target for early stage malignant disease.

  4. Daily profiles of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin, and of pituitary PRL mRNA and GH mRNA in male Long Evans rats in acute phase of adjuvant arthritis.

    PubMed

    Roman, Olha; Seres, Janette; Herichova, Iveta; Zeman, Michal; Jurcovicova, Jana

    2003-09-01

    We studied the effects of adjuvant arthritis (AA) on the endocrine circadian rhythms of plasma prolactin (PRL), growth hormone (GH), insulin-like growth factor-1 (IGF-1), luteinizing hormone (LH), testosterone, and melatonin and of pituitary PRL and GH mRNA in male Long Evans rats. Groups of control and AA rats (studied 23 days after AA induction) that were housed under a 12/12 h light/dark cycle (light on at 06:00 h) were killed at 4 h intervals starting at 14:00 h. Cosinor analysis revealed a significant 12 h rhythm in PRL and PRL mRNA (p < 0.001) in controls with peaks at 14:00 h and 02:00 h, respectively. The peak at 02:00 h was abolished in the AA group resulting in a significant 24 h rhythm in parallel with that of PRL (p < 0.05) and PRL mRNA (p < 0.0001). Growth hormone showed no rhythm, but a significant rhythm of GH mRNA was present in both groups (p < 0.0001). Insulin-like growth factor-1 showed a 24 h rhythm in control but not in AA rats. The mean values of GH, GH mRNA, and IGF-1 were significantly reduced in AA. Luteinizing hormone displayed a significant 24 h rhythm (p < 0.01) peaking in the dark period in the control but not AA group. Testosterone showed in phase temporal changes of LH levels with AA abolishing the 02:00 h peak. Melatonin exhibited a significant 24 h rhythm in control (p < 0.001) and AA (p < 0.01) rats with maximum levels during the dark phase; the mesor value was higher in the AA males. These results demonstrate that AA interferes with the rhythms of all the studied hormones except the non-24 h (arrhythmic) GH secretion pattern and the rhythm in melatonin. The persistence of a distinct melatonin rhythm in AA suggests the observed disturbances of hormonal rhythms in this condition do not occur at the level of the pineal gland.

  5. Area 3 Support Buildings (A3SB) H5-0992, H5-0996 PRL 218 Confirmatory Sampling Report

    NASA Technical Reports Server (NTRS)

    Mrdjenovich, Timothy

    2015-01-01

    The Area 3 Support Buildings site (A3SB) consists of two separate areas located on the north side of Beach Road in the northern portion of Kennedy Space Center, Florida (KSC), outside the secured perimeter of KSC. The A3SB areas are approximately 0.6 miles apart, and were developed as Shiffler's Grocery Store and Service Station (west site) and as a residence (east site) prior to acquisition by the National Aeronautics and Space Administration (NASA) in 1963. Both areas were used by the Bendix Company in support of NASA as chemical laboratories from 1963 through 1969. Both of the buildings were demolished by 1987. The west portion of the site was used by the US Fish & Wildlife Service (F&W) in support of the Merritt Island National Wildlife Refuge (MINWR) for parking at the entrance to the Hammock Trails from 1969 to the present. The east portion of the site was used for intermittent suspect materials staging in the early 1990s and is still used as an apiary location, but is otherwise no longer active. In support of the NASA HSWA permit requirements, this site was identified as Potential Release Location (PRL) 218 and a Solid Waste Management Unit (SWMU) Assessment (SA) was conducted in 2013. Confirmatory Sampling (CS) was recommended and approved by the KSC Remediation Team (KSCRT). Three locations of concern (LOCs) were identified and sampled at the site. The LOCs include two former chemical labs and a former suspect staging area. The CS was conducted in March of 2015 at three locations by means of Direct Push Technology (DPT) groundwater sampling and at one location for soil sampling. The samples were collected and analyzed in accordance with the approved CS Work Plan. There were no exceedances of criteria detected in any of the samples from the three LOCs. The results of this investigation indicate that past and/or present operations have not negatively impacted environmental media at the A3SB. Based upon no confirmed groundwater detections above GCTLs and no

  6. [Polymorphism of POU1F1 gene and PRL gene and their combined effects on milk performance traits in Chinese Holstein cattle].

    PubMed

    Jia, Xiang-Jie; Wang, Chang-Fa; Yang, Gui-Wen; Huang, Jin-Ming; Li, Qiu-Ling; Zhong, Ji-Feng

    2011-12-01

    Three novel SNPs were found by DNA sequencing, PCR-RFLP and CRS-PCR methods were used for genotyping in 979 Chinese Holstein cattle. One SNP, G1178C, was identified in exon 2 of POU1F1 gene. Two novel SNPs, A906G and A1134G, were identified in 5'-flanking regulatory region (5'-UTR) of PRL gene. The association between polymorphisms of the two genes and milk performance traits were analyzed with PROC GLM of SAS. The results showed that GC genotype at 1178 locus of POU1F1 gene was advantageous for milk yield, milk protein yield, and milk fat yield. AG genotype at 906 locus was advantageous for milk yield. There was no significant difference between 1134 locus and milk performance traits of 5'-UTR of PRL gene. Analysis of genotype combination effect on milk production traits showed that the effect of combined genotype was not simple sum of single genotypes and the effects of gene pyramiding seemed to be more important in molecular breeding.

  7. P.R.L. Platelet Rich Lipotransfert: Our Experience and Current State of Art in the Combined Use of Fat and PRP

    PubMed Central

    Cervelli, V.; Bocchini, I.; Di Pasquali, C.; De Angelis, B.; Cervelli, G.; Curcio, C. B.; Orlandi, A.; Scioli, M. G.; Tati, E.; Delogu, P.; Gentile, Pietro

    2013-01-01

    The authors report their experience about the use of P.R.L. PLATELET RICH LIPOTRANSFERT method (platelet rich plasma mixed fat grafting) in 223 patients affected by soft tissue defects (ulcers, Romberg syndrome, Hemifacial atrophy, loss of substance, and signs of aging). This paper introduces the reader to PRP therapy and reviews the current literature on this emerging treatment modality, showing at the current clinical use of PRP in plastic and reconstructive surgery, with description of innovative methods and future prospects. This technique provides a promising alternative to surgery by promoting safe and natural healing. Here recent studies concerning the use of PRP in the treatment of chronic ulcers and soft tissue defect are reviewed. PMID:24191244

  8. [Study of genetic variation in Yakutian cattle (Bos taurus L.) using the prolactin bPRL, growth hormone bGH, and transcription factor bPit-1 genes].

    PubMed

    Lazebnaia, I V; Lazebnyĭ, O E; Sulimova, G E

    2010-03-01

    The genetic structure of the Yakutian cattle breed was studied using the following genes: bPRL (RsaI site in exon 3), bGH (AluI site in exon 5), and bPit-1 (HinfI site in exon 6). The values of observed heterozygosity were 0.36 for bPRL, 0.29 for bGH, and 0.16 for bPit-1. These values are within the range of values for this parameter established for a number of Bos taurus breeds. The results obtained show that genetic variation is preserved in this aboriginal Russian breed, despite a catastrophic reduction of the number of animals.

  9. Hypothyroidism advances mammary involution in lactating rats through inhibition of PRL signaling and induction of LIF/STAT3 mRNAs.

    PubMed

    Campo Verde Arboccó, Fiorella; Sasso, Corina V; Actis, Esteban A; Carón, Rubén W; Hapon, María Belén; Jahn, Graciela A

    2016-01-05

    Thyroid diseases have deleterious effects on lactation, litter growth and survival, and hinder the suckling-induced hormone release, leading in the case of hyperthyroidism, to premature mammary involution. To determine the effects of hypothyroidism (HypoT) on late lactation, we analyzed the effect of chronic 6-propyl-2-thiouracil (PTU)-induced HypoT on mammary histology and the expression of members of the JAK/STAT/SOCS signaling pathway, milk proteins, prolactin (PRLR), estrogen (ER), progesterone (PR) and thyroid hormone (TR) receptors, markers of involution (such as stat3, lif, bcl2, BAX and PARP) on lactation (L) day 21. HypoT mothers showed increased histological markers of involution compared with control rats, such as adipose/epithelial ratio, inactive alveoli, picnotic nuclei and numerous detached apoptotic cells within the alveolar lumina. We also found decreased PRLR, β-casein and α-lactoalbumin mRNAs, but increased SOCS1, SOCS3, STAT3 and LIF mRNAs, suggesting a decrease in PRL signaling and induction of involution markers. Furthermore, Caspase-3 and 8 and PARP labeled cells and the expression of structural proteins such as β-Actin, α-Tubulin and Lamin B were increased, indicating the activation of apoptotic pathways and tissue remodelation. HypoT also increased PRA (mRNA and protein) and erβ and decreased erα mRNAs, and increased strongly TRα1, TRβ1, PRA and ERα protein levels. These results show that lactating HypoT rats have premature mammary involution, most probably induced by the inhibition of prolactin signaling along with the activation of the LIF-STAT3 pathway.

  10. A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus.

    PubMed

    Aoki, Naohito; Matsuda, Tsukasa

    2002-01-01

    In the present study we examined involvement of nuclear protein tyrosine phosphatase TC-PTP in PRL-mediated signaling. TC-PTP could dephosphorylate signal transducer and activator of transcription 5a (STAT5a) and STAT5b, but the apparent dephosphorylation activity of TC-PTP was weaker than that of cytosolic PTP1B 30 min after PRL stimulation in transfected COS-7 cells, whereas both STAT5a and STAT5b were dephosphorylated to the same extent by recombinant TC-PTP and PTP1B in vitro. Tyrosine-phosphorylated STAT5 was coimmunoprecipitated with substrate trapping mutants of TC-PTP, suggesting that STAT5 is a specific substrate of TC-PTP. These observations were further extended in mammary epithelial COMMA-1D cells stably expressing TC-PTP. A time-course study revealed that dephosphorylation of STAT5 by TC-PTP was delayed compared with that by cytosolic PTP1B due to nuclear localization of TC-PTP throughout PRL stimulation in mammary epithelial cells. Endogenous beta-casein gene expression and beta-casein gene promoter activation in COS-7 cells were largely suppressed by TC-PTP wild type as well as catalytically inactive mutants, suggesting that stable complexes formed between STAT5 and TC-PTP in the nucleus. Taken together, we conclude that TC-PTP is catalytically competent with respect to dephosphorylation and deactivation of PRL-activated STAT5 in the nucleus.

  11. Organization and partial sequence of a DNA region of the Rhizobium leguminosarum symbiotic plasmid pRL6JI containing the genes fixABC, nifA, nifB and a novel open reading frame.

    PubMed Central

    Grönger, P; Manian, S S; Reiländer, H; O'Connell, M; Priefer, U B; Pühler, A

    1987-01-01

    By hybridization and heteroduplex studies the fixABC and nifA genes of the Rhizobium leguminosarum symbiotic plasmid pRL6JI have been identified. DNA sequencing of the region containing nifA showed an open reading frame of 1557 bp encoding a protein of 56, 178 D. Based on sequence homology, this ORF was confirmed to correspond to the nifA gene. Comparison of three nifA proteins (Klebsiella pneumoniae, Rhizobium meliloti, Rhizobium leguminosarum) revealed only a weak relationship in their N-terminal regions, whereas the C-terminal parts exhibited strong homology. Sequence analysis also showed that the R. leguminosarum nifA gene is followed by nifB and preceded by fixC with an open reading frame inserted in between. This novel ORF of 294 bp was found to be highly conserved also in R. meliloti. No known promoter and termination signals could be defined on the sequenced R. leguminosarum fragment. Images PMID:3029674

  12. Price-Responsive Load (PRL) Program - Framing Paper No.1

    SciTech Connect

    Goldman, Charles A.

    2002-03-01

    By definition, effective and efficient competitive markets need a supply side and a demand side. One criticism of electric restructuring efforts in many states is that most of the attention has been focused on the supply side, in a market focused on the short term. In general, the demand side of the market has been under-addressed. The objective of the New England Demand Response Initiative (NEDRI) is to develop a comprehensive, coordinated set of demand response programs for the New England regional power markets. NEDRI aims to maximize the capability of demand response to compete in the wholesale market and to improve the economic efficiency and environmental profile of the electric sector. To those ends, NEDRI is focusing its efforts in four interrelated areas: (1) ISO-level reliability programs, (2) Market-based price-responsive load programs, (3) Demand response at retail through pricing, rate design, and advanced metering, and (4) End-use energy efficiency resources as demand response. The fourth area, energy efficiency, is the subject of this framing paper. Energy efficiency reduces the energy used by specific end-use devices and systems, typically without affecting the level of service and without loss of amenity. Energy savings and peak load reductions are achieved by substituting technically more advanced equipment, processes, or operational strategies to produce the same or an improved level of end-use service with less electricity. In contrast, load management programs lower peak demand during specific, limited time periods by either (1) influencing the timing of energy use by shifting load to another time period, or (2) reducing the level of energy use by curtailing or interrupting the load, typically with some loss of service or amenity.

  13. PRL S-030A Verification Survey at Former McClellan AFB, Sacramento, CA

    DTIC Science & Technology

    2013-03-25

    contractor had completed the majority of the excavation of contaminated soils from the site. Radium -226 was the sole radionuclide of concern. Cabrera...of Aerospace Medicine (USAFSAM), former McClellan AFB, radium -226, verification survey, final status survey, independent radiological assessment 16...majority of the excavation of contaminated soils from the site. Radium -226 (Ra-226) was the sole radionuclide of concern. Cabrera Services, Inc

  14. 321 B North and PRL-S006 Verification Surveys at Former McClellan AFB, Sacramento, CA

    DTIC Science & Technology

    2013-01-22

    remediation and after the contractor had completed its Final Status Survey (FSS) sampling. Radium -226 was the sole radionuclide of concern...Medicine (USAFSAM), former McClellan AFB, radium -226, verification survey, final status survey, independent radiological assessment 16. SECURITY...after the contractor had completed its Final Status Survey (FSS) sampling. Radium -226 (Ra-226) was the sole radionuclide of concern. Environmental

  15. Driving with Central Visual Field Loss II: How Scotomas above or below the Preferred Retinal Locus (PRL) Affect Hazard Detection in a Driving Simulator

    PubMed Central

    Bowers, Alex R.; Goldstein, Robert; Peli, Eli

    2015-01-01

    We determined whether binocular central scotomas above or below the preferred retinal locus affect detection of hazards (pedestrians) approaching from the side. Seven participants with central field loss (CFL), and seven age-and sex-matched controls with normal vision (NV), each completed two sessions of 5 test drives (each approximately 10 minutes long) in a driving simulator. Participants pressed the horn when detecting pedestrians that appeared at one of four eccentricities (-14°, -4°, left, 4°, or 14°, right, relative to car heading). Pedestrians walked or ran towards the travel lane on a collision course with the participant’s vehicle, thus remaining in the same area of the visual field, assuming participant's steady forward gaze down the travel lane. Detection rates were nearly 100% for all participants. CFL participant reaction times were longer (median 2.27s, 95% CI 2.13 to 2.47) than NVs (median 1.17s, 95%CI 1.10 to 2.13; difference p<0.01), and CFL participants would have been unable to stop for 21% of pedestrians, compared with 3% for NV, p<0.001. Although the scotomas were not expected to obscure pedestrian hazards, gaze tracking revealed that scotomas did sometimes interfere with detection; late reactions usually occurred when pedestrians were entirely or partially obscured by the scotoma (time obscured correlated with reaction times, r = 0.57, p<0.001). We previously showed that scotomas lateral to the preferred retinal locus delay reaction times to a greater extent; however, taken together, the results of our studies suggest that any binocular CFL might negatively impact timely hazard detection while driving and should be a consideration when evaluating vision for driving. PMID:26332315

  16. Driving with Central Visual Field Loss II: How Scotomas above or below the Preferred Retinal Locus (PRL) Affect Hazard Detection in a Driving Simulator.

    PubMed

    Bronstad, P Matthew; Albu, Amanda; Bowers, Alex R; Goldstein, Robert; Peli, Eli

    2015-01-01

    We determined whether binocular central scotomas above or below the preferred retinal locus affect detection of hazards (pedestrians) approaching from the side. Seven participants with central field loss (CFL), and seven age-and sex-matched controls with normal vision (NV), each completed two sessions of 5 test drives (each approximately 10 minutes long) in a driving simulator. Participants pressed the horn when detecting pedestrians that appeared at one of four eccentricities (-14°, -4°, left, 4°, or 14°, right, relative to car heading). Pedestrians walked or ran towards the travel lane on a collision course with the participant's vehicle, thus remaining in the same area of the visual field, assuming participant's steady forward gaze down the travel lane. Detection rates were nearly 100% for all participants. CFL participant reaction times were longer (median 2.27s, 95% CI 2.13 to 2.47) than NVs (median 1.17s, 95%CI 1.10 to 2.13; difference p<0.01), and CFL participants would have been unable to stop for 21% of pedestrians, compared with 3% for NV, p<0.001. Although the scotomas were not expected to obscure pedestrian hazards, gaze tracking revealed that scotomas did sometimes interfere with detection; late reactions usually occurred when pedestrians were entirely or partially obscured by the scotoma (time obscured correlated with reaction times, r = 0.57, p<0.001). We previously showed that scotomas lateral to the preferred retinal locus delay reaction times to a greater extent; however, taken together, the results of our studies suggest that any binocular CFL might negatively impact timely hazard detection while driving and should be a consideration when evaluating vision for driving.

  17. Changes in biomarkers of the nitrooxidative stress response and Prolactin (PRL) signal transduction elements (STE) to E. coli infection (INFec) in the mammary gland (MG)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Key features of the MG response to INFec include (a) the cellular generation of reactive oxynitrogen molecules (Roxn) derived from nitric oxide (NO) and superoxide anion (SO) and (b) loss of responsiveness to lactogenic hormone signaling. Of significance to the MG is the damage done to mammary epit...

  18. Completion of One Year Bioventing Tests: Tank Farm #2; Tank Form #4; SA-6; PRL-T46; Davis Global Communications

    DTIC Science & Technology

    2007-11-02

    conducted to give a qualitative indication of changes in contaminant mass at each site within the Bioventing Initiative. Soil gas samples are somewhat...volatile contaminant mass (See Addendum One to Test Plan and Technical Protocol for a Field Treatability Test for Bioventing - Using Soil Gas Surveys...to Determine Bioventing Feasibility and Natural Attenuation Potential, February 1994). Soil samples, on the other hand, are discrete point samples

  19. Discovery of conventional prolactin from the holocephalan elephant fish, Callorhinchus milii.

    PubMed

    Yamaguchi, Yoko; Takagi, Wataru; Kuraku, Shigehiro; Moriyama, Shunsuke; Bell, Justin D; Seale, Andre P; Lerner, Darren T; Grau, E Gordon; Hyodo, Susumu

    2015-12-01

    The conventional prolactin (PRL), also known as PRL1, is an adenohypophysial hormone that critically regulates various physiological events in reproduction, metabolism, growth, osmoregulation, among others. PRL1 shares its evolutionary origin with PRL2, growth hormone (GH), somatolactin and placental lactogen, which together form the GH/PRL hormone family. Previously, several bioassays implied the existence of PRL1 in elasmobranch pituitaries. However, to date, all attempts to isolate PRL1 from chondrichthyans have been unsuccessful. Here, we cloned PRL1 from the pituitary of the holocephalan elephant fish, Callorhinchus milii, as the first report of chondrichthyan PRL1. The putative mature protein of elephant fish PRL1 (cmPRL1) consists of 198 amino acids, containing two conserved disulfide bonds. The orthologous relationship of cmPRL1 to known vertebrate PRL1s was confirmed by the analyses of molecular phylogeny and gene synteny. The cmPRL1 gene was similar to teleost PRL1 genes in gene synteny, but was distinct from amniote PRL1 genes, which most likely arose in an early amphibian by duplication of the ancestral PRL1 gene. The mRNA of cmPRL1 was predominantly expressed in the pituitary, but was considerably less abundant than has been previously reported for bony fish and tetrapod PRL1s; the copy number of cmPRL1 mRNA in the pituitary was less than 1% and 0.1% of that of GH and pro-opiomelanocortin mRNAs, respectively. The cells expressing cmPRL1 mRNA were sparsely distributed in the rostral pars distalis. Our findings provide a new insight into the studies on molecular and functional evolution of PRL1 in vertebrates.

  20. Administration of Additional Phosphorylated Prolactin During Pregnancy Inhibits Mammary Ductal Branching and Promotes Premature Lobuloalveolus Development

    DTIC Science & Technology

    2002-07-01

    promotes differentiation. Further, we have demonstrated that these effects of U-PRL and S179D PRL are produced directly on the mammary gland. In...addition, we have been able to show that U-PRL and S179D PRL exert these very different effects by changing the balance of signaling between the two major

  1. 77 FR 5070 - Self-Regulatory Organizations; Chicago Mercantile Exchange, Inc.; Notice of Filing of Proposed...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-01

    ... potential residual loss (``PRL'') and the 90-day trailing average gross notional open interest outstanding... trailing average of such Clearing Member's PRL performance bond requirement (95% weight) and its average... Guaranty Fund Contribution PRL Component--95% weight Total average aggregate CDS $10,000,000,000 PRL...

  2. Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain.

    PubMed

    Patil, Mayur J; Ruparel, Shivani B; Henry, Michael A; Akopian, Armen N

    2013-11-01

    Prolactin (PRL) is a hormone produced in the anterior pituitary but also synthesized extrapituitary where it can influence diverse cellular processes, including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sex-dependent inflammatory pain is unknown. We found that PRL regulates transient receptor potential (TRP) channels in a sex-dependent manner in sensory neurons. At >20 ng/ml, PRL sensitizes TRPV1 in female, but not male, neurons. This effect is mediated by PRL receptor (PRL-R). Likewise, TRPA1 and TRPM8 were sensitized by 100 ng/ml PRL only in female neurons. We showed that complete Freund adjuvant (CFA) upregulated PRL levels in the inflamed paw of both male and female rats, but levels were higher in females. In contrast, CFA did not change mRNA levels of long and short PRL-R in the dorsal root ganglion or spinal cord. Analysis of PRL and PRL-R knockout (KO) mice demonstrated that basal responses to cold stimuli were only altered in females, and with no significant effects on heat and mechanical responses in both sexes. CFA-induced heat and cold hyperalgesia were not changed in PRL and PRL-R KO compared with wild-type (WT) males, whereas significant reduction of heat and cold post-CFA hyperalgesia was detected in PRL and PRL-R KO females. Attenuation of CFA-induced mechanical allodynia was observed in both PRL and PRL-R KO females and males. Thermal hyperalgesia in PRL KO females was restored by administration of PRL into hindpaws. Overall, we demonstrate a sex-dependent regulation of peripheral inflammatory hyperalgesia by the PRL system.

  3. Biological and binding activities of ovine and porcine prolactins in porcine mammary tissue

    SciTech Connect

    Jerry, D.J.

    1987-01-01

    The concentration of prolactin receptors may play a critical role in regulating growth and development of the mammary gland during gestation and tumor development; however, the discrepancy between specific binding of ovine prolactin (oPRL) and porcine prolactin (pPRL) in porcine mammary tissue was disturbing. It was possible that /sup 125/I-oPRL may be an unsuitable ligand for the procine prolactin receptor. The validate the use of oPRL in binding assays, the biological and binding activities of oPRL and pPRL were compared. A lactogenic bioassay of pPRL was developed using porcine mammary explants cultured in Medium 199 containing insulin, cortisol, and pPRL. The potencies of oPRL and pPRL were compared using this bioassay. Oxidation of glucose and incorporation of glucose into lipids were similarly enhanced by physiological concentrations of both oPRL and pPRL. However, specific binding of /sup 125/I-oPRL was 20%, while less than 1% of /sup 125/I-pPRL was bound. /sup 125/I-oPRL bound to high affinity sites.

  4. A study of the effect of the thyrotropin-releasing hormone metabolite, histidyl-proline diketopiperazine, on prolactin secretion in vivo.

    PubMed

    Emerson, C H; Alex, S; Braverman, L E; Safran, M S

    1981-11-01

    TRH, a PRL secretogogue, is metabolized to histidyl-proline diketopiperazine (HPD) in brain and plasma. HPD has been reported to inhibit PRL secretion in vitro. In the present study, intravascular pulse injections or infusions of HPD were carried out in the rat to determine whether HPD affected 1) TRH-induced PRL secretion, 2) the PRL proestrous surge, 3) the PRL surge in the ovariectomized, estrogen-primed rat and 4) pimozide-induced hyperprolactinemia. HPD had no effect on TRH-induced PRL secretion in estrogen-primed male rats when administered in molar ratios of 1:1.5 to 1:150 (TRH:HPD). The infusion of 1 microgram/min HPD for 360 min to rats before and during the proestrous PRL surge did not inhibit or augment PRL secretion, nor was there any influence of pulse injections of HPD on PRL secretion during the proestrous surge. HPD did not influence spontaneous PRL surges in the ovariectomized estrogen-primed rat. Finally, HPD, given with pimozide and again 2 days later, did not influence the PRL surge after pimozide administration or the elevated serum PRL concentrations noted 2 days after pimozide treatment. Despite the promising in vitro data demonstrating that the TRH metabolite, HPD, has PRL inhibitory factor activity, this study does not support the concept that HPD is a physiological PRL inhibitory factor.

  5. Gene expression of lymphocyte prolactin receptor was suppressed in lactating mothers.

    PubMed

    Maeda, Hironobu; Izumi, Shun-ichiro; Kato, Yukio; Cai, Li-yi; Kato, Takako; Suzuki, Takahiro; Nakamura, Eri; Sugiyama, Taro; Fuda, Takayo; Takahashi, Kazumi; Kondo, Akane; Matsumoto, Tadashi; Ishimoto, Hitoshi

    2010-07-20

    Prolactin (PRL) receptor (PRL-R) was proven to be ubiquitously expressed by cells in the immune system, while the physiological role of PRL was established in milk production in mammary glands. We analyzed the mRNA content of PRL-R in human lymphocytes in normo- and hyperprolactinemic conditions to document the presence of functioning PRL-R of human lymphocytes. Blood samples were obtained prior to treatment, and with written informed consent, from outpatients with ovarian dysfunction and hyperprolactinemia (n = 8; 19 ~ 41 y/o), from breast-feeding mothers after normal delivery (n = 12; 27 ~ 36 y/o), and from healthy volunteers: men (n = 9; 33 ~ 40 y/o) and women (n = 9; 26 ~ 36 y/o). Subsequently, total RNA was prepared from the lymphocytes separated. The quantity of PRL-R mRNA was examined by reverse transcription and polymerase chain reaction and normalized with a simultaneously measured amount of b actin. The resultant mRNA level of PRL-R was analyzed for its correlation with serum concentration of PRL measured by immunoassay. PRL-R mRNA levels of lymphocytes were significantly suppressed in lactating mothers, while there was a statistically significant negative correlation between PRL-R mRNA and serum PRL levels. However, there was no significant difference of PRL-R mRNA in the pathological condition of outpatients with ovarian dysfunction and/or hyperprolactinemia. While a few investigators reported the extra-mammary regulation on PRL-R by PRL, our data suggest that the PRL-R levels of circulating lymphocytes could be down-regulated by the elevated serum levels of PRL and that pituitary PRL may participate in regulating the expression of PRL-R genes on cells of the human immune system, especially in physiological circumstances such as in the postpartum period.

  6. Prolactin receptor and signal transduction to milk protein genes

    SciTech Connect

    Djiane, J.; Daniel, N.; Bignon, C.

    1994-06-01

    After cloning of the mammary gland prolactin (PRL) receptor cDNA, a functional assay was established using co-transfection of PRL receptor cDNA together with a milk protein promoter/chloramphenicol acetyl transferase (CAT) construct in Chinese hamster ovary (CHO) cells. Different mutants of the PRL receptor were tested in this CAT assay to delimit the domains in the receptor necessary for signal transduction to milk protein genes. In CHO cells stably transfected with PRL receptor cDNA, high numbers of PRL receptor are expressed. By metabolic labeling and immunoprecipitation, expressed PRL receptor was identified as a single species of 100 kDa. Using these cells, we analyzed the effects of PRL on intracellular free Ca{sup ++} concentration. PRL stimulates Ca{sup ++} entry and induces secondary Ca{sup ++} mobilization. The entry of Ca{sup ++} is a result of an increase in K{sup +} conductance that hyperpolarizes the membranes. We have also analyzed tyrosine phosphorylation induced by PRL. In CHO cells stably transfected with PRL receptor cDNA, PRL induced a very rapid and transient tyrosine phosphorylation of a 100-kDa protein which is most probably the PRL receptor. The same finding was obtained in mammary membranes after PRL injection to lactating rabbits. Whereas tyrosine kinase inhibitors genistein and lavendustin were without effect, PRL stimulation of milk protein gene promoters was partially inhibited by 2 {mu}M herbimycin in CHO cells co-transfected with PRL receptor cDNA and the {Beta} lactoglobulin CAT construct. Taken together these observations indicate that the cytoplasmic domain of the PRL receptor interacts with one or several tyrosine kinases, which may represent early postreceptor events necessary for PRL signal transduction to milk protein genes. 14 refs., 4 figs.

  7. The orphan nuclear receptor Nur77 regulates decidual prolactin expression in human endometrial stromal cells

    SciTech Connect

    Jiang, Yue; Hu, Yali; Zhao, Jing; Zhen, Xin; Yan, Guijun; Sun, Haixiang

    2011-01-14

    Research highlights: {yields} Decidually produced PRL plays a key role during pregnancy. {yields} Overexpression of Nur77 increased PRL mRNA expression and enhanced decidual PRL promoter activity. {yields} Knockdown of Nur77 decreased decidual PRL secretion induced by 8-Br-cAMP and MPA. {yields} Nur77 is a novel transcription factor that plays an active role in decidual prolactin expression. -- Abstract: Prolactin (PRL) is synthesized and released by several extrapituitary tissues, including decidualized stromal cells. Despite the important role of decidual PRL during pregnancy, little is understood about the factors involved in the proper regulation of decidual PRL expression. Here we present evidence that the transcription factor Nur77 plays an active role in decidual prolactin expression in human endometrial stromal cells (hESCs). Nur77 mRNA expression in hESCs was significantly increased after decidualization stimulated by 8-Br-cAMP and medroxyprogesterone acetate (MPA). Adenovirus-mediated overexpression of Nur77 in hESCs markedly increased PRL mRNA expression and enhanced decidual PRL promoter (dPRL/-332Luc) activity in a concentration-dependent manner. Furthermore, knockdown of Nur77 in hESCs significantly decreased decidual PRL promoter activation and substantially attenuated PRL mRNA expression and PRL secretion (P < 0.01) induced by 8-Br-cAMP and MPA. These results demonstrate that Nur77 is a novel transcription factor that contributes significantly to the regulation of prolactin gene expression in human endometrial stromal cells.

  8. Prolactin Family of the Guinea Pig, Cavia porcellus

    PubMed Central

    Alam, S. M. Khorshed; Konno, Toshihiro; Rumi, M. A. Karim; Dong, Yafeng; Weiner, Carl P.; Soares, Michael J.

    2010-01-01

    Prolactin (PRL) is a multifunctional hormone with prominent roles in regulating growth and reproduction. The guinea pig (Cavia porcellus) has been extensively used in endocrine and reproduction research. Thus far, the PRL cDNA and protein have not been isolated from the guinea pig. In the present study, we used information derived from the public guinea pig genome database as a tool for identifying guinea pig PRL and PRL-related proteins. Guinea pig PRL exhibits prominent nucleotide and amino acid sequence differences when compared with PRLs of other eutherian mammals. In contrast, guinea pig GH is highly conserved. Expression of PRL and GH in the guinea pig is prominent in the anterior pituitary, similar to known expression patterns of PRL and GH for other species. Two additional guinea pig cDNAs were identified and termed PRL-related proteins (PRLRP1, PRLRP2). They exhibited a more distant relationship to PRL and their expression was restricted to the placenta. Recombinant guinea pig PRL protein was generated and shown to be biologically active in the PRL-responsive Nb2 lymphoma cell bioassay. In contrast, recombinant guinea pig PRLRP1 protein did not exhibit PRL-like bioactivity. In summary, we have developed a new set of research tools for investigating the biology of the PRL family in an important animal model, the guinea pig. PMID:20534723

  9. Molecular cloning of giant panda pituitary prolactin cDNA and its expression in Escherichia coli.

    PubMed

    Zhang, Zhi-He; Zheng, Xu; Hu, Xi-lian; Zhu, Mu-Yuan; Hou, Rong; Shen, Fu-Jun; Zhang, Liang; Liao, Ming-Juan; Lv, Xiao-Ping

    2005-01-01

    cDNA encoding pituitary (PRL) of giant panda was obtained using RT-PCR and expressed in E. coli. The results revealed that panda PRL cDNA encodes a precursor protein of 229 amino acids including a putative signal peptide of 30 amino acids and a mature protein of 199 residues with one potential N-glycosylation site. Sequence comparison indicated that panda PRL shares a high degree of identity to other known PRL sequences ranging from 98% with mink PRL to about 50% with rodent PRL. Six cysteine residues and 29 conserved residues distributed in four domains (PD1, PD2, PD3, and PD4) of PRL were observed. through multiple sequence alignment. Fourteen key residues of binding sites 1 and 2 involved in receptor binding are conserved in panda PRL. GST fused recombinant panda PRL protein was efficiently expressed with the form of insoluble inclusion bodies in E. coli BL21 transformed with a pGEX-4T-1 expression vector containing the DNA sequence encoding mature panda PRL. Western blot analysis indicated that GST-panda PRL recombinant protein could be recognized by antibody against human PRL. Our results would contribute to further elucidating the structural and functional characteristics of pituitary PRL and provide a basis for the production of recombinant panda prolactin for future use in the breeding of giant panda.

  10. Isolated Prolactin Deficiency Associated With Serum Autoantibodies Against Prolactin-Secreting Cells

    PubMed Central

    Iwama, Shintaro; Welt, Corrine K.; Romero, Christopher J.; Radovick, Sally

    2013-01-01

    Context: Isolated prolactin (PRL) deficiency is a rare entity of unknown etiology manifesting as failure of puerperal lactogenesis. Objective: The aim of the study was to determine the cause of isolated PRL deficiency in an affected woman. Design and Setting: We examined genetic and autoimmune causes of isolated PRL deficiency at academic medical centers. Patient: The patient was a 39-year-old woman with puerperal alactogenesis after two deliveries and undetectable PRL. The other pituitary axes, serum calcium levels, and cranial magnetic resonance imaging were normal. Intervention: Recombinant human PRL (r-hPRL) was administered to the patient. Main Outcome Measures: We measured the sequencing of candidate genes and immunofluorescence analysis of autoantibodies directed against pituitary endocrine cells. Results: There were no rare sequence variants in the genes encoding for PRL, putative PRL-releasing peptide, putative PRL-releasing peptide receptor, or in other genes important for lactotroph lineage development (POU1F1, PROP1, LHX3, LHX4, HESX1, OTX2, and LSD1). The patient serum, on the contrary, contained autoantibodies that specifically recognized a subset of PRL-secreting cells but not PRL itself or any other pituitary cells or hormones. The mother was able to lactate fully after 17 days of treatment with r-hPRL 60 μg/kg every 12 hours, but alactogenesis resumed after treatment was completed. Conclusions: These studies report a new autoimmune etiology for women with isolated PRL deficiency and puerperal alactogenesis. PMID:23940128

  11. 75 FR 53734 - Patriot Rail, LLC, Patriot Rail Holdings LLC, and Patriot Rail Corp.-Continuance in Control...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-01

    ... Exemption--Piedmont & Northern Railway, Inc. Patriot Rail, LLC (PRL) and its subsidiaries, Patriot Rail... carrier.\\1\\ \\1\\ PRL is a noncarrier limited liability company that owns not less than 51% of the...

  12. Dopaminergic control of prolactin mRNA accumulation in the pituitary of the male rat.

    PubMed

    Brocas, H; van Coevorden, A; Seo, H; Refetoff, S; Vassart, G

    1981-04-01

    Dopaminergic control of the expression of the prolactin gene was investigated by administration of bromoergocryptine (CB154) to male rats. The effects of the drug on the following parameters were measured: (i) circulating levels of GH and PRL; (ii) synthesis of GH and PRl measured by pulse labeling pituitary fragments in vitro; (iii) GH and PRL mRNA activities; and (iv) content of PRL and mRNA. After 1 day of CB154 administration, serum PRL fell to undetectable levels whereas it took 3 days to observe a 50% reduction in PRL synthesis. This effect was accounted for by a parallel decrease in PRL mRNA activity and content. GH synthesis and GH mRNA were not affected by the treatment. Our results show that the dopaminergic inhibition of PRL production involves regulation at a pre-translational level.

  13. A major prolactin-binding complex on human milk fat globule membranes contains cyclophilins A and B: the complex is not the prolactin receptor.

    PubMed

    Lorenson, Mary Y; Ueda, Eric K; Chen, KuanHui E; Walker, Ameae M

    2012-03-01

    Prolactin (PRL) in milk influences maturation of gastrointestinal epithelium and development of both the hypothalamo-pituitary and immune systems of offspring. Here, we demonstrate that most PRL in human milk is part of a novel, high-affinity, multicomponent binding complex found on the milk fat globule membrane and not in whey. To examine properties of the complex, a sensitive ELISA was developed such that human PRL (hPRL) binding to the complex was measured by loss of hPRL detectability; thus, as much as 50 ng of hPRL was undetectable in the presence of 10 μl of human milk. Using the same methodology, no comparable complex formation was observed with human serum or amniotic fluid. hPRL complexation in milk was rapid, time dependent, and cooperative. Antibodies to or competitors of the hPRL receptor (placental lactogen and growth hormone) showed the hPRL receptor was not involved in the complex. However, hPRL complexation was antagonized by cyclosporine A and anti-cyclophilins. The complex was very stable, resisting dissociation in SDS, urea, and dithiothreitol. Western analysis revealed an ∼75-kDa complex that included hPRL, cyclophilins A and B, and a 16-kDa cyclophilin A. Compared with noncomplexed hPRL, complexed hPRL in whole milk showed similar activation of STAT5 but markedly delayed activation of ERK. Alteration of signaling suggests that complex formation may alter hPRL biological activity. This is the first report of a unique, multicomponent, high-capacity milk fat reservoir of hPRL; all other analyses of milk PRL have utilized defatted milk.

  14. Prolactin regulates transcription of the ion uptake Na+/Cl- cotransporter (ncc) gene in zebrafish gill

    USGS Publications Warehouse

    Breves, Jason P.; Serizier, Sandy B.; Goffin, Vincent; McCormick, Stephen D.; Karlstrom, Rolf O.

    2013-01-01

    Prolactin (PRL) is a well-known regulator of ion and water transport within osmoregulatory tissues across vertebrate species, yet how PRL acts on some of its target tissues remains poorly understood. Using zebrafish as a model, we show that ionocytes in the gill directly respond to systemic PRL to regulate mechanisms of ion uptake. Ion-poor conditions led to increases in the expression of PRL receptor (prlra), Na+/Cl− cotransporter (ncc; slc12a10.2), Na+/H+ exchanger (nhe3b; slc9a3.2), and epithelial Ca2+ channel (ecac; trpv6) transcripts within the gill. Intraperitoneal injection of ovine PRL (oPRL) increased ncc and prlra transcripts, but did not affect nhe3b or ecac. Consistent with direct PRL action in the gill, addition of oPRL to cultured gill filaments stimulated ncc in a concentration-dependent manner, an effect blocked by a pure human PRL receptor antagonist (Δ1-9-G129R-hPRL). These results suggest that PRL signaling through PRL receptors in the gill regulates the expression of ncc, thereby linking this pituitary hormone with an effector of Cl− uptake in zebrafish for the first time.

  15. MATERNAL EXPOSURE TO ATRAZINE DURING LACTATION SUPPRESSES SUCKLING-INDUCED PROLACTIN RELEASE AND RESULTS IN PROSTATITIS IN THE ADULT OFFSPRING

    EPA Science Inventory

    The availability of prolactin (PRL) to the neonatal brain is known to affect the development of the tuberoinfundibular (TIDA) neurons and, as a consequence, lead to alterations in subsequent PRL regulation. Without early lactational exposure to PRL (derived from the dam's milk), ...

  16. Acute effect of prolactin on ornithine decarboxylase activity in the rat testis.

    PubMed

    de Las Heras, M A; Calandra, R S

    1992-01-01

    A study was conducted to evaluate the effect of the acute treatment with prolactin (PRL) on ornithine decarboxylase (ODC) activity in the rat testis. Injection of a single SC dose of ovine PRL to puberal rats resulted in the activation of ODC from whole testis. This effect was maximal at 4 h after injection, and statistically significant at the dose of 500 micrograms. The effect of PRL was confined to the interstitial space; no change was observed in seminiferous tubules. PRL was unable to further increase testicular ODC activity when injected together with a stimulatory dose of human chorionic gonadotropin (hCG). The effect of PRL was mimicked by injection of a single dose of the dopamine antagonist sulpiride, which provoked a ninefold increase in serum PRL levels. In contrast, PRL did not stimulate testicular ODC activity in hypophysectomized rats, either under basal conditions or during treatment with PRL-hCG, indicating the requirement of a functional hypophysis for the expression of PRL action. These results suggest that the stimulation of testicular ODC activity by PRL is a marker of the trophic response of the testis to this hormone, different from the stimulation of steroidogenesis. This activity could be useful for the study of PRL action on the testis as well as of the interaction between PRL and LH at the testicular level.

  17. 75 FR 45185 - Self-Regulatory Organizations; New York Stock Exchange LLC and NYSE Amex LLC; Order Approving...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-02

    ... that executes odd-lot interest and the odd-lot portion of ``part of round lot'' or ``PRL'' interest... Odd-lot Systems, all odd-lot interest and the odd-lot portion of PRL interest is executed against the... portion of PRL interest would be accepted and executed in the Display Book, enabling such interest...

  18. Heat stress abatement during the dry period influences prolactin signaling in lymphocytes Heat stress abatement during the dry period influences prolactin signaling in lymphocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heat stress perturbs PRL release and affects dairy cow lactational performance and immune cell function. We hypothesized that greater PRL concentration in plasma of heat-stressed cows would decrease expression of PRL-R mRNA and increase mRNA expression of suppressors of cytokine signaling (SOCS) in ...

  19. 75 FR 76520 - Tennessee Southern Railroad Company, Patriot Rail, LLC, Patriot Rail Holdings LLC, and Patriot...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-08

    ... (PRL) and its subsidiaries, Patriot Rail Holdings LLC (PRH) and Patriot Rail Corp. (Patriot... within a corporate family. PRL proposes to restructure its corporate family by converting two of its...) will become Piedmont & Northern Railway, LLC (PNRLLC). PRL directly controls noncarrier PRH, which...

  20. Relative prolactin-to-progesterone concentrations around farrowing influence colostrum yield in primiparous sows.

    PubMed

    Loisel, F; Farmer, C; van Hees, H; Quesnel, H

    2015-10-01

    In swine, colostrum production is induced by the drop of progesterone (P4) concentrations which leads to the prepartum peak of prolactin (PRL). PRL regulates mammary cell turnover and stimulates lacteal nutrient synthesis. P4 inhibits PRL secretion and downregulates the PRL receptor in the mammary gland. The aim of the present study was to determine if the relative prepartum concentrations of P4 and PRL (PRL/P4 ratio) influence sow colostrum production. The performance of 29 Landrace × Large White primiparous sows was analyzed. Colostrum yield was estimated during 24 h starting at the onset of parturition (T0) using litter weight gains. Colostrum was collected at T0 and 24 h later (T24). Repeated jugular blood samples were collected during the peripartum period, that is, from -72 to +24 h related to farrowing and were assayed for P4 and PRL. Sows were retrospectively categorized in 2 groups according to their PRL/P4 ratio 24 h before farrowing being either <2 (low PRL/P4, n = 16) or >3 (high PRL/P4, n = 13). During the peripartum period, the circulating concentrations of P4 were lower (P < 0.05) and those of PRL tended to be greater (P < 0.10) in high PRL/P4 compared with low PRL/P4 sows. Colostrum yield was greater in high PRL/P4 compared with low PRL/P4 sows (4.11 vs 3.48 kg [root mean square error = 0.69], P < 0.05). Colostrum composition (dry matter, energy, protein, lipid, and lactose contents) and IgG and IgA concentrations did not differ between the 2 groups of sows (P > 0.10). The Na/K ratio in colostrum 24 h after the onset of farrowing was lower in high PRL/P4 compared with low PRL/P4 sows (P < 0.05). Piglet mortality between birth and T24 averaged 10.0% in low PRL/P4 litters and 7.0% in high PRL/P4 litters (P = 0.29). In conclusion, a greater PRL/P4 ratio 24 h prepartum, characterized by lower P4 concentrations and a trend for greater PRL concentrations peripartum, led to increased colostrum yield in primiparous sows.

  1. Prolactin receptor attenuation induces zinc pool redistribution through ZnT2 and decreases invasion in MDA-MB-453 breast cancer cells

    SciTech Connect

    Bostanci, Zeynep; Alam, Samina; Soybel, David I.; Kelleher, Shannon L.

    2014-02-15

    Prolactin receptor (PRL-R) activation regulates cell differentiation, proliferation, cell survival and motility of breast cells. Prolactin (PRL) and PRL-R over-expression are strongly implicated in breast cancer, particularly contributing to tumor growth and invasion in the more aggressive estrogen-receptor negative (ER−) disease. PRL-R antagonists have been suggested as potential therapeutic agents; however, mechanisms through which PRL-R antagonists exert their actions are not well-understood. Zinc (Zn) is a regulatory factor for over 10% of the proteome, regulating critical cell processes such as proliferation, cell signaling, transcription, apoptosis and autophagy. PRL-R signaling regulates Zn metabolism in breast cells. Herein we determined effects of PRL-R attenuation on cellular Zn metabolism and cell function in a model of ER-, PRL-R over-expressing breast cancer cells (MDA-MB-453). PRL-R attenuation post-transcriptionally increased ZnT2 abundance and redistributed intracellular Zn pools into lysosomes and mitochondria. ZnT2-mediated lysosomal Zn sequestration was associated with reduced matrix metalloproteinase 2 (MMP-2) activity and decreased invasion. ZnT2-mediated Zn accumulation in mitochondria was associated with increased mitochondrial oxidation. Our results suggest that PRL-R antagonism in PRL-R over-expressing breast cancer cells may reduce invasion through the redistribution of intracellular Zn pools critical for cellular function. - Highlights: • PRL-R attenuation increased ZnT2 expression. • PRL-R attenuation increased lysosomal and mitochondrial Zn accumulation. • PRL-R attenuation decreased MMP-2 and invasion. • PRL-R antagonists may modulate lysosomal and mitochondrial Zn pools.

  2. Cysteamine, zinc, and thiols modify detectability of rat pituitary prolactin: a comparison with effects on bovine prolactin suggests differences in hormone storage

    SciTech Connect

    Jacobs, L.S.; Lorenson, M.Y.

    1986-03-01

    Little is known about the structure of prolactin (PRL) within secretory granules. Evidence from our previous studies in bovine tissue preparations suggests that control of secretion may reside, in part, in the conversion of storage hormone to releasable PRL. The conversion can be monitored by measuring changes in immunodetectability since the oligomeric, storage form is poorly recognized by antisera raised against monomeric PRL. Since many investigators use rats to study the secretory process and changes in detectability of rat pituitary PRL occur during lactation (depletion-transformation), we undertook the present immunodetectability studies to gain insight into the storage structure of rat (r) PRL. Cysteamine and zinc inhibited tissue PRL immunoassayability in male rat pituitary homogenates and also in partially purified secretory granules as they had inhibited bovine (b) PRL; however, zinc inhibited the rodent hormone less potently than the bovine. In vitro incubation of rat tissue samples without additions resulted in increases in rPRL detectability of up to 84% after 180 minutes; such incubation of bovine samples had no significant effect. A striking additional difference between the species was that exposure to reduced glutathione (GSH), cysteine, homocysteine, mercaptoethanol, and dithiothreitol inhibited rPRL by up to 44%. This compared to thiol stimulation of bPRL by as much as 450%. The inhibitory GSH effect on rPRL was abolished when 0.5% sodium dodecyl sulfate (SDS) was included; in contrast, the stimulatory GSH effect on bPRL did not change with added SDS. SDS alone had no effect on rat homogenate PRL, and only increased rat granule rPRL by 23% compared to its ability to increase bPRL assayability by 44%.

  3. Prolactin messenger ribonucleic acid levels, prolactin synthesis, and radioimmunoassayable prolactin during the estrous cycle in the Golden Syrian hamster

    SciTech Connect

    Massa, J.S. ); Blask, D.E. )

    1990-01-01

    The purpose of this study was to observe the molecular dynamics of pituitary prolactin (PRL) gene expression during the estrous cycle of the Golden Syrian hamster. PRL messenger ribonucleic acid (mRNA) levels, PRL synthesis were measured in the morning on each day of the cycle. We observed that all of these PRL indices declined or did not change from Day 2 to Day 3 of the cycle. From Day 3 to Day 4 however, PRL mRNA levels increased 33-38% and media {sup 3}H-PRL increased 32-42%, while there were no significant changes in pituitary {sup 3}H-PRL, or RIA-PRL in the media or pituitary. From Day 4 to Day 1 (estrus) there was reciprocal change in the levels of {sup 3}H-PRL in the pituitary vs. the media, with the former increasing 37-50% and the latter decreasing 25-32%. Pituitary RIA-PRL did also increased 45-64% from Day 4 to Day 1 while media RIA-PRL did not change. These data are consistent with the following hypothesis: On the morning of proestrus(Day 4) in the hamster, PRL mRNA levels are elevated compared to those on Day 3, signaling an increase in PRL synthesis. This newly synthesized PRL is shunted into a readily releasable pool on the morning of Day 4 (contributing to the afternoon surge of serum PRL), and into a preferentially stored pool by the morning of Day 1.

  4. Prolactin messenger ribonucleic acid concentrations throughout the ovine estrous cycle: Assessment relative to prolactin serum and pituitary amounts

    SciTech Connect

    Landefeld, T.; Roulia, V.; Bagnell, T.; Ballard, T.; Levitan, I. )

    1991-01-01

    Prolactin (PRL) mRNA concentrations were assessed by nucleic acid hybridization assays in pituitaries of ewes representing the defined stages of the ovine estrous cycle. Concomitantly, pituitary and serum PRL concentrations were measured in these ewes using radioimmunoassays. It was observed that PRL serum, pituitary and mRNA concentrations tended to increase near the time of the gonadotropin preovulatory surge, particularly between 24 hrs before behavioral estrus to 5 hours after estrus. However, the changes in PRL mRNA, serum and pituitary concentrations were shown not to be statistically significant. These data suggest that PRL production during the sheep estrous cycle is maintained without dramatic changes in synthesis or secretion.

  5. Identification of proteins suppressing the functions of oncogenic phosphatase of regenerating liver 1 and 3

    PubMed Central

    Lee, Ju-Dong; Jung, Haiyoung; Min, Sang-Hyun

    2016-01-01

    The phosphatase of regenerating liver (PRL) family, including PRL-1, PRL-2, and PRL-3, comprises protein tyrosine phosphatases whose deregulation is associated with the tumorigenesis and metastasis of many types of cancer. However, the underlying mechanism is poorly understood. In this study, aiming to increase understanding of the molecular mechanisms underlying the functions of PRL-1 and PRL-3, a yeast two-hybrid system was employed to screen for their interacting proteins. Alignment with the NCBI BLAST database revealed 12 interactive proteins: Synaptic nuclear envelope protein 2, emerin, mannose 6-phosphate receptor-binding protein 1, low-density lipoprotein receptor-related protein 10, Rab acceptor 1, tumor protein D52-like 2, selectin P ligand (SELPLG), guanylate binding protein 1, transmembrane and ubiquitin-like domain-containing 2, NADH:ubiquinone oxidoreductase subunit B8, syndecan 4 and FK506-binding protein 8 (FKBP8). These proteins are associated with cell proliferation, apoptosis, immune response, cell fate specification and metabolic process in biological process categories, and involved in various signaling pathways, including Alzheimer's disease, Parkinson's disease, Huntington's disease, hypertrophic cardiomyopathy and cell adhesion molecules. Interactions of PRL-1 with the prey proteins SELPLG and FKBP8 were confirmed by immunoprecipitation or immunostaining. Furthermore, SELPLG and FKBP8 suppressed PRL-1− or PRL-3-mediated p53 activity. Identification of the proteins interacting with PRL family proteins may provide valuable information to better understand the mechanism of PRL-mediated signal transduction in cancer and other diverse diseases. PMID:27882103

  6. Macroprolactinemia: Diagnostic, Clinical, and Pathogenic Significance

    PubMed Central

    Hattori, Naoki

    2012-01-01

    Macroprolactinemia is characterized by a large molecular mass of PRL (macroprolactin) as the main molecular form of PRL in sera, the frequent elevation of serum PRL (hyperprolactinemia), and the lack of symptoms. Macroprolactin is largely a complex of PRL with immunoglobulin G (IgG), especially anti-PRL autoantibodies. The prevalence of macroprolactinemia is 10–25% in patients with hyperprolactinemia and 3.7% in general population. There is no gender difference and a long-term followup demonstrates that macroprolactinemia develops before middle age and is likely a chronic condition. Polyethylene-glycol- (PEG-) precipitation method is widely used for screening macroprolactinemia, and gel filtration chromatography, protein A/G column, and I125-PRL binding studies are performed to confirm and clarify its nature. The cross-reactivity of macroprolactin varies widely according to the immunoassay systems. The epitope on PRL molecule recognized by the autoantibodies is located close to the binding site for PRL receptors, which may explain that macroprolactin has a lower biological activity. Hyperprolactinemia frequently seen in macroprolactinemic patients is due to the delayed clearance of autoantibody-bound PRL. When rats are immunized with rat pituitary PRL, anti-PRL autoantibodies are produced and hyperprolactinemia develops, mimicking macroprolactinemia in humans. Screening of macroprolactinemia is important for the differential diagnosis of hyperprolactinemia to avoid unnecessary examinations and treatments. PMID:23304187

  7. Water Extract of Fructus Hordei Germinatus Shows Antihyperprolactinemia Activity via Dopamine D2 Receptor

    PubMed Central

    Wang, Xiong; Ma, Li; Zhang, En-jing; Zou, Ji-li; Guo, Hao; Peng, Si-wei; Wu, Jin-hu

    2014-01-01

    Objective. Fructus Hordei Germinatus is widely used in treating hyperprolactinemia (hyperPRL) as a kind of Chinese traditional herb in China. In this study, we investigated the anti-hyperPRL activity of water extract of Fructus Hordei Germinatus (WEFHG) and mechanism of action. Methods. Effect of WEFHG on serum prolactin (PRL), estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and hypothalamus protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) levels of hyperPRL rats were investigated. And effect of WEFHG on PRL secretion, D2 receptors, and dopamine transporters (DAT) was studied in MMQ, GH3, and PC12 cells, respectively. Results. WEFHG reduced the secretion of PRL in hyperPRL rats effectively. In MMQ cell, treatment with WEFHG at 1–5 mg/mL significantly suppressed PRL secretion and synthesis. Consistent with a D2-action, WEFHG did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D2 receptor expression but significantly increased the expression of D2 receptors and DAT in PC12 cells. In addition, WEFHG reduced the cAMP and PKA levels of hypothalamus in hyperPRL rats significantly. Conclusions. WEFHG showed anti-hyperPRL activity via dopamine D2 receptor, which was related to the second messenger cAMP and PKA. PMID:25254056

  8. Prolactin and autoimmunity.

    PubMed

    Vera-Lastra, Olga; Jara, Luis J; Espinoza, Luis R

    2002-12-01

    Prolactin (PRL) is a versatile hormone that is produced by the anterior pituitary gland and various extrapituitary sites including immune cells. Furthermore, PRL has widespread influences on proliferation and differentiation of a variety of cells in the immune system and is, in effect, a cytokine. PRL-receptors (PRL-R) are distributed throughout the immune system and are included as members of the cytokine receptor superfamily. PRL-R signal transduction is mediated by a complex array of signaling molecules of which JAK2, Stat1 and Stat5 pathway have been well studied. In PRL-stimulated T cells, the transcription factor gene, interferon regulatory factor-1 provides a mechanism whereby PRL can regulate the immune response. The human PRL gene is situated on the short arm of chromosome 6 close to the major histocompatibility complex. Polymorphisms of the human PRL gene have implications for production of lymphocyte PRL in SLE. Mild and moderate hyperprolactinemia (HPRL) has been demonstrated in 20-30% of SLE patients and is associated with active disease. HPRL may have a role in lupus nephritis and central nervous system involvement of SLE patients. HPRL stimulated the production of autoantibodies. These evidences support the important role of PRL in autoimmunity and autoimmune diseases, mainly SLE.

  9. Effects of preferred retinal locus placement on text navigation and development of advantageous trained retinal locus.

    PubMed

    Watson, Gale R; Schuchard, Ronald A; De l'Aune, William R; Watkins, Erica

    2006-01-01

    Sixty readers were evaluated for visual function and text-navigation ability. The visual field and preferred retinal locus (PRL) were measured with a scanning laser ophthalmoscope (SLO). We found significant differences in text-navigation ability based on scotoma and PRL placement. Readers with a PRL to the left of or above a scotoma had significantly less text-navigation abilities. Readers with a PRL to the left of a scotoma tended to misread words with similar beginnings and omit the last word on a line. Readers with a PRL above a scotoma tended to skip a line or reread the same line twice. In a follow-up study, seven subjects with a nonadvantageous PRL quickly developed a trained retinal locus (TRL) during instruction with an SLO. Although the readers developed the TRL in about 15 minutes, they read slower with the TRL than the PRL. This TRL research provides promising pilot data.

  10. The role of the prolactin/vasoinhibin axis in rheumatoid arthritis: an integrative overview.

    PubMed

    Clapp, Carmen; Adán, Norma; Ledesma-Colunga, María G; Solís-Gutiérrez, Mariana; Triebel, Jakob; Martínez de la Escalera, Gonzalo

    2016-08-01

    Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease destroying articular cartilage and bone. The female preponderance and the influence of reproductive states in RA have long linked this disease to sexually dimorphic, reproductive hormones such as prolactin (PRL). PRL has immune-enhancing properties and increases in the circulation of some patients with RA. However, PRL also suppresses the immune system, stimulates the formation and survival of joint tissues, acquires antiangiogenic properties upon its cleavage to vasoinhibins, and protects against joint destruction and inflammation in the adjuvant-induced model of RA. This review addresses risk factors for RA linked to PRL, the effects of PRL and vasoinhibins on joint tissues, blood vessels, and immune cells, and the clinical and experimental data associating PRL with RA. This information provides important insights into the pathophysiology of RA and highlights protective actions of the PRL/vasoinhibin axis that could lead to therapeutic benefits.

  11. Prolactin-like hormone in the nematode Trichinella spiralis larvae.

    PubMed

    Quintanar, J Luis; Salinas, Eva; Guerrero, Raquel; Gómez, Rigoberto; Vidal, Sergio; Aranda, Jorge; Clapp, Carmen

    2007-06-01

    Expression of prolactin (PRL) or prolactin-like hormone has been reported in invertebrates. We investigated the larval phase of Trichinella spiralis: (a) to express 23 kDa PRL, (b) to define its localization and (c) to test its possible biological activity. Immunostaining in isolated larvae demonstrated positive material to 23 kDa PRL by all along the stichosome, specifically in the stichocytes. Homogenized immunoblot larvae showed a 23 kDa protein band. To assess PRL release and its biological activity, larvae were incubated in culture medium and the excretory/secretory products were analyzed by the Nb2 cells bioassay. A cellular growth equivalent until 10 nM PRL and using antibody against 23 kDa PRL, the growth was blocked. In conclusion our result provides evidence that PRL-like hormone is expressed and secreted by the larvae of T. spiralis.

  12. Morphologic effects of bromocriptine on spontaneously occurring pituitary prolactin-cell hyperplasia in old Long-Evans rats.

    PubMed Central

    McComb, D. J.; Hellmann, P.; Thorner, M. O.; Scott, D.; Evans, W. S.; Kovacs, K.

    1986-01-01

    The effect of bromocriptine (BEC), a dopaminergic agonist, on nontumorous pituitary prolactin (PRL) cells of aging female Long-Evans rats, was studied histologically, immunocytologically, electron-microscopically, and morphometrically. Rats were arbitrarily divided into two control groups, one with normal (less than 20 ng/ml) and one with elevated serum PRL concentrations, and into four BEC-treated groups, all of which had increased serum PRL levels prior to commencement of BEC administration. In hyperprolactinemic control rats, compared with normoprolactinemic control rats, pituitary weight and percentage of pituitary PRL cells were increased. The morphologic features of PRL cells in these two groups did not differ markedly, which suggested that hyperprolactinemia was due to increased PRL-cell number and not increased PRL-cell function. Compared with age-matched hyperprolactinemic control rats, hyperprolactinemic rats treated with BEC showed a reversible decrease in serum PRL levels, pituitary weight as well as percentage of pituitary PRL cells, and by ultrastructural morphometry an increase in the volume density of lysosomes. BEC caused no striking changes in nuclear and cytoplasmic areas, volume densities of RER, Golgi regions, mitochondria, lipid droplets, and size and volume densities of forming and storage granules. Since spontaneously hyperplastic PRL cells show less conspicuous morphologic changes following BEC treatment than PRL cells rendered hyperplastic by estrogen administration or pituitary transplantation, it is suggested that PRL cells with no increased endocrine function respond less markedly to dopaminergic suppression than endocrinologically hyperactive PRL cells. It can be concluded that BEC suppresses spontaneous proliferation of PRL cells which occurs with aging. Images Figure 1 Figure 2 PMID:3942200

  13. Pregnancy-Related Systemic Lupus Erythematosus: Clinical Features, Outcome and Risk Factors of Disease Flares — A Case Control Study

    PubMed Central

    Zhao, Lidan; Wang, Qian; Leng, Xiaomei; Zheng, Wenjie; Zhang, Fengchun; Tang, Fulin; Zhang, Xuan

    2014-01-01

    Objective To investigate the clinical features, outcome, and risk factors of disease flares in patients with pregnancy-related lupus (PRL). Methods Medical charts of 155 consecutive PRL inpatients were systematically reviewed, including demographic data, clinical features, laboratory findings, treatment, complications, and outcome. Results PRL cases were divided into active (a-PRL) (n = 82, 53.0%) and stable lupus (s-PRL) (n = 73, 47.0%). Compared with nonpregnant active female systemic lupus erythematosus (SLE) patients, a-PRL including new-onset lupus (n-PRL) and flare lupus (f-PRL) (n = 41 respectively), had a higher incidence of renal and hematological involvement but less mucocutaneous and musculoskeletal involvement (p<0.05). The incidence of preeclampsia/eclampsia, fetal loss, and preterm birth were significantly higher in a-PRL than in s-PRL (p<0.05). Despite receiving a more vigorous glucocorticoid treatment, a-PRL mothers had a poorer prognosis (p<0.001). Five (6.1%) of them died and 13 (15.9%) developed severe irreversible organ failure, whereas none of these events was observed in the s-PRL group. Multivariate logistic analysis indicated that a history of lupus flares and serological activity (hypocomplementemia and/or anti-dsDNA positivity) at the time of conception were associated with lupus flares in PRL mothers. Conclusions SLE patients with a flare history and serological activity at the time of conception were at an increased risk of disease flares during pregnancy and puerperium. a-PRL patients were more prone to renal and hematological involvement, pregnancy complications, and a poorer prognosis despite more vigorous glucocorticoid treatment. PMID:25118692

  14. In vivo inhibition followed by exogenous supplementation demonstrates galactopoietic effects of prolactin on mammary tissue and milk production in dairy cows.

    PubMed

    Lollivier, V; Lacasse, P; Angulo Arizala, J; Lamberton, P; Wiart, S; Portanguen, J; Bruckmaier, R; Boutinaud, M

    2015-12-01

    It has been previously shown that the long-term inhibition of milking-induced prolactin (PRL) release by quinagolide (QN), a dopamine agonist, reduces milk yield in dairy cows. To further demonstrate that PRL is galactopoietic in cows, we performed a short-term experiment that used PRL injections to restore the release of PRL at milking in QN-treated cows. Nine Holstein cows were assigned to treatments during three 5-d periods in a 3×3 Latin square design: 1) QN: twice-daily i.m. injections of 1mg of QN; 2) QN-PRL: twice-daily i.m. injections of 1mg of QN and twice-daily (at milking time) i.v. injections of PRL (2µg/kg body weight); and 3) control: twice-daily injections of the vehicles. Mammary epithelial cells (MEC) were purified from milk so that their viability could be assessed, and mammary biopsies were harvested for immunohistological analyses of cell proliferation using PCNA and STAT5 staining. In both milk-purified MEC and mammary tissue, the mRNA levels of milk proteins and BAX were determined using real-time reverse-transcription PCR. Daily QN injections reduced milking-induced PRL release. The area under the PRL curve was similar in the control and PRL injection treatments, but the shape was different. The QN treatment decreased milk, lactose, protein, and casein production. Injections of PRL did not restore milk yield but tended to increase milk protein yield. In mammary tissue, the percentage of STAT5-positive cells was reduced during QN but not during QN-PRL in comparison with the control treatment. The percentage of PCNA-positive cells was greater during QN-PRL injections than during the control or QN treatment and tended to be lower during QN than during the control treatment. In milk-purified MEC, κ-casein and α-lactalbumin mRNA levels were lower during QN than during the control treatment, but during QN-PRL, they were not different from the control treatment. In mammary tissue, the BAX mRNA level was lower during QN-PRL than during QN. The

  15. Suppression of breast tumor growth by DNA vaccination against phosphatase of regenerating liver 3.

    PubMed

    Lv, J; Liu, C; Huang, H; Meng, L; Jiang, B; Cao, Y; Zhou, Z; She, T; Qu, L; Wei Song, S; Shou, C

    2013-08-01

    Phosphatase of regenerating liver (PRL)-3 is highly expressed in multiple cancers and has important roles in cancer development. Some small-molecule inhibitors and antibodies targeting PRL-3 have been recently reported to inhibit tumor growth effectively. To determine whether PRL-3-targeted DNA vaccination can induce immune response to prevent or inhibit the tumor growth, we established mouse D2F2 breast cancer cells expressing PRL-3 (D2F2/PRL-3) and control cells (D2F2/NC) with lentivirus, and constructed pVAX1-Igκ-PRL-3 plasmid (named as K-P3) as DNA vaccine to immunize BALB/c mice. We found that the K-P3 vaccine delivered by gene gun significantly prevented the growth of D2F2/PRL-3 compared with pVAX1-vector (P<0.01), but not of D2F2/NC, and improved the survival of D2F2/PRL-3-innoculated mice. Both PRL-3-targeted cytotoxic T lymphocytes (CTLs) and T-helper type 1 cell immune response (production of high levels of interferon-γ and tumor necrosis factor-α) were found to be involved in the preventive effect. Furthermore, PRL-3-targeted DNA immunization inhibited tumor growth of D2F2/PRL-3 cells in mice. We also evaluated the potential of immunization with PRL-3 protein, but no significant therapeutic or preventive effect was obtained on tumor growth. To enhance the immunity of PRL-3, we incorporated different molecular adjuvants, such as Mycobacterium tuberculosis heat-shock protein, CTL antigen 4 and M. tuberculosis T-cell stimulatory epitope (MT), into K-P3 vaccine for expressing the fusion proteins. We found that these adjuvant molecules did not significantly improve the antitumor activity of PRL-3 vaccine, but enhanced the production of PRL-3 antibodies in immunized mice. Summarily, our findings demonstrate that PRL-3-targeted DNA vaccine can generate significantly preventive and therapeutic effects on the growth of breast cancer expressing PRL-3 through the induction of cellular immune responses to PRL-3.

  16. Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase.

    PubMed

    LaPensee, Elizabeth W; Schwemberger, Sandy J; LaPensee, Christopher R; Bahassi, El Mustapha; Afton, Scott E; Ben-Jonathan, Nira

    2009-08-01

    Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G(2)/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by gamma-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTmu, but not the pi, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options.

  17. A 14-kilodalton prolactin-like fragment is secreted by the hypothalamo-neurohypophyseal system of the rat.

    PubMed

    Torner, L; Mejía, S; López-Gómez, F J; Quintanar, A; Martínez de la Escalera, G; Clapp, C

    1995-12-01

    The recently described expression of the PRL gene, and the occurrence of a 14-kilodalton (kDa)PRL-like immunoreactive protein in the hypothalamo-neurohypophyseal system of the rat have raised the possibility that PRL variants are released from neurohypophyseal terminals into the blood. In this study, we investigated the local production of a hypothalamo-neurohypophyseal 14-kDa PRL-like protein by showing an independent origin from adenohypophyseal PRL. No 14-kDa PRL-like protein was detected in adenohypophyseal extracts by Western blots, whereas chronic hypophysectomy produced no change in the immunocytochemical detection of PRLs in supraoptic and paraventricular magnocellular neurons. In addition, a 14-kDa immunoreactive PRL-like protein was released into the medium by incubated neurohypophyseal lobes. Western blot analysis showed that significantly more of this 14-kDa protein was released into calcium-containing medium (1.8 mM) than into calcium-free medium. Furthermore, depolarizing concentrations of potassium (56 mM) increased by 3-fold the release of immunoreactive PRL by incubated hypothalamo-neurohypophyseal explants. In addition, a 14-kDa PRL-like antigen was detected in the circulation of the rat by Western blot analysis. These results are consistent with the local synthesis and calcium-dependent release of neurohypophyseal PRL-like proteins that include a predominant 14-kDa form.

  18. Melatonin effects on prolactin secretion in pituitary-grafted male rats.

    PubMed

    Villanua, M A; Agrasal, C; Tresguerres, J A; Vaughan, M K; Esquifino, A I

    1989-01-01

    Melatonin influences prolactin (PRL) secretion through unknown mechanisms. This work was undertaken to study the effects of melatonin administration on PRL secretion in pituitary-grafted male rats. Melatonin administration 5 hours before dark resulted in a marked decrease of previously high basal plasma PRL levels in pituitary-grafted rats, whereas a marked increase was detected in sham-operated animals. Vehicle treatment did not modify basal PRL values in grafted or sham-operated animals. Luteinizing hormone-releasing hormone (LHRH) administration resulted in a marked decrease of plasma PRL levels in vehicle-treated, sham-operated or grafted rats, as well as in melatonin-treated sham-operated rats. An increase in PRL levels was shown in grafted rats treated with melatonin. Estradiol benzoate (EB) administration resulted in an increase in plasma PRL levels both in sham-operated and grafted vehicle-treated rats. No PRL response could be detected in sham-operated, melatonin-treated animals after EB administration. In pituitary-grafted animals given melatonin, PRL response to EB administration was slight and delayed. From these data, melatonin appears to modify PRL secretion through multiple complex mechanisms that may depend on the physiological status (hormonal and neurotransmitter) of the animals. A direct effect at the pituitary level altering lactotroph sensitivity seems to be one plausible explanation for the current findings, although an hypothalamic site of action cannot be excluded.

  19. Evidence for a Role of Prolactin in Mediating Effects of Photoperiod during the Dry Period

    PubMed Central

    Crawford, Heather M.; Morin, Dawn E.; Wall, Emma H.; McFadden, Thomas B.; Dahl, Geoffrey E.

    2015-01-01

    Photoperiod manipulation during the lactation cycle alters milk yield, with long days (LDPP) increasing yield in lactation and short days (SDPP) in the dry period improving subsequent yield. Circulating prolactin (PRL) is directly related to day length, with LDPP increasing and SDPP decreasing PRL, respectively. Two blocks of 24 multiparous Holstein cows were used during two consecutive years to test the hypothesis that the mammary response to SDPP is the result of decreased concentrations of PRL in the circulation relative to LDPP. Cows were randomly assigned to one of three treatment groups during the dry period: SDPP, LDPP, or SDPP+PRL. Cows were returned to ambient photoperiod at calving and milk yield and DMI recorded for 120 d and 42 d, respectively. Mammary biopsies were obtained to determine rates of [3H]-thymidine incorporation into DNA in vitro. Treatment of SDPP cows with PRL caused a rapid increase in systemic PRL that reached concentrations similar to cows under LDPP. The periparturient PRL surge was similar for LDPP and SDPP+PRL cows, but those groups had greater surge concentrations versus SDPP. Cows exposed to SDPP produced more milk than LDPP cows, and there was a trend for SDPP+PRL cows to produce more milk than LDPP cows. Milk production was inversely related to the periparturient PRL surge. There was a trend for a treatment effect on mammary cell proliferation with greater proliferation in mammary tissue of SDPP cows relative to LDPP or SDPP+PRL on day −20 relative to parturition. Replacement of PRL to cows on SDPP when dry resulted in milk yield intermediate to cows on SDPP or LDPP, supporting the concept of a link between dry period PRL and yield. PMID:26479387

  20. Allometric relations of total volumes of prolactin cells and corticotropic cells to body length in the annual cyprinodont Cynolebias whitei: effects of environmental salinity, stress and ageing.

    PubMed

    Ruijter, J M; Wendelaar Bonga, S E

    1987-09-01

    An analysis of the allometric relations of the total volumes occupied by prolactin (PRL) and corticotropic (ACTH) cells (PRL volume and ACTH volume, respectively) to body length and a study of the immunocytochemical staining intensity of PRL and ACTH cells were used to determine the differences in activity of PRL and ACTH cells in freshwater-reared and in saltwater-reared Cynolebias whitei during the entire lifespan of this annual cyprinodont fish. An inflection in the allometric relation of PRL volume to body length was observed in fish of one-week old. The relatively large PRL volume in younger fish may be related to PRL cell activity before hatching. No inflections were observed in the allometric relations of PRL volume and ACTH volume to body length at the onset of maturation and the onset of ageing, indicating that the increased pituitary growth in maturing and ageing C. whitei is not the result of changes in PRL or ACTH cells. The slope of the allometric relation of PRL volume to body length in freshwater-reared fish was significantly steeper than the slope in saltwater-reared fish. The PRL volume in adult freshwater-reared fish was eight times larger than that in saltwater-reared fish of the same length. The intensity of immunocytochemical staining of saltwater PRL cells was significantly reduced. These volumetric and staining differences correspond to the low functional demand put upon PRL cells in saltwater-adapted fish. In contrast, the slope of the allometric relation of ACTH volume to body length and the intensity of immunocytochemical staining of ACTH cells were similar in freshwater-reared and in saltwater-reared fish.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Evaluation of hyperprolactinaemia with the use of the intervals for prolactin after macroforms separation.

    PubMed

    Beda-Maluga, K; Pisarek, H; Komorowski, J; Swietoslawski, J; Fuss-Chmielewska, J; Winczyk, K

    2014-06-01

    Macroprolactin (MaPRL) - a complex of monomeric prolactin (PRL) with immunoglobulin G, may be a cause of laboratory diagnosed hyperprolactinaemia. To quantify MaPRL, a precipitation with polyethylene glycol may be performed. This method involves calculating of recovery ratio but the cut-off value is not precisely determined. Moreover, it is proposed that the assessment of macroprolactinaemia should include also the evaluation of real PRL concentration which means the level of the hormone after macroforms separation. The study included 245 patients with hyperprolactinaemia, in whom precipitation was performed. A recovery ratio ≤40% indicated macroprolactinaemia. The real PRL concentrations of the studied subjects were compared with reference ranges suggested by the assay manufacturer and with new intervals for PRL after macroforms separation. On the base of the recovery ratio after the precipitation, macroprolactinaemia was detected in 21 persons. In these patients true hyperprolactinaemia (elevation of real PRL concentration above manufacturer's reference ranges) was noted in 9 cases. Among 224 patients with a recovery >40%, real PRL concentration turned out to be within the manufacturer's reference range (pseudohyperprolactinaemia) in 36 persons. The new intervals for PRL after macroforms separation were about 20% lower than the manufacturer's reference ranges. After applying new ranges in patients with macroprolactinaemia, true hyperprolactinaemia was observed in 14 persons, while in the group without MaPRL dominance, pseudohyperprolactinaemia was noted in 5 patients. The use of the recovery ratio only to recognize macroprolactinaemia may lead in some subjects to the misclassification of the results. For that reason the assessment of the PRL concentration after macroforms separation that can help to distinguish true hyperprolactinaemia and pseudohyperprolactinaemia, seems to be reasonable. To evaluate the real PRL concentration, the reference intervals

  2. Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors

    PubMed Central

    Bogorad, Roman L.; Courtillot, Carine; Mestayer, Chidi; Bernichtein, Sophie; Harutyunyan, Lilya; Jomain, Jean-Baptiste; Bachelot, Anne; Kuttenn, Frédérique; Kelly, Paul A.; Goffin, Vincent; Touraine, Philippe

    2008-01-01

    There is currently no known genetic disease linked to prolactin (Prl) or its receptor (PrlR) in humans. Given the essential role of this hormonal system in breast physiology, we reasoned that genetic anomalies of Prl/PrlR genes may be related to the occurrence of breast diseases with high proliferative potential. Multiple fibroadenomas (MFA) are benign breast tumors which appear most frequently in young women, including at puberty, when Prl has well-recognized proliferative actions on the breast. In a prospective study involving 74 MFA patients and 170 control subjects, we identified four patients harboring a heterozygous single nucleotide polymorphism in exon 6 of the PrlR gene, encoding Ile146→Leu substitution in its extracellular domain. This sole substitution was sufficient to confer constitutive activity to the receptor variant (PrlRI146L), as assessed in three reconstituted cell models (Ba/F3, HEK293 and MCF-7 cells) by Prl-independent (i) PrlR tyrosine phosphorylation, (ii) activation of signal transducer and activator of transcription 5 (STAT5) signaling, (iii) transcriptional activity toward a Prl-responsive reporter gene, and (iv) cell proliferation and protection from cell death. Constitutive activity of PrlRI146L in the breast sample from a patient was supported by increased STAT5 signaling. This is a unique description of a functional mutation of the PrlR associated with a human disease. Hallmarks of constitutive activity were all reversed by a specific PrlR antagonist, which opens potential therapeutic approaches for MFA, or any other disease that could be associated with this mutation in future. PMID:18779591

  3. Prolactin affects bovine oocytes through direct and cumulus-mediated pathways.

    PubMed

    Lebedeva, Irina Y; Singina, Galina N; Volkova, Natalia A; Vejlsted, Morten; Zinovieva, Natalia A; Schmidt, Mette

    2014-11-01

    The available evidence points to participation of PRL in regulation of mammalian oocyte maturation. The aim of the present study was to characterize pathways of PRL action on bovine oocytes. We analyzed (1) the presence of the PRL receptor and its mRNA isoforms in oocytes and cumulus cells; (2) the effect of PRL on meiosis resumption and the role of cumulus cells, the NO/NO synthase system, protein kinase C, and tyrosine kinases in this effect; and (3) PRL effects in the presence of gonadotropins on the developmental capacity of cumulus-free and cumulus-enclosed oocytes. The transcript and protein expression of the PRL receptor in the cells were detected by reverse transcription polymerase chain reaction and immunocytochemistry, respectively. The nuclear status of oocytes was assessed after culture of cumulus-oocyte complexes (COCs) and denuded oocytes (DOs) with or without PRL (5-500 ng/mL) for 7, 14, or 24 hours. Besides, DOs were incubated for 7 hours in the absence or the presence of PRL (50 ng/mL) and/or L-NAME (an inhibitor of NO synthase), genistein (an inhibitor of tyrosine kinases), or calpostin C (a protein kinase C inhibitor). After IVM in 2 different systems containing PRL (50 ng/mL) and/or gonadotropic hormones, a part of oocytes underwent IVF and IVC and the embryo development was tracked until the blastocyst stage. Messenger RNA of long and short isoforms of the PRL receptor was revealed in both oocytes and cumulus cells. Immunocytochemistry confirmed the presence of the PRL receptor in oocytes and the cumulus investment. In the absence of gonadotropins (system 1), PRL retarded meiosis resumption in DOs but not in cumulus-enclosed oocytes, with this effect being short term, dose dependent, suppressed by L-NAME and genistein, and unaffected by calpostin. In systems containing gonadotropins, PRL did not affect nuclear maturation and the cleavage rate of cumulus-free and cumulus-enclosed oocytes. However, in the case of COCs, it raised the blastocyst

  4. SOEMPI: A Secure Open Enterprise Master Patient Index Software Toolkit for Private Record Linkage

    PubMed Central

    Toth, Csaba; Durham, Elizabeth; Kantarcioglu, Murat; Xue, Yuan; Malin, Bradley

    2014-01-01

    To mitigate bias in multi-institutional research studies, healthcare organizations need to integrate patient records. However, this process must be accomplished without disclosing the identities of the corresponding patients. Various private record linkage (PRL) techniques have been proposed, but there is a lack of translation into practice because no software suite supports the entire PRL lifecycle. This paper addresses this issue with the introduction of the Secure Open Enterprise Master Patient Index (SOEMPI). We show how SOEMPI covers the PRL lifecycle, illustrate the implementation of several PRL protocols, and provide a runtime analysis for the integration of two datasets consisting of 10,000 records. While the PRL process is slower than a non-secure setting, our analysis shows the majority of processes in a PRL protocol require several seconds or less and that SOEMPI completes the process in approximately two minutes, which is a practical amount of time for integration. PMID:25954421

  5. Depletion of pituitary prolactin by cysteamine is due to loss of immunological activity.

    PubMed

    Scammell, J G; Dannies, P S

    1984-03-01

    The mechanism by which cysteamine reduces the PRL content of pituitary cells was studied in primary cultures of estradiol-induced pituitary tumors in Fischer 344 rats. The PRL content of these cells was effectively decreased by cysteamine, with an IC50 of 0.2 mM. Cells previously labeled with [3H]leucine were exposed to cysteamine (0.25 mM), and the intracellular content of [3H]PRL was measured by immunological or nonimmunological means, that is by immunoprecipitation and electrophoresis or by electrophoresis alone. The intracellular concentration of immunoreactive [3H]PRL was reduced by 53% by cysteamine, whereas [3H]PRL quantified by electrophoresis alone was not significantly affected. Our data indicate that cysteamine reduces the PRL content of pituitary tumor cells by causing the loss of its immunoreactivity.

  6. Circulating prolactin and its response to TRH following administration of testosterone undecanoate in normal men.

    PubMed

    Kicovic, P M; Luisi, M; Franchi, F; Krempl, S

    1978-10-01

    To investigate the effect of orally administered testosterone undercanoate (TU) on circulating prolactin (PRL) and PRL response to TRH stimulation, 8 eugonadal male volunteers, aged 19--30, presenting with normal plasma levels of FSH, LH, testosterone (T), estradiol (E2) and PRL, were given 120 mg/day of TU for 6 days. Plasma PRL levels were measured daily during the pre-treatment phase (3 days), treatment phase (6 days) and post-treatment phase (3 days) by radioimmunoassay. The TRH Test (200 micrograms iv) was done on the 3rd day of the pretreatment phase and on the treatment phase. No significant changes in circulating PRL levels or in PRL response to TRH stimulation were observed. Plasma T and E2 levels showed a slight, but not significant tendency to increase, while gonadotropin levels remained unchanged.

  7. Depletion of pituitary prolactin by cysteamine is due to loss of immunological activity

    SciTech Connect

    Scammell, J.G.; Dannies, P.S.

    1984-03-01

    The mechanism by which cysteamine reduces the prolactin(PRL) content of pituitary cells was studied in primary cultures of estradiol-induced pituitary tumors in Fischer 344 rats. The PRL content of these cells was effectively decreased by cysteamine, with an IC50 of 0.2 mM. Cells previously labeled with (/sup 3/H)leucine were exposed to cysteamine (0.25 mM), and the intracellular content of (/sup 3/H)PRL was measured by immunological or nonimmunological means, that is by immunoprecipitation and electrophoresis or by electrophoresis alone. The intracellular concentration of immunoreactive (/sup 3/H)PRL was reduced by 53% by cysteamine, whereas (/sup 3/H)PRL quantified by electrophoresis alone was not significantly affected. Our data indicate that cysteamine reduces the PRL content of pituitary tumor cells by causing the loss of its immunoreactivity.

  8. Antipsychotic drugs inhibit prolactin release from rat anterior pituitary cells in culture by a mechanism not involving the dopamine receptor.

    PubMed

    West, B; Dannies, P S

    1979-04-01

    Bromocriptine, a dopamine agonist, inhibited secretion of PRL and did not affect GH release from rat anterior pituitary cells in culture. The reversal of this inhibition of PRL release by butaclamol, a dopamine antagonist, was stereospecific; 10 nM d-butaclamol completely reversed the inhibition caused by 10 nM bromocriptine, while l-butaclamol had no effect at concentrations up to 10 microM. However, both enantiomers at 10 microM inhibited PRL release to 30% and GH release to 91% of control values. Two other dopamine antagonists also inhibited hormone release. Haloperidol (10 microM) inhibited PRL release to 23% of control values and did not affect GH release; 3.3 microM pimozide inhibited PRL and GH release to 18% and 38% of control values, respectively. These data indicate that, the inhibition of PRL by antipsychotic drugs is not mediated through the dopamine receptor.

  9. Differences between rat strains in the development of PRL-secreting pituitary tumors with long-term estrogen treatment: In vitro insulin-like growth factor-1-induced lactotroph proliferation and gene expression are affected in Wistar-Kyoto rats with low estrogen-susceptibility.

    PubMed

    Mitsui, Tetsuo; Ishida, Maho; Izawa, Michi; Arita, Jun

    2013-01-01

    There are differences in the susceptibility of rat strains to pituitary growth and lactotroph proliferation caused by long-term treatment with estrogens. To investigate the pituitary mechanism for this strain difference in estrogen-induced lactotroph proliferation, we compared the abilities of 17-β estradiol (E2) and insulin-like growth factor-1 (IGF-1) to modulate lactotroph proliferation and gene expression in vitro in Wistar and Wistar-Kyoto (WKY) rats. These two strains of rats have a high and very low susceptibility to estrogen, respectively. Long-term in vivo treatment with E2 was confirmed to markedly increase pituitary weight and lactotroph proliferation in ovariectomized Wistar, but not in WKY rats. Pituitary lactotrophs in primary cultures showed similar proliferative responsiveness to the culture condition-dependent, stimulatory and inhibitory actions of E2 in both strains. The only difference in lactotroph proliferation in vitro was a lower response to IGF-1 in WKY cells compared with Wistar cells. This difference in proliferation was associated with strain differences in IGF-1-induced gene expression in Wistar and WKY cultured cells. Of the genes tested, IGF-1-induced expression of the Wnt4, Stc1, Mybl1, and Myc genes was attenuated or abolished in WKY cells. These results suggest that the proliferative response to estrogen in lactotrophs in primary culture does not reflect the proliferative response to long-term estrogen treatment observed in vivo in Wistar and WKY rats. The strain difference in proliferation and gene expression to IGF-1 may be implicated in the variable degree of susceptibility for lactotroph proliferation observed in different strains of rats following long-term estrogen treatment.

  10. Uncoupling clutch size, prolactin, and luteinizing hormone using experimental egg removal.

    PubMed

    Ryan, Calen P; Dawson, Alistair; Sharp, Peter J; Williams, Tony D

    2015-03-01

    Clutch size is a key avian fitness and life history trait. A physiological model for clutch size determination (CSD), involving an anti-gonadal effect of prolactin (PRL) via suppression of luteinizing hormone (LH), was proposed over 20 years ago, but has received scant experimental attention since. The few studies looking at a PRL-based mechanistic hypothesis for CSD have been equivocal, but recent experiments utilizing a pharmacological agent to manipulate PRL in the zebra finch (Taeniopygia guttata) found no support for a role of this hormone in clutch size determination. Here, we take a complementary approach by manipulating clutch size through egg removal, examining co-variation in PRL and LH between two breeding attempts, as well as through experimentally-extended laying. Clutch size increased for egg removal females, but not controls, but this was not correlated with changes in PRL or LH. There were also no differences in PRL between egg removal females and controls, nor did PRL levels during early, mid- or late-laying of supra-normal clutches predict clutch size. By uncoupling PRL, LH and clutch size in our study, several key predictions of the PRL-based mechanistic model for CSD were not supported. However, a positive correlation between PRL levels late in laying and days relative to the last egg (clutch completion) provides an alternative explanation for the equivocal results surrounding the conventional PRL-based physiological model for CSD. We suggest that females coordinate PRL-mediated incubation onset with clutch completion to minimize hatching asynchrony and sibling hierarchy, a behavior that is amplified in females laying larger clutches.

  11. Prolactin Induces Apoptosis of Lactotropes in Female Rodents

    PubMed Central

    Ferraris, Jimena; Zárate, Sandra; Jaita, Gabriela; Boutillon, Florence; Bernadet, Marie; Auffret, Julien; Seilicovich, Adriana; Binart, Nadine; Pisera, Daniel

    2014-01-01

    Anterior pituitary cell turnover occurring during female sexual cycle is a poorly understood process that involves complex regulation of cell proliferation and apoptosis by multiple hormones. In rats, the prolactin (PRL) surge that occurs at proestrus coincides with the highest apoptotic rate. Since anterior pituitary cells express the prolactin receptor (PRLR), we aimed to address the actual role of PRL in the regulation of pituitary cell turnover in cycling females. We showed that acute hyperprolactinemia induced in ovariectomized rats using PRL injection or dopamine antagonist treatment rapidly increased apoptosis and decreased proliferation specifically of PRL producing cells (lactotropes), suggesting a direct regulation of these cell responses by PRL. To demonstrate that apoptosis naturally occurring at proestrus was regulated by transient elevation of endogenous PRL levels, we used PRLR-deficient female mice (PRLRKO) in which PRL signaling is totally abolished. According to our hypothesis, no increase in lactotrope apoptotic rate was observed at proestrus, which likely contributes to pituitary tumorigenesis observed in these animals. To decipher the molecular mechanisms underlying PRL effects, we explored the isoform-specific pattern of PRLR expression in cycling wild type females. This analysis revealed dramatic changes of long versus short PRLR ratio during the estrous cycle, which is particularly relevant since these isoforms exhibit distinct signaling properties. This pattern was markedly altered in a model of chronic PRLR signaling blockade involving transgenic mice expressing a pure PRLR antagonist (TGΔ1–9-G129R-hPRL), providing evidence that PRL regulates the expression of its own receptor in an isoform-specific manner. Taken together, these results demonstrate that i) the PRL surge occurring during proestrus is a major proapoptotic signal for lactotropes, and ii) partial or total deficiencies in PRLR signaling in the anterior pituitary may result

  12. Lower prolactin levels during cabergoline treatment are associated to tumor shrinkage in prolactin secreting pituitary adenoma.

    PubMed

    Lombardi, M; Lupi, I; Cosottini, M; Rossi, G; Manetti, L; Raffaelli, V; Sardella, C; Martino, E; Bogazzi, F

    2014-12-01

    Dopamine agonists are considered as the first line therapy in prolactin (PRL) secreting pituitary adenomas inducing a normalization of serum PRL and reduction of tumor size. It is known that serum PRL levels, obtained during treatment, are a predictor of tumor shrinkage. Whether PRL suppression below the lower limit of the normal range is related to a greater chance of tumor shrinkage than just its normalization has not been established. This retrospective cohort study was carried out in a tertiary center. Clinical records of 151 patients with PRL-secreting pituitary adenomas (73 micro-, 78 macroadenomas) treated with cabergoline for at least 24 months were analyzed. The adenoma size was analyzed by MRI before and after 24 months of treatment. PRL levels were evaluated every 6 months, assigning a score at each time point (PRL 0 = suppressed; 1 = normal; 2 = above normal). The total score, after 24 months of treatment, was expressed as the sum of the score at each time point and ranged between 0 and 8. A tumor shrinkage was observed in 102/151 patients (67.5%) and it was significantly associated to a lower PRL total score (p = 0.021, OR = 0.85, CI = 0.73-0.97), being significantly more frequent in patients with suppressed PRL than in those with normal PRL (p = 0.045, OR = 0.42, CI = 0.18-0.98) at 24 months. Cabergoline therapy with the goal of achieving PRL levels below the lower limit of normal range can increase the chance to obtain tumor shrinkage of PRL-secreting pituitary adenomas.

  13. Antagonism of Taxol Cytotoxicity by Prolactin: Implication for Patient Resistance to Chemotherapy

    DTIC Science & Technology

    2009-03-01

    ethacrynic acid ). Whereas PRL effectively antagonized cisplatin cytotoxicity in the presence of the MRP inhibitor, it failed to protect the cells when...the cells with ethacrynic acid abolished the ability of PRL to decrease cisplatin binding to DNA (Fig 6, right panel). Since ethacrynic acid alone...or ethacrynic acid (10 µM) for 1 hr before PRL (100 ng/ml) for 24 hrs. This was followed by treatment with 800 ng/ml cisplatin for 24 hrs. Cell

  14. Expression of phosphatase of regenerating liver-3 is associated with prognosis of Wilms’ tumor

    PubMed Central

    Sun, Fengyin; Li, Wenyi; Wang, Lie; Jiao, Changfeng

    2017-01-01

    Objective The current study was undertaken to explore the clinical and prognostic value of phosphatase of regenerating liver-3 (PRL-3) expression in Wilms’ tumor. Methods Seventy-six patients with Wilms’ tumor in Qilu Hospital from January 2003 to July 2009 were enrolled in the study. Protein expression level of PRL-3 was examined by immunohistochemical staining, and the correlation between PRL-3 expression and histopathological parameters, clinical variables, and outcome of patients with Wilms’ tumor were analyzed. Results We found that 19% of patients with unfavorable histology had tumor recurrence and 16% of patients died following the operation. PRL-3 was expressed in 15 out of 76 tumors (19%) and expressed highly in unfavorable histology Wilms’ tumor (P=0.04). PRL-3 protein expression level was correlated to 2.5-fold increase in recurrence rate of Wilms’ tumor (P=0.06) without any statistically significant difference. However, in favorable histology Wilms’ tumor, PRL-3 expression was correlated to an increase of 3.4-fold in recurrence rate (P=0.03). Conclusion The expression of PRL-3 protein was correlated with an increased recurrence rate of favorable histology Wilms’ tumor. PRL-3 may serve as a promising biomarker for predicting patients with high risk of Wilms’ tumor. Further investigations are warranted to investigate the clinical function of PRL-3 in Wilms’ tumor. PMID:28138254

  15. Possible modulation of N-methyl-D,L-aspartic acid induced prolactin release by testicular steroids in the adult male rhesus monkey

    SciTech Connect

    Arslan, M.; Rizvi, S.S.R.; Jahan, S.; Zaidi, P.; Shahab, M. )

    1991-01-01

    N-methyl-D,L-aspartic acid (NMA), an agonist of the neurotransmitter glutamate has been shown to acutely stimulate the release of prolactin (PRL) in intact rats and monkeys. To further investigate the role of neuroexcitatory amino acids in PRL secretion, the effects of NMA administration were examined on PRL release in long term orchidectomized adult rhesus monkeys, in both the absence and presence of testosterone. Intact and long term castrated adult male monkeys weighing between 8-13 kg, were implanted with a catheter via the saphenous vein for blood withdrawal and drug infusion. Blood samples were collected at 10 min intervals for 50 min before and 70 min after administration of the drug or vehicle. Plasma PRL concentrations were estimated using radioimmunoassay. Whereas a single iv injection of NMA induced a prompt discharge of PRL in intact monkeys, an identical dose had surprisingly no effect on PRL secretion in orchidectomized animals. On the other hand, plasma PRL increases in response to a challenge dose of thyrotropin releasing hormone were similar in magnitude in the two groups of monkeys. Testosterone replacement in orchidectomized animals by parenteral administration of testosterone enanthate reinitiated the PRL responsiveness to acute NMA stimulation. These results indicate that N-methyl-D-aspartic acid (NMDA) dependent drive to PRL release in the adult male rhesus monkey may be overtly influenced by the sex steroid milieu.

  16. New insights into the importance of prolactin in dairy ruminants.

    PubMed

    Lacasse, P; Ollier, S; Lollivier, V; Boutinaud, M

    2016-01-01

    In most mammals, prolactin (PRL) is essential for maintaining lactation, and the suppression of PRL inhibits lactation. However, the involvement of PRL in the control of ruminant lactation is less clear, because inconsistent effects on milk yield have been observed with the short-term suppression of PRL by bromocriptine. Therefore, several experiments have been conducted to assess the galactopoietic role of PRL. In an initial experiment, cows in early lactation received daily injections of the dopamine agonist quinagolide for 9 wk. Quinagolide reduced milking-induced PRL release and caused a faster decline in milk production. Quinagolide also reduced mammary epithelial cell activity, survival, and proliferation. In goats, cabergoline, another dopamine agonist, caused a 28% decrease in milk yield the day after injection. In another experiment, cows were injected for 5d with quinagolide, with quinagolide plus bovine PRL injected at milking time, or with vehicles only. Again, quinagolide reduced milk, protein, and lactose yields. Although PRL injections were not sufficient to restore milk yield, they tended to increase milk protein and lactose yields and increased the viability of mammary epithelial cells purified from milk. Recently, our team stimulated PRL secretion with daily injections of the dopamine antagonist domperidone for 5 wk. Milk production increased gradually and was greater in domperidone-treated cows during the last 4 wk of the treatment period. In most experiments where PRL secretion was manipulated, feed intake paralleled the changes of PRL concentration, supporting the idea that PRL increases feed intake to provide the nutrients necessary to support lactation in dairy ruminants. In late-lactation cows, quinagolide and cabergoline decreased milk production within the first day of treatment and induced more rapid changes in several markers of mammary gland involution after drying-off. In addition, quinagolide improved the resistance to intramammary

  17. Prolactin and blood-brain barrier permeability.

    PubMed

    Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Hamilton, W Ryan; Ramirez-Lee, Manuel A; Ali, Syed F; Gonzalez, Carmen

    2013-11-01

    The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins.

  18. Treating prolactinoma can prevent autoimmune diseases.

    PubMed

    Watad, Abdulla; Versini, Mathilde; Jeandel, Pierre-Yves; Amital, Howard; Shoenfeld, Yehuda

    2015-04-01

    Prolactin (PRL) is a pleiotropic hormone; in addition to a wide variety of endocrine effects, PRL also exhibits immunostimulating effects. Therefore, there is increasing evidence linking PRL with a large number of systemic and organ specific autoimmune diseases. Herein, we report the case of an adolescent girl diagnosed with multiple sclerosis (MS) occurring in the context of untreated prolactinoma evolving since childhood. This raises the exciting question of the involvement of PRL in the pathogenesis of MS. It is likely that early treatment of hyperprolactinemia in this case would have significantly reduced the risk of developing MS or even prevented its occurrence.

  19. The ultrastructure of prolactin cells in the annual cyprinodont Cynolebias whitei during its life cycle. A morphometric study in freshwater- and saltwater-reared fish.

    PubMed

    Ruijter, J M; Creuwels, L A

    1988-08-01

    Prolactin (PRL) cells were studied electron-microscopically and morphometrically in the annual cyprinodont fish, Cynolebias whitei during its life cycle. In prehatching larvae, PRL cells possessed small secretory granules, giant mitochondria and a well-developed Golgi apparatus. During hatching, no changes were observed in the volume density of the secretory granules, indicating that no increased release of PRL occurs at hatching. A significant change in the composition of PRL cells, i.e., the volume densities per cytoplasm volume of the different organelles, occurred between one day and one week of age. Thereafter, only minor differences were observed between age groups, indicating that no major changes occur in PRL cell activity during the lifespan of C. whitei. However, the volume density per cell volume of the nucleus decreased steadily with age during the lifespan. A comparison of the PRL cells in young and adult fish reared in fresh water (FW) with siblings reared from hatching in diluted sea water (1/3 SW) did not reveal any differences with respect to the volume densities of the organelles, including the secretory granules. However, significant differences were observed with respect to the diameter, electron-dense content and affinity to anti-PRL serum of the secretory granules. These differences indicate that, despite the similar volumetric composition of the PRL cells, their secretory granules contain a substantially higher concentration of PRL in FW-reared fish than in 1/3 SW-reared fish.

  20. Studies on the regulatory effect of Peony-Glycyrrhiza Decoction on prolactin hyperactivity and underlying mechanism in hyperprolactinemia rat model.

    PubMed

    Wang, Di; Wang, Wei; Zhou, Yulin; Wang, Juan; Jia, Dongxu; Wong, Hei Kiu; Zhang, Zhang-Jin

    2015-10-08

    Clinical trials have demonstrated the beneficial effects of Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL) in schizophrenic patients. In previous experiment, PGD suppressed prolactin (PRL) level in MMQ cells, involving modulating the expression of D2 receptor (DRD2) and dopamine transporter (DAT). In the present study, hyperPRL female rat model induced by dopamine blocker metoclopramide (MCP) was applied to further confirm the anti-hyperpPRL activity of PGD and underlying mechanism. In MCP-induced hyperPRL rats, the elevated serum PRL level was significantly suppressed by either PGD (2.5-10 g/kg) or bromocriptine (BMT) (0.6 mg/kg) administration for 14 days. However, in MCP-induced rats, only PGD restored the under-expressed serum progesterone (P) to control level. Both PGD and BMT administration restore the under-expression of DRD2, DAT and TH resulted from MCP in pituitary gland and hypothalamus. Compared to untreated group, hyperPRL animals had a marked reduction on DRD2 and DAT expression in the arcuate nucleus. PGD (10 g/kg) and BMT (0.6 mg/kg) treatment significant reversed the expression of DRD2 and DAT. Collectively, the anti-hyperPRL activity of PGD associates with the modulation of dopaminergic neuronal system and the restoration of serum progesterone level. Our finding supports PGD as an effective agent against hyperPRL.

  1. The role of prolactin in the development of reproductive photorefractoriness and postnuptial molt in the European starling (Sturnus vulgaris).

    PubMed

    Dawson, A; Sharp, P J

    1998-02-01

    Seasonal breeding in many birds, including the European starling, is terminated by the development of absolute reproductive photorefractoriness, followed by a postnuptial molt, when photo-induced PRL secretion is at its seasonal maximum. To determine whether this photo-induced increase in PRL secretion has a causal role in the development of photorefractoriness or molt, European starlings were actively immunized against vasoactive intestinal polypeptide (VIP), the PRL releasing hormone in birds, or against PRL, during a photo-induced breeding cycle. In half of the VIP-immunized birds, the photo-induced increase in PRL was completely suppressed. Although these birds became photorefractory, the rate of gonadal regression was markedly slowed. These birds did not molt. In the remaining VIP-immunized birds, the photo-induced increase in PRL was inhibited but not completely suppressed. In these birds, and in those immunized against PRL, gonadal regression was also slowed, but molt progressed as normal. There were no significant differences in concentrations of plasma thyroxine between treatment and control groups, indicating that the effects of immunization on gonadal regression were not mediated by the induction of hypothyroidism. These results are consistent with the view that in the European starling the seasonal photo-induced increase in PRL accelerates gonadal regression during the onset of photorefractoriness but does not itself cause photorefractoriness. Further, the seasonal increase in PRL is required for the induction of the postnuptial molt.

  2. Actions of Prolactin in the Brain: From Physiological Adaptations to Stress and Neurogenesis to Psychopathology

    PubMed Central

    Torner, Luz

    2016-01-01

    Prolactin (PRL) is one of the most versatile hormones known. It is considered an adaptive hormone due to the key roles it plays in the modulation of the stress response and during pregnancy and lactation. Within the brain, PRL acts as a neuropeptide to promote physiological responses related to reproduction, stress adaptation, neurogenesis, and neuroprotection. The action of PRL on the nervous system contributes to the wide array of changes that occur in the female brain during pregnancy and result in the attenuation of the hypothalamic–pituitary–adrenal axis. Together, all these changes promote behavioral and physiological adaptations of the new mother to enable reproductive success. Brain adaptations driven by PRL are also important for the regulation of maternal emotionality and well-being. PRL also affects the male brain during the stress response, but its effects have been less studied. PRL regulates neurogenesis both in the subventricular zone and in the hippocampus. Therefore, alterations in the PRL system due to stress or exposure to substances that reduce neurogenesis or other conditions, could contribute to maladaptive responses and pathological behavioral outcomes. Here, we review the PRL system and the role it plays in the modulation of stress response and emotion regulation. We discuss the effects of PRL on neurogenesis and neuroprotection, the putative neuronal mechanisms underlying these effects, and their contribution to the onset of psychopathological states such as depression. PMID:27065946

  3. Prolactin response to suckling and maintenance of postpartum amenorrhea among intensively breastfeeding Nepali women.

    PubMed

    Stallings, J F; Worthman, C M; Panter-Brick, C; Coates, R J

    1996-02-01

    The aim of the study was to determine the association between PRL responses to suckling and maintenance of postpartum amenorrhea among breastfeeding mothers. Three blood spot samples (5, 30, and 50 min following a timed nursing bout) were collected from 71 intensively breastfeeding Nepali women for PRL determination. Maternal age, BMI (weight/height2), menstrual status, caste, infant age, nursing bout length, and duration of supplementation were recorded at time of sample collection. Independent and paired t tests, linear regression analyses, and general linear models were used to evaluate differences between cycling (n = 36) and amenorrheic (n = 35) women and associations among variables. Logistic regression analyses were used to relate PRL measures to the odds of maintaining lactational amenorrhea. Amenorrheic breastfeeding mothers had higher (P < .001) PRL levels at all 3 collection times than cycling breastfeeding mothers, and PRL levels declined with time since birth (P < 0.05). The odds (OR) of having ceased lactational amenorrhea was significantly higher (OR = 5.0, 95% Cl = 1.3-19.9) among mothers with lower PRL levels (< or = 10 ng/mL) at 50 min post-sucking, and PRL at 50 min showed a significant dose response relationship with menstrual status. The association between 50 min PRL levels and lactational amenorrhea appears to be independent of time postpartum, maternal age, BMI, nursing bout length, and duration of supplementation. Among intensively nursing women, maintenance of elevated PRL levels across the interbout interval increases the odds of maintaining lactational amenorrhea.

  4. Chicken egg antibodies for immunohistochemical labeling of growth hormone and prolactin in bovine pituitary gland.

    PubMed

    Schmidt, P; Erhard, M H; Schams, D; Hafner, A; Folger, S; Lösch, U

    1993-09-01

    We describe the production of polyclonal chicken antibodies specific for bovine growth hormone (bGH) and prolactin (PRL). Antibodies were generated by immunization of laying hens with recombinant bGH (rbGH), pituitary derived bGH (pbGH), and ovine PRL (oPRL). After the lipoprotein fraction was removed by dextran sulfate precipitation the antibodies were isolated from the egg yolks by ammonium sulfate precipitation. Immunization with rbGH and oPRL generated large amounts of specific antibodies, as revealed by ELISA and Western blot analysis. Antibodies against pbGH showed pronounced crossreactions with oPRL. The antibodies against rbGH and oPRL were well suited for sensitive and specific labeling of the GH- and PRL-synthesizing cells in bovine pituitary glands by immunohistochemistry. In addition, a quick and sensitive procedure for demonstration of both bGH- and PRL-synthesizing cells in a single paraffin section by double immunohistochemistry is presented. The chicken anti-bGH antibodies showed excellent results in combination with rabbit anti-PRL antibodies. The main advantage of avian antibodies in double immunostaining methods is the lack of crossreactions between avian antibodies and mammalian immunoglobulins and receptors which bind to the crystalline fragment of mammalian immunoglobulins (Fc receptors).

  5. Prolactin and growth hormone responses to hypoglycemia in patients with systemic sclerosis and psoriatic arthritis.

    PubMed

    Rovensky, Jozef; Raffayova, Helena; Imrich, Richard; Radikova, Zofia; Penesova, Adela; Macho, Ladislav; Lukac, Jozef; Matucci-Cerinic, Marco; Vigas, Milan

    2006-06-01

    This study compared prolactin (PRL) and growth hormone (GH) responses to hypoglycemia in premenopausal females with systemic sclerosis (SSc) and psoriatic arthritis (PsA) with those in matched healthy controls. No differences were found in glucose and GH responses to hypoglycemia in both groups of patients compared to controls. SSc patients had lower PRL response (P < 0.05) to hypoglycemia compared to controls. PRL response tended to be lower also in PsA patients, however the difference did not reach level of statistical significance (P = 0.11). The present study showed decreased PRL response to hypoglycemia in premenopausal females with SSc.

  6. Hyperprolactinemia and medications for bipolar disorder: systematic review of a neglected issue in clinical practice.

    PubMed

    Pacchiarotti, Isabella; Murru, Andrea; Kotzalidis, Georgios D; Bonnin, C Mar; Mazzarini, Lorenzo; Colom, Francesc; Vieta, Eduard

    2015-08-01

    Drug-induced changes in serum prolactin (sPrl) levels constitute a relevant issue due to the potentially severe consequences on physical health of psychiatric patients such as sexual dysfunctions, osteoporosis and Prl-sensitive tumors. Several drugs have been associated to sPrl changes. Only antipsychotics have been extensively studied as sPrl-elevating agents in schizophrenia, but the extent to which bipolar disorder (BD) treatments affect sPrl levels is much less known. The objective of this systematic review is to summarize the evidence of the effects of drugs used in BD on Prl. This review followed the PRISMA statement. The MEDLINE/PubMed/Index Medicus, EMBASE, and Cochrane Library databases were systematically searched for articles in English appearing from any time to May 30, 2014. Twenty-six studies were included. These suggest that treatments for BD are less likely to be associated with Prl elevations, with valproate, quetiapine, lurasidone, mirtazapine, and bupropion reported not to change PRL levels significantly and lithium and aripiprazole to lower them in some studies. Taking into account the effects of the different classes of drugs on Prl may improve the care of BD patients requiring long-term pharmacotherapy. Based on the results of this review, lithium and valproate appear to be safer due to their low potential to elevate sPrL; among antipsychotics, quetiapine, lurasidone and aripiprazole appear to be similarly safe.

  7. The ontogenesis of human fetal hormones. III. Prolactin.

    PubMed Central

    Aubert, M J; Grumbach, M M; Kaplan, S L

    1975-01-01

    The synthesis and release of human prolactin (hPRL) in the human fetus was assessed by radioimmunoassay analysis of the content and concentration of hPRL in 82 pituitary glands and the concentration of serum hPRL in 47 fetuses of gestational age 68 days to term. Fetal hPRL exhibited parallelism with the reference standard (Lewis 203-1). hPRL was detected by 68 days of gestation (10 wk), the earliest fetal pituitary gland studied; 8 out of 33 pituitaries had a prolactin (PRL) content above 2.0 ng between 10-15 wk gestation. The mean ocntent of PRL in the pituitary gland increased sharply from 14.8 plus or minus 4.6 ng at 15-19 wk to 405 plus or minus 142 ng at 20-24 wk and 542 plus or minus ng at 25-29 wk gestation. By term, the mean content was 2,039 plus or minus 459 (range 493-3,689) and the mean concentration 15.9 plus or minus 2.4 ng/mg (range 7-20). There was a significant positive correlation (P less than 0.001) between the hPRL and human growth hormone (hGH) content of fetal pituitary glands; at term the hPRL/hGH ratio was 1/290. The concentration of serum hPRL between 12 and 24 wk ranged from 2.9 to 67 ng/ml, mean 19.5 plus or minus 2.5 ng/ml )n = 21); by 26 wk fetal serum hPRL increased sharply and attained levels of 300-500 ng/ml in late gestation. At delivery, the mean plasma concentration of hPRL was 167 plus or minus 14.2 ng/ml in 36 umbilical venous specimens and 111.8 plus or minus 12.3 ng/ml in the matched maternal venous specimens. No correlation between serum hPRL and the pituitary content or concentration of hPRL was demonstrable in 12 matched fetal specimens. In five anencephalic infants, umbilical venous hPRL levels were between 65 and 283 ng/ml. In two anencephalic infants, thyrotropin releasing factor (TRF) (200 mug IV) evoked a rise in serum hPRL in one patient from 43 to 156 ng/ml at 30 min, and in the other from 65 to 404 ng/ml at 120 min. In both patients, plasma thyroid-stimulating hormone (TSH) rose from undetectable base-line levels to

  8. Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells.

    PubMed

    Barcus, Craig E; Keely, Patricia J; Eliceiri, Kevin W; Schuler, Linda A

    2016-07-26

    Estrogen receptor α positive (ERα+) breast cancer accounts for most breast cancer deaths. Both prolactin (PRL) and extracellular matrix (ECM) stiffness/density have been implicated in metastatic progression of this disease. We previously demonstrated that these factors cooperate to fuel processes involved in cancer progression. Culture of ERα+ breast cancer cells in dense/stiff 3D collagen-I matrices shifts the repertoire of PRL signals, and increases crosstalk between PRL and estrogen to promote proliferation and invasion. However, previous work did not distinguish ECM stiffness and collagen density. In order to dissect the ECM features that control PRL signals, we cultured T47D and MCF-7 cells on polyacrylamide hydrogels of varying elastic moduli (stiffness) with varying collagen-I concentrations (ligand density). Increasing stiffness from physiological to pathological significantly augmented PRL-induced phosphorylation of ERK1/2 and the SFK target, FAK-Y925, with only modest effects on pSTAT5. In contrast, higher collagen-I ligand density lowered PRL-induced pSTAT5 with no effect on pERK1/2 or pFAK-Y925. Disrupting focal adhesion signaling decreased PRL signals and PRL/estrogen-induced proliferation more efficiently in stiff, compared to compliant, extracellular environments. These data indicate that matrix stiffness shifts the balance of PRL signals from physiological (JAK2/STAT5) to pathological (FAK/SFK/ERK1/2) by increasing PRL signals through focal adhesions. Together, our studies suggest that PRL signaling to FAK and SFKs may be useful targets in clinical aggressive ERα+ breast carcinomas.

  9. Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells

    PubMed Central

    Barcus, Craig E.; Keely, Patricia J.; Eliceiri, Kevin W.; Schuler, Linda A.

    2016-01-01

    Estrogen receptor α positive (ERα+) breast cancer accounts for most breast cancer deaths. Both prolactin (PRL) and extracellular matrix (ECM) stiffness/density have been implicated in metastatic progression of this disease. We previously demonstrated that these factors cooperate to fuel processes involved in cancer progression. Culture of ERα+ breast cancer cells in dense/stiff 3D collagen-I matrices shifts the repertoire of PRL signals, and increases crosstalk between PRL and estrogen to promote proliferation and invasion. However, previous work did not distinguish ECM stiffness and collagen density. In order to dissect the ECM features that control PRL signals, we cultured T47D and MCF-7 cells on polyacrylamide hydrogels of varying elastic moduli (stiffness) with varying collagen-I concentrations (ligand density). Increasing stiffness from physiological to pathological significantly augmented PRL-induced phosphorylation of ERK1/2 and the SFK target, FAK-Y925, with only modest effects on pSTAT5. In contrast, higher collagen-I ligand density lowered PRL-induced pSTAT5 with no effect on pERK1/2 or pFAK-Y925. Disrupting focal adhesion signaling decreased PRL signals and PRL/estrogen-induced proliferation more efficiently in stiff, compared to compliant, extracellular environments. These data indicate that matrix stiffness shifts the balance of PRL signals from physiological (JAK2/STAT5) to pathological (FAK/SFK/ERK1/2) by increasing PRL signals through focal adhesions. Together, our studies suggest that PRL signaling to FAK and SFKs may be useful targets in clinical aggressive ERα+ breast carcinomas. PMID:27344177

  10. Chondroregulatory action of prolactin on proliferation and differentiation of mouse chondrogenic ATDC5 cells in 3-dimensional micromass cultures

    SciTech Connect

    Seriwatanachai, Dutmanee; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Mouse chondrogenic ATDC5 cells expressed PRL receptor mRNAs and proteins. Black-Right-Pointing-Pointer Low PRL concentration (10 ng/mL) increased chondrocyte viability and differentiation. Black-Right-Pointing-Pointer Higher PRL concentrations ( Greater-Than-Or-Slanted-Equal-To 100 ng/mL) decreased viability and increased apoptosis. -- Abstract: A recent investigation in lactating rats has provided evidence that the lactogenic hormone prolactin (PRL) increases endochondral bone growth and bone elongation, presumably by accelerating apoptosis of hypertrophic chondrocytes in the growth plate and/or subsequent chondrogenic matrix mineralization. Herein, we demonstrated the direct chondroregulatory action of PRL on proliferation, differentiation and apoptosis of chondrocytes in 3-dimensional micromass culture of mouse chondrogenic ATDC5 cell line. The results showed that ATDC5 cells expressed PRL receptor (PRLR) transcripts, and responded typically to PRL by downregulating PRLR expression. Exposure to a low PRL concentration of 10 ng/mL, comparable to the normal levels in male and non-pregnant female rats, increased chondrocyte viability, differentiation, proteoglycan accumulation, and mRNA expression of several chondrogenic differentiation markers, such as Sox9, ALP and Hspg2. In contrast, high PRL concentrations of Greater-Than-Or-Slanted-Equal-To 100 ng/mL, comparable to the levels in pregnancy or lactation, decreased chondrocyte viability by inducing apoptosis, with no effect on chondrogenic marker expression. It could be concluded that chondrocytes directly but differentially responded to non-pregnant and pregnant/lactating levels of PRL, thus suggesting the stimulatory effect of PRL on chondrogenesis in young growing individuals, and supporting the hypothesis of hypertrophic chondrocyte apoptosis in the growth plate of lactating rats.

  11. Non-classical effects of prolactin on the innate immune response of bovine mammary epithelial cells: Implications during Staphylococcus aureus internalization.

    PubMed

    Medina-Estrada, Ivan; Alva-Murillo, Nayeli; López-Meza, Joel E; Ochoa-Zarzosa, Alejandra

    2015-12-01

    Staphylococcus aureus has the ability to invade mammary epithelial cells (bMECs) causing mastitis. This event depends primarily on the α5β1 integrin in the host cell. In addition, bMECs are a target for the hormone prolactin (PRL), which can regulate β1 integrin-dependent actions related to differentiation and lactation. Previously, we demonstrated that bovine PRL (bPRL, 5 ng/ml) stimulates S. aureus internalization into bMECs. TLR2 is important during S. aureus infections, but its activation by PRL has not yet been established. The objective of this study was to determine the role of α5β1 integrin and TLR2 during S. aureus internalization into bMECs stimulated with bPRL. We demonstrated that the prolactin-stimulated internalization of S. aureus decreases in response to the blockage of α5β1 integrin (∼ 80%) and TLR2 (∼ 80%). bPRL increases the membrane abundance (MA) of α5β1 integrin (∼ 20%) and induces TLR2 MA (∼ 2-fold). S. aureus reduces the α5β1 integrin MA in bMECs treated with bPRL (∼ 75%) but induces TLR2 MA in bMECs (∼ 3-fold). Bacteria and bPRL did not modify TLR2 MA compared with the hormone alone. S. aureus induces the activation of the transcription factor AP-1, which was inhibited in bMECs treated with bPRL and infected. In general, bPRL induces both pro- and anti-inflammatory responses in bMECs, which are abated in response to bacterial challenge. Interestingly, the canonical Stat-5 transcription factor was not activated in the challenged bMECs and/or treated with bPRL. Taken together, these results support novel functions of prolactin as a modulator of the innate immune response that do not involve the classical prolactin pathway.

  12. High Levels of Serum Prolactin Protect Against Diabetic Retinopathy by Increasing Ocular Vasoinhibins

    PubMed Central

    Arnold, Edith; Rivera, José C.; Thebault, Stéphanie; Moreno-Páramo, Daniel; Quiroz-Mercado, Hugo; Quintanar-Stéphano, Andrés; Binart, Nadine; Martínez de la Escalera, Gonzalo; Clapp, Carmen

    2010-01-01

    OBJECTIVE Increased retinal vasopermeability (RVP) occurs early in diabetes and is crucial for the development of sight-threatening proliferative diabetic retinopathy (DR). The hormone prolactin (PRL) is proteolytically processed to vasoinhibins, a family of peptides that inhibit the excessive RVP related to DR. Here, we investigate the circulating levels of PRL in association with DR in men and test whether increased circulating PRL, by serving as a source of ocular vasoinhibins, can reduce the pathological RVP in diabetes. RESEARCH DESIGN AND METHODS Serum PRL was evaluated in 40 nondiabetic and 181 diabetic men at various stages of DR. Retinal vasoinhibins were measured in rats rendered hyperprolactinemic by placing two anterior pituitary grafts under the kidney capsule and in PRL receptor–null mice. RVP was determined in hyperprolactinemic rats subjected to the intraocular injection of vascular endothelial growth factor (VEGF) or made diabetic with streptozotocin. RESULTS The circulating levels of PRL increased in diabetes and were higher in diabetic patients without retinopathy than in those with proliferative DR. In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye. Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP. This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion, which lowers the levels of circulating PRL and retinal vasoinhibins. CONCLUSIONS Circulating PRL influences the progression of DR after its intraocular conversion to vasoinhibins. Inducing hyperprolactinemia may represent a novel therapy against DR. PMID:20823101

  13. Prolactin-binding components in rabbit mammary gland: characterization by partial purification and affinity labeling

    SciTech Connect

    Katoh, M.; Djiane, J.; Kelly, P.A.

    1985-06-01

    The molecular characteristics of the PRL receptor isolated from rabbit mammary gland microsomes were investigated. Two approaches were employed: 1) affinity purification of PRL receptors and direct electrophoretic analysis, and 2) affinity cross-linking of microsomal receptors with (/sup 125/I)ovine PRL ((/sup 125/I)oPRL). PRL receptors were solubilized from mammary microsomes with 3-((3-cholamidopropyl)dimethylammonio)1-propane sulfonate and purified using an oPRL agarose affinity column. Sodium dodecylsulfate-polyacrylamide gel electrophoresis and silver staining of the gel revealed at least nine bands, including a 32,000 mol wt band which was most intensively labeled with /sup 125/I using the chloramine-T method. Covalent labeling of PRL receptors with (/sup 125/I)oPRL was performed using N-hydroxysuccinimidyl-4-azido benzoate, disuccinimidyl suberate, or ethylene glycol bis (succinimidyl succinate). A single band of 59,000 mol wt was produced by all three cross-linkers when sodium dodecylsulfate-polyacrylamide gel electrophoresis was performed under reducing conditions. Assuming 1:1 binding of hormone and binding subunit and by subtracting the mol wt of (/sup 125/I)oPRL, which was estimated from the migration distance on the gel, the mol wt of the binding subunit was calculated as 32,000. In the absence of dithiothreitol during electrophoresis, only one major hormone-receptor complex band was observed. The same mol wt binding components were also detected in microsomal fractions of rabbit kidney, ovary, and adrenal. A slightly higher mol wt binding subunit was observed in rat liver microsomes. Rabbit liver microsomes revealed five (/sup 125/I)oPRL-binding components, three of which were considered to be those of a GH receptor. Moreover, affinity labeling of detergent-solubilized and affinity purified mammary PRL receptors showed a similar major binding subunit.

  14. Experimental Modification of Rat Pituitary Prolactin Cell Function During and After Spaceflight

    NASA Technical Reports Server (NTRS)

    Hymer, W. C.; Salada, T.; Avery, L.; Grindeland, R. E.

    1996-01-01

    Experimental modification of rat pituitary prolactin cell function during and after spaceflight. This study was done to evaluate the effects of microgravity on prolactin (PRL) cells of the male rat pituitary gland. We used the identical passive closed-vial cell culture system that was described for the culture of growth hormone cells (W C. Hymer, R. E. Grindeland, T. Salada, P. Nye, E. Grossman, and R Lane). After an 8-day spaceflight, all flight media (containing released PRL), as well as extracts (containing intracellular PRL), contained significantly lower amounts of immunoreactive PRL than their corresponding ground control samples. On the other hand, these same samples, when assessed for their biological activities by two different in vitro lymphocyte assays, yielded disparate results that may reflect posttranslational modifications to the hormone molecule. Other data showed that: (1) the apparent molecular weights of released PRL molecules were not altered by microgravity; but (2) the region from which the PRL cells came (dorsal or ventral) made a significant difference in the amount and activity of PRL released from the flight cells. Because there is much current interest in the role that PRL may play in the regulation of the immune system and because changes in both cellular and humoral immunity accompany spaceflight, this study could help define future microgravity research in this area.

  15. EFFECT OF ATRAZINE ON IMPLANTATION AND EARLY PREGNANCY IN FOUR STRAINS OF RATS

    EPA Science Inventory

    Atrazine (ATR) is an herbicide that has been shown to have adverse reproductive effects including alterations in levels of pituitary hormones such as prolactin (prl) and luteinizing hormone (LH). Since prl's action to promote progesterone secretion is essential for the initiatio...

  16. Chromatin remodeling as a mechanism for circadian prolactin transcription: rhythmic NONO and SFPQ recruitment to HLTF.

    PubMed

    Guillaumond, Fabienne; Boyer, Benedicte; Becquet, Denis; Guillen, Severine; Kuhn, Lauriane; Garin, Jerome; Belghazi, Maya; Bosler, Olivier; Franc, Jean-Louis; François-Bellan, Anne-Marie

    2011-08-01

    Most clock-controlled genes (CCGs) lack the specific E-box response element necessary for direct circadian regulation. This is the case for the prolactin (Prl) gene, the expression of which oscillates in individual lactotrope pituitary cells. To characterize the processes underlying this oscillation, we used a lactotrope cell line (GH4C1 cells). In these cells, Prl gene expression fluctuated significantly during 24 h (P=0.0418). Circadian Prl transcription depended on an interaction between the pituitary-specific transcription factor, PIT-1, and the helicase-like transcription factor (HLTF), a SWI/SNF chromatin remodeler, shown here to bind the Prl promoter on an E-box that differs from the specific E-box preferentially bound by clock proteins. Circadian Prl transcription was further accompanied by marked daily chromatin transitions. While neither HLTF nor PIT-1 was rhythmically expressed, NONO and SFPQ, identified as HLTF-associated proteins by mass spectrometry, displayed a circadian pattern and bound rhythmically to the Prl promoter. Furthermore, NONO and SFPQ were functionally involved in circadian Prl transcription since overexpression of both proteins greatly reduced Prl promoter activity (P<0.001) and disrupted its circadian pattern. A mechanism involving a rhythm in paraspeckle protein recruitment is proposed to explain how the core oscillator can generate a circadian pattern of CCGs lacking the specific E-box response element.

  17. Biochemical evaluation of virtual screening methods reveals a cell-active inhibitor of the cancer-promoting phosphatases of regenerating liver.

    PubMed

    Hoeger, Birgit; Diether, Maren; Ballester, Pedro J; Köhn, Maja

    2014-12-17

    Computationally supported development of small molecule inhibitors has successfully been applied to protein tyrosine phosphatases in the past, revealing a number of cell-active compounds. Similar approaches have also been used to screen for small molecule inhibitors for the cancer-related phosphatases of regenerating liver (PRL) family. Still, selective and cell-active compounds are of limited availability. Since especially PRL-3 remains an attractive drug target due to its clear role in cancer metastasis, such compounds are highly demanded. In this study, we investigated various virtual screening approaches for their applicability to identify novel small molecule entities for PRL-3 as target. Biochemical evaluation of purchasable compounds revealed ligand-based approaches as well suited for this target, compared to docking-based techniques that did not perform well in this context. The best hit of this study, a 2-cyano-2-ene-ester and hence a novel chemotype targeting the PRLs, was further optimized by a structure-activity-relationship (SAR) study, leading to a low micromolar PRL inhibitor with acceptable selectivity over other protein tyrosine phosphatases. The compound is active in cells, as shown by its ability to specifically revert PRL-3 induced cell migration, and exhibits similar effects on PRL-1 and PRL-2. It is furthermore suitable for fluorescence microscopy applications, and it is commercially available. These features make it the only purchasable, cell-active and acceptably selective PRL inhibitor to date that can be used in various cellular applications.

  18. Prolactin secretion patterns: basic mechanisms and clinical implications for reproduction.

    PubMed

    Egli, Marcel; Leeners, Brigitte; Kruger, Tillmann H C

    2010-11-01

    Prolactin (PRL) is one of the most versatile hormones in the mammalian body affecting reproductive, sexual, metabolic, immune, and other functions. It is therefore not surprising that the neural control of PRL secretion is complex, involving the coordinated actions of several hypothalamic nuclei. A plethora of experimental data exists on the hypothalamic control of hormone secretion under various physiological stimuli. There have been even mathematical models and computer studies published, which help to understand the complex hypothalamic-pituitary network. Nevertheless, the putative role of PRL for human reproduction still has to be clarified. Here, we review data on the underlying mechanisms controlling PRL secretion using both experimental and mathematical approaches. These investigations primarily focus on rhythmic secretion in rats during early pregnancy or pseudopregnancy, and they point to the important role of oxytocin as a crucial PRL-releasing factor. Recent data on human studies and their theoretical and clinical implications are reviewed as well. In particular, studies demonstrating a sustained PRL surge after sexual climax in males and females are presented, indicating possible implications for both sexual satiation and reproductive functions. Taking these data together, there is evidence for the hypothesis that the PRL surge induced by sexual activity, together with the altered PRL rhythmic pattern, is important for successful initialization of pregnancy not only in rodents but also possibly in humans. However, further investigations are needed to clarify such a role in humans.

  19. What Can We Learn from Rodents about Prolactin in Humans?

    PubMed Central

    Ben-Jonathan, Nira; LaPensee, Christopher R.; LaPensee, Elizabeth W.

    2008-01-01

    Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans. PMID:18057139

  20. Stimulation of prolactin receptor induces STAT-5 phosphorylation and cellular invasion in glioblastoma multiforme

    PubMed Central

    Alkharusi, Amira; Yu, Shengze; Landázuri, Natalia; Zadjali, Fahad; Davodi, Belghis; Nyström, Thomas; Gräslund, Torbjörn; Rahbar, Afsar; Norstedt, Gunnar

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans and is characterized with poor outcome. In this study, we investigated components of prolactin (Prl) system in cell models of GBM and in histological tissue sections obtained from GBM patients. Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique. In addition, stimulation of U251-MG and U87-MG cells but not U373 with Prl resulted in increased STAT5 phosphorylation and only in U251-MG cells with increased cellular invasion. Furthermore, STAT5 phosphorylation and cellular invasion induced in Prl stimulated cells were significantly reduced by using a Prl receptor antagonist that consists of Prl with four amino acid replacements. We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion. PMID:27788487

  1. Variation in the coding and 3’ untranslated regions of the porcine prolactin receptor short form modifies protein expression and function

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The actions of prolactin (PRL) are mediated by both long (LF) and short isoforms (SF) of the PRL receptor (PRLR). Here, we report on a genetic and functional analysis of the porcine PRLR (pPRLR) SF. Three single nucleotide polymorphisms (SNPs) within exon 11 of the pPRLR-SF give rise to four amino a...

  2. Reliability and Expected Loss: A Unifying Principle.

    ERIC Educational Resources Information Center

    Cooil, Bruce; Rust, Roland T.

    1994-01-01

    It is proposed that proportional reduction in loss (PRL) be used as a theoretical basis to derive, justify, and interpret reliability measures to gauge reliability on a zero-to-one scale. This PRL approach simplifies the interpretation of existing measures (e.g., generalizability-theory measures). (SLD)

  3. Tissue-specific Regulation of Porcine Prolactin Receptor Expression by Estrogen, Progesterone and Prolactin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prolactin (PRL) acts through its receptor (PRLR) via both endocrine and local paracrine/autocrine pathways to regulate biological processes including reproduction and lactation. We analyzed the tissue and stage of gestation-specific regulation of PRL and PRLR expression in various tissues of pigs. ...

  4. Identification of Polymorphisms in the Enhancer Region of the Bovine Prolactin Gene and Association with Fertility in Beef Cows

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives were to investigate the polymorphic nature of the enhancer region of the bovine prolactin (PRL) gene and determine the association of these polymorphisms with fertility in beef cows. Primers were designed to amplify a 500 base pair fragment 892 to 1392 bases upstream of the bovine PRL gen...

  5. Bovine lactotroph cultures for the study of prolactin synthesis functions.

    PubMed

    Wang, Jianfa; Yang, Zhanqing; Fu, Shoupeng; Liu, Bingrun; Wu, Dianjun; Wang, Wei; Sun, Dongbo; Wu, Rui; Liu, Juxiong

    2016-03-01

    The aim of this study was to establish a bovine anterior pituitary-derived lactotroph (BAPDL) line that expresses prolactin (PRL) in vitro to study the mechanisms of bovine PRL synthesis and secretion. Immunohistochemistry assay of PRL in the newborn calves' anterior pituitary glands showed that most lactotrophs were located within the superior border of the lateral wings of the anterior pituitary. Tissues of the superior border of the lateral wings of the anterior pituitary were dispersed and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). The limiting dilution method was used to establish BAPDL from single cell clone. BAPDL cells constantly expressed mRNAs for PRL and pituitary-specific transcription factor 1 (Pit-1) gene and grew steadily and rapidly in the DMEM supplemented with 10% FBS. PRL immunoreactivity was present in BAPDL at passage 20. The concentration of bovine PRL in BAPDL at passage 20 culture supernatant was decreased to below 35% compared with that in BAPDL at passage 1. The effects of human epidermal growth factor (hEGF) and dopamine (DA) on the expression and secretion of PRL in BAPDL at passage 4 were also investigated. The results are consistent with those of previous studies. Thus, it can be used successfully for studying the mechanisms of stimuli regulating PRL synthesis and release.

  6. Coexistence of macroprolactinaemia and hyperprolactinaemia in women with oligo-/amenorrhoea is associated with high risk of pituitary adenomas.

    PubMed

    Lewandowski, Krzysztof C; Gasior-Perczak, Danuta; Kowalska, Aldona; Lewinski, Andrzej

    2014-05-01

    Macroprolactin may cause elevation of prolactin (PRL) concentrations measured by standard assays. In our study, we assessed the prevalence of pituitary lesions in women with macroprolactinaemia and either oligomenorrhoea or secondary amenorrhoea. Pituitary MRI scans were performed in 61 women aged 31.0  ±  6.7 years (mean  ±  SD), with raised PRL concentrations due to macroprolactinaemia, detected by 25% polyethylene glycol (PEG) precipitation method (PRL recovery <40%). After PEG precipitation of macroprolactin, free PRL concentrations were still raised in 36 (59%) women. Microadenomas were detected in 10 patients out of 61 (16.4%), with raised free PRL in 9 of these cases, while macroadenomas were detected in 4 out of 61 (6.6%) women, all of whom also had raised free PRL. In case of coexistence of macroprolactinaemia and raised free PRL after PEG precipitation of macroprolactin, the chance of finding of either a micro- or a macroadenoma was 36% (13 cases out of 36). We conclude that hyperprolactinaemia and macroprolactinaemia may coexist in the same patient. Furthermore, if free PRL is raised after PEG precipitation of macroprolactin, then the chance of finding either a pituitary micro- or macroadenoma in women with oligo-/amenorrhoea is over 30%. Therefore pituitary magnetic resonance imaging is mandatory in all such cases.

  7. Proliferation and mRNA expression of absorptive villous cell markers and mineral transporters in prolactin-exposed IEC-6 intestinal crypt cells.

    PubMed

    Teerapornpuntakit, Jarinthorn; Wongdee, Kannikar; Thongbunchoo, Jirawan; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2012-06-01

    During pregnancy and lactation, prolactin (PRL) enhances intestinal absorption of calcium and other minerals for fetal development and milk production. Although an enhanced absorptive efficiency is believed to mainly result from the upregulation of mineral transporters in the absorptive villous cells, some other possibilities, such as PRL-enhanced crypt cell proliferation and differentiation to increase the absorptive area, have never been ruled out. Here, we investigated cell proliferation and mRNA expression of mineral absorption-related genes in the PRL-exposed IEC-6 crypt cells. As expected, the cell proliferation was not altered by PRL. Inasmuch as the mRNA expressions of villous cell markers, including dipeptidylpeptidase-4, lactase and glucose transporter-5, were not increased, PRL was not likely to enhance crypt cell differentiation into the absorptive villous cells. In contrast to the previous findings in villous cells, PRL was found to downregulate the expression of calbindin-D(9k), claudin-3 and occludin in IEC-6 crypt cells, while having no effect on transient receptor potential vanilloid family channels-5/6, plasma membrane Ca(2+)-ATPase (PMCA)-1b and Na(+)/Ca(2+) exchanger-1 expression. In conclusion, IEC-6 crypt cells did not respond to PRL by increasing proliferation or differentiation into villous cells. The present results thus supported the previous hypothesis that PRL enhanced mineral absorption predominantly by increasing transporter expression and activity in the absorptive villous cells.

  8. Identification of the reptilian prolactin and its receptor cDNAs in the leopard gecko, Eublepharis macularius.

    PubMed

    Kato, Keisuke; Ikemoto, Tadahiro; Park, Min Kyun

    2005-02-14

    In spite of their physiological significance, there is no available information about the nucleotide sequences of prolactin (PRL) and its receptor in reptilian species. In order to fill this gap, PRL and its receptor cDNAs were identified in a reptilian species, the leopard gecko Eublepharis macularius. The deduced leopard gecko PRL polypeptide showed high identities with the corresponding polypeptides of other reptiles. The leopard gecko PRL receptor (PRLR) was estimated to have tandem repeated regions in its extracellular domain, which had been originally found in avian PRLR. Molecular phylogenetic analysis suggests that these tandem repeated regions were generated by the duplication of the extracellular region in the latest common ancestor among reptiles and birds. In addition, tissue distributions of PRL and PRLR in the leopard gecko were examined by the reverse transcription-polymerase chain reaction (RT-PCR). PRLR mRNA was detected in all tissues examined and highly expressed in the whole brain, pituitary, intestine, kidney, ovary, oviduct and testis. Whereas, PRL mRNA was expressed in the whole brain, pituitary, ovary and testis. The co-expressions of PRL and its receptor in some extrapituitary organs suggest that PRL acts as an autocrine/paracrine factor in such organs of the leopard gecko.

  9. Serum prolactin is associated with apoptosis in men with human immunodeficiency virus infection.

    PubMed

    Parra, A; Ramírez-Peredo, J; Larrea, F; Pérez-Romano, B; Cabrera, V; Torres, I; Reyes-Núñez, V; Ruiz-Argüelles, G; Ruiz-Argüelles, A

    2001-06-01

    We examined the in vivo and in vitro production of prolactin (PRL) in 20 untreated HIV-infected men compared to 14 uninfected men and its association with the cell cycle and apoptosis. Compared to uninfected men, the HIV-infected men had: (i) higher fasting serum bioactive (BIO) PRL; (ii) lower serum immunoreactive (RIA) and BIO-PRL responses to intravenous metoclopramide; (iii) greater BIO-RIA PRL ratio both fasting and during intravenous metoclopramide; (iv) lower percentage of non-stimulated PBMC in the G0/G1 phase, but a higher percentage in the S phase, of the cell cycle with normal response to Concanavalin-A; and (v) higher in vitro production of BIO-PRL by non-stimulated PBMC, which was blocked after Concanavalin-A. Fasting serum BIO-PRL positively correlated with the percent of non-stimulated PBMC in S + G2/M phases. The percentage of apoptotic PBMC negatively correlated with CD4+ T lymphocytes and with the area under the serum RIA-PRL curve, but positively correlated with the area under the curve for the BIO/RIA ratio. These results suggest that in these HIV-infected men: (i) a diminished dopaminergic tone may exist, as an adaptive mechanism attempting to survive; and (ii) BIO-PRL may participate as a cofactor in the stimulation of T-cell proliferation.

  10. Prolactin has a pathogenic role in systemic lupus erythematosus.

    PubMed

    Jara, Luis J; Medina, Gabriela; Saavedra, Miguel A; Vera-Lastra, Olga; Torres-Aguilar, Honorio; Navarro, Carmen; Vazquez Del Mercado, Monica; Espinoza, Luis R

    2017-01-28

    Prolactin, a 23-kDa peptide hormone, is produced by the anterior pituitary gland and extrapituitary sites including the immune cells. Prolactin (PRL) participates in innate and adaptive immune response. PRL stimulates the immune cells by binding to receptor (PRL-R). Binding of PRL to its receptor activates the Janus kinase-signal transducer (JAK-STAT). Activation of these cascades results in endpoints such as immunoestimulator and immunosupressor action. Prolactin belongs to the network of immune-neuroendocrine interaction. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE), and new evidence has confirmed a significant correlation between serum PRL levels and disease activity. PRL participates in activation of SLE during pregnancy and in pathogenesis of lupus nephritis, neuropsychiatric, serosal, hematologic, articular, and cutaneous involvement. Hyperprolactinemia was associated with increase IgG concentrations, anti-DNA antibodies, immune complex, glomerulonephritis, and accelerated mortality in murine lupus. Bromocriptine, a dopamine analog that suppresses PRL secretion, was associated with decreased lupus activity, prolonged lifespan, and restoration of immune competence in experimental model. In clinical trials, bromocriptine and derivative drugs showed beneficial therapeutic effect in treating human lupus, including pregnancy. Taken together, clinical and experimental results leave little doubt that PRL indeed contributes to the pathogenesis and clinical expression of SLE.

  11. Receptor-Independent Ectopic Activity of Prolactin Predicts Aggressive Lung Tumors and Indicates HDACi-Based Therapeutic Strategies

    PubMed Central

    Le Bescont, Aurore; Vitte, Anne-Laure; Debernardi, Alexandra; Curtet, Sandrine; Buchou, Thierry; Vayr, Jessica; de Reyniès, Aurélien; Ito, Akihiro; Guardiola, Philippe; Brambilla, Christian; Yoshida, Minoru; Brambilla, Elisabeth

    2015-01-01

    Abstract Aims: Ectopic activation of tissue-specific genes accompanies malignant transformation in many cancers. Prolactin (PRL) aberrant activation in lung cancer was investigated here to highlight its value as a biomarker. Results: PRL is ectopically activated in a subset of very aggressive lung tumors, associated with a rapid fatal outcome, in our cohort of 293 lung tumor patients and in an external independent series of patients. Surprisingly PRL receptor expression was not detected in the vast majority of PRL-expressing lung tumors. Additionally, the analysis of the PRL transcripts in lung tumors and cell lines revealed systematic truncations of their 5′ regions, including the signal peptide-encoding portions. PRL expression was found to sustain cancer-specific gene expression circuits encompassing genes that are normally responsive to hypoxia. Interestingly, this analysis also indicated that histone deacetylase (HDAC) inhibitors could counteract the PRL-associated transcriptional activity. Innovation and Conclusion: Altogether, this work not only unravels a yet unknown oncogenic mechanism but also indicates that the specific category of PRL-expressing aggressive lung cancers could be particularly responsive to an HDAC inhibitor-based treatment. Antioxid. Redox Signal. 23, 1–14. PMID:24512221

  12. Radioautographic localization of prolactin messenger RNA on histological sections by in situ hybridization.

    PubMed

    Pochet, R; Brocas, H; Vassart, G; Toubeau, G; Seo, H; Refetoff, S; Dumont, J E; Pasteels, J L

    1981-05-04

    In situ hybridization of complementary [H3]DNA ([H3]cDNA) synthetized from purified rat prolactin messenger RNA (rPRL mRNA) was performed to specifically identify on histologic sections of rat hypophysis cells expressing the PRL gene. Radioautographic labelling occurred over weakly acidophilic cells, while other acidophils, with darker cytoplasm did not contain more silver grains than blood vessels.

  13. Increased demand for steroid therapy in hyperprolactinemic patients with rheumatoid arthritis.

    PubMed

    Rovenský, J; Bakosová, J; Payer, J; Lukác, J; Raffayová, H; Vigas, M

    2001-01-01

    The role of increased plasma prolactin (PRL) in rheumatoid arthritis (RA) is not fully explained. The aim of this study was to compare the clinical features and the treatment administered in RA patients with normal and elevated plasma PRL concentrations. Forty-nine patients with rheumatoid arthritis and 16 healthy subjects were included in this study In healthy controls, PRL concentrations were 7.6 micro/l (median), in 34 patients plasma PRL was less than 20 micro/l (9.9 micro/l) and in 15 patients it was elevated, with a median of 26.7 micro/l. No differences in clinical features were found compared with normal or increased plasma PRL. The introduction of corticoid therapy produced a significant difference. Steroid therapy was administered to 93% of the patients with hyperprolactinemia, compared with 59% of those with normal PRL concentrations. Daily prednisone doses higher than 5 mg were administered to 43% of the patients with elevated PRL, compared with 25% of patients with normal prolactin concentrations. In conclusion, the clinical feature of patients with rheumatoid arthritis did not differ in subjects with elevated PRL concentrations and in those with normal concentrations. The difference between these two groups was in the higher demand for steroid therapy in patients with hyperprolactinemia.

  14. Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents

    PubMed Central

    Matera, Emilia; Petruzzelli, Maria G.; Simone, Marta; Lamanna, Anna L.; Pastore, Adriana; Palmieri, Vincenzo O.; Margari, Francesco

    2015-01-01

    The aim of this prospective observational study was to investigate the variations of serum prolactin hormone (PRL) in a sample of 34 drug-naive patients (mean age 13 years) who started risperidone therapy assuming that several factors may favor the increase in serum PRL. Serum PRL and hyperprolactinemia clinical signs were examined at baseline (T0) and after almost 3 months of treatment (T1). We considered sex, pubertal status, risperidone dosage, psychiatric diagnosis, and any personal/family history of autoimmune diseases. The mean serum PRL value increased between T0 and T1 (P=0.004). The mean serum PRL was higher in females in the pubertal/postpubertal stage and for risperidone dosage up 1 mg/day. Hyperprolactinemia was found in 20% of patients at T0 and in 38% of patients at T1 (P=0.03). The mean serum PRL increase was greater in early-onset schizophrenia spectrum psychosis patients compared with no-early-onset schizophrenia spectrum psychosis patients (P=0.04). The increase in PRL was higher in patients with a personal and a family history of autoimmune diseases. This study suggests that the increase in serum PRL in patients treated with risperidone may be linked not only to the drug and its dosage but also to several risk factors such as sex, pubertal stage, psychiatric disease, and autoimmune disorders. PMID:25514607

  15. Prolactin circadian rhythm persists throughout lactation in women.

    PubMed

    Stern, J M; Reichlin, S

    1990-01-01

    To determine whether the prolactin (PRL) circadian rhythm, with its characteristic nocturnal rise, persists during the hyperprolactinemia of lactation, PRL levels were analyzed in blood samples collected hourly for 24 h from 20 mothers, 4-46 months postpartum. The circadian rhythm of PRL persisted throughout lactation as manifested by: (1) significantly higher mean nighttime than daytime PRL levels in the whole sample, despite higher daytime nursing durations; (2) the distribution of zenith levels which most frequently occur between 23.00 and 07.00 h, when nursing duration is lowest, and which are almost absent between 07.00 and 23.00 h, when nursing duration is highest, and of nadir levels, which have an opposite pattern; (3) spontaneous PRL surges that are more frequent, longer, and of higher magnitude at night than during the day, and (4) the larger magnitude of suckling-induced PRL release from late afternoon through the night compared to the morning in some women. Our data suggest that the mechanisms responsible for the circadian rhythm in PRL secretion are relatively independent of the mechanisms of suckling-induced release. We propose that the nocturnal rise in PRL during lactation functions to ensure a robust milk supply during an extensive nonsuckling interval.

  16. Prolactin stimulates sodium and chloride ion channels in A6 renal epithelial cells

    PubMed Central

    Greenlee, Megan M.; Mitzelfelt, Jeremiah D.; Duke, Billie Jeanne; Al-Khalili, Otor; Bao, Hui-Fang

    2015-01-01

    Many hormonal pathways contribute to the regulation of renal epithelial sodium channel (ENaC) function, a key process for maintaining blood volume and controlling blood pressure. In the present study, we examined whether the peptide hormone prolactin (PRL) regulates ENaC function in renal epithelial cells (A6). Basolateral application of several different concentrations of PRL dramatically stimulated the transepithelial current in A6 cells, increasing both amiloride-sensitive (ENaC) and amiloride-insensitive currents. Using cell-attached patch clamp, we determined that PRL increased both the number (N) and open probability (Po) of ENaC present in the apical membrane. Inhibition of PKA with H-89 abolished the effect of PRL on amiloride-sensitive and insensitive transepithelial currents and eliminated the increase in ENaC NPo with PRL exposure. PRL also increased cAMP in A6 cells, consistent with signaling through the cAMP-dependent PKA pathway. We also identified that PRL induced activity of a 2-pS anion channel with outward rectification, electrophysiological properties consistent with ClC4 or ClC5. RT-PCR only detected ClC4, but not ClC5 transcripts. Here, we show for the first time that PRL activates sodium and chloride transport in renal epithelial cells via ENaC and ClC4. PMID:25587116

  17. The Lipidosterolic Extract fromSerenoa repens Interferes with Prolactin Receptor Signal Transduction.

    PubMed

    Vacher, P.; Prevarskaya, N.; Skryma, R.; Audy, M.C.; Vacher, A.M.; Odessa, M.F.; Dufy, B.

    1995-10-01

    The lipidosterolic extract from the saw palmetto Serenoa repens (LSESr) is commonly used for medical treatment of benign prostatic hypertrophia due to its ability to inhibit 5alpha-reductase which permits the conversion of testosterone to dihydrotestosterone, the active androgen on prostate cell proliferation. However, the complete action mechanism of LSESr is still unknown. Several lines of evidence suggest that, in addition to inhibition of 5alpha-reductase, it may interfere with the action of prolactin (PRL). We therefore investigated a possible interference of this plant extract with another hormone that controls prostate gland growth, PRL. As the action mechanism of PRL is now fully documented in Chinese hamster ovary cells expressing the PRL receptor, we have conducted our experiments on these cells. In this study, using electrophysiological (whole-cell recording and single-channel recording), microspectrofluorimetric and biochemical techniques, we show that LSESr (1-30 &mgr;g/ml) reduced the basal activity of a K(+) channel and of protein kinase C (PKC) in CHO cells. In addition, pretreatment of the cells with 1-10 &mgr;g/ml LSESr for 6-36 h abolished the effects of PRL on [Ca(2+)](i), K(+) conductance and PKC. LSESr may block PRL-induced prostate growth by inhibiting several steps of PRL receptor signal transduction. LSESr may also be useful for diseases implicating PRL. Copyright 1995 S. Karger AG, Basel

  18. Dopamine–prolactin pathway potentially contributes to the schizophrenia and type 2 diabetes comorbidity

    PubMed Central

    Gragnoli, C; Reeves, G M; Reazer, J; Postolache, T T

    2016-01-01

    Schizophrenia (SCZ) and type 2 diabetes (T2D) are clinically associated, and common knowledge attributes this association to side effects of antipsychotic treatment. However, even drug-naive patients with SCZ are at increased risk for T2D. Dopamine dysfunction has a central role in SCZ. It is well-known that dopamine constitutively inhibits prolactin (PRL) secretion via the dopamine receptor 2 (DR2D). If dopamine is increased or if dopamine receptors hyperfunction, PRL may be reduced. During the first SCZ episode, low PRL levels are associated with worse symptoms. PRL is essential in human and social bonding, as well as it is implicated in glucose homeostasis. Dopamine dysfunction, beyond contributing to SCZ symptoms, may lead to altered appetite and T2D. To our knowledge, there are no studies of the genetics of the SCZ–T2D comorbidity focusing jointly on the dopamine and PRL pathway in the attempt to capture molecular heterogeneity correlated to possible disease manifestation heterogeneity. In this dopamine–PRL pathway-focused-hypothesis-driven review on the association of SCZ with T2D, we report a specific revision of what it is known about PRL and dopamine in relation to what we theorize is one of the missing links between the two disorders. We suggest that new studies are necessary to establish the genetic role of PRL and dopamine pathway in SCZ–T2D comorbidity. PMID:27093067

  19. Mechanisms subserving the physiological nocturnal relative hypoprolactinemia of healthy older men: dual decline in prolactin secretory burst mass and basal release with preservation of pulse duration, frequency, and interpulse interval--a General Clinical Research Center study.

    PubMed

    Iranmanesh, A; Mulligan, T; Veldhuis, J D

    1999-03-01

    Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21-34 yr) and 8 older (aged 62-72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (+/- SEM) serum PRL concentration was significantly reduced at 4.3 +/- 0.78 microg/L in older men compared with 9.5 +/- 1.2 microg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = +0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 +/- 0.23 (older) vs. 3.9 +/- 0.57 microg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 +/- 0.00027 (older) vs. 0.00065 +/- 0.0002 microg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 +/- 5.3% in young and 99 +/- 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging. Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic

  20. Effects of cysteamine on pituitary, MTTW15 tumor, and serum prolactin levels measured by rat lymphoma cell bioassay and radioimmunoassay

    SciTech Connect

    Parsons, J.A.; Peterson, E.K.; Hartfel, M.A.

    1984-05-01

    Cysteamine (CSH), a sulfhydryl compound, reduces both serum and anterior pituitary (AP) PRL measured by RIA. We have used the Nb2 lymphoma cell bioassay (BIO) for PRL to evaluate possible CSH-related changes in PRL levels in sera and tissues of male and MtTW15 mammosomatotropic tumor-bearing female rats. Experimental animals received a single sc injection of CSH (300 mg/kg), and samples were collected 0.5-24 h later. Since CSH and serum from CSH rats were toxic in BIO, samples were dialyzed before assay. All samples were evaluated for PRL and GH by RIA as well. A significant decrease (P less than 0.05) in BIO serum PRL was evident in male rats 0.5 h after CSH; levels remained low for 24 h. Serum PRL by RIA was significantly depressed at 4 h but not at 0.5 h or 24 h. PRL in AP extracts was decreased (60-90%) at all times by BIO and RIA. Significant decreases of BIO- and RIA-detectable PRL were recorded in serum and tissues (AP and tumors) at 4 h in tumor rats. Sequentially bled (0.5-4 h) CSH-treated tumor-bearing rats showed 50% and 80% reductions in serum PRL at 1 and 4 h by both BIO and RIA. CSH had no effect on GH levels in sera and tissues of any animal studied at any time interval. Our results substantiate earlier reports on CSH-induced decreases in RIA-detectable PRL. They show that such changes cannot be attributed to assay effects alone, as significant decreases in circulating and stored PRL (both AP and tumor) were evident by BIO. Results with tissue extracts were the most dramatic. They suggest an action of CSH or a metabolic intermediate with stored PRL which reduces both extractable PRL and hormone release. Such an effect of CSH on PRL extraction has been suggested by others. Whatever the mechanism, it appears to be relatively specific, since GH cells were not affected.

  1. Prolactin induces tuberoinfundibular dopaminergic neurone differentiation in Snell dwarf mice if administered beginning at 3 days of age.

    PubMed

    Khodr, C E; Hurley, D L; Phelps, C J

    2009-06-01

    The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones secrete dopamine, which inhibits prolactin secretion. TIDA neurone numbers are deficient in Ames (df/df) and Snell (dw/dw) dwarf mice, which lack prolactin, growth hormone and thyroid-stimulating hormone. Prolactin therapy initiated before 21 days maintains normal-sized TIDA neurone numbers in df/df mice and, when initiated as early as 7 days, maintains the maximum TIDA neurone numbers observed in dw/dw development, which are decreased compared to those in normal mice. The present study investigated the effect of prolactin dose and species on TIDA neurone development. Snell dwarf and normal mice were treated with saline, 5 microg of ovine prolactin (oPRL), 50 microg of oPRL, or 50 microg of recombinant mouse prolactin (rmPRL) beginning at 3 days of age. Brains were analysed at 45 days using catecholamine histofluorescence, and immunohistochemistry for tyrosine hydroxylase or bromodeoxyuridine. Normal mice had greater (P PRL-treated dw/dw mice were greater (P PRL- and rmPRL-treated dw/dw mice, which were greater (P PRL-treated dw/dw mice also had greater (P < 0.01) TIDA neurone numbers than the maximum numbers observed in untreated dw/dw mice development. Among saline, 5 microg oPRL and 50 microg oPRL treatments, but not rmPRL, A14 neurone numbers were higher (P PRL, but not oPRL, had increased BrdU incorporation in the periventricular area surrounding the third ventricle and median eminence and in the arcuate nucleus. The data obtained in the present study indicate that oPRL, but not rmPRL, when given at a high enough

  2. Role of prostaglandin E2 and leukotriene B4 in skin reaction induced by transdermal application of propranolol.

    PubMed

    Kobayashi, I; Hosaka, K; Maruo, H; Saeki, Y; Kamiyama, M; Konno, C; Gemba, M

    2000-02-01

    Dermal application of propranolol (PRL) induced formation of erythema and edema, and pseudoeosinophil infiltration in epidermis and dermis at the application site in guinea pigs. We investigated the production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) at the application site of PRL and the role of these inflammatory chemical mediators in the occurrence of the skin reactions. PGE2 was found to be produced at the application site slightly after the accumulation of PRL released from the adhesive bandage in the patch test, and the amount of PGE2 increased continuously, with a peak value obtained at 24 h after application. The time-course changes resembled those of delta a* value, the index of erythema formation determined by colorimetric measurement, and edema formation. The production of PGE2 by dermal application of PRL was suppressed by local pretreatment with dexamethasone or indomethacin. However, no notable production of LTB4 was observed at the application site of PRL.

  3. Polyhormonal regulation of avian and mammalian corticosteroidogenesis in vitro.

    PubMed

    Carsia, R V; Scanes, C G; Malamed, S

    1987-01-01

    1. The combined actions of ACTH, corticosterone and prolactin (PRL) in the acute regulation of corticosteroidogenesis were investigated using isolated adrenocortical cells from intact and hypophysectomized (hypox) rats (Rattus norvegicus) and from intact male domestic fowl (Gallus gallus domesticus). 2. Exogenous corticosterone suppressed to about 50% ACTH-induced corticosterone production of cells from either species. This suppression, in part, was due to corticosterone degradation. 3. oPRL, in the presence or absence of ACTH, raised corticosterone production of hypox rat cells, but not intact rat and domestic fowl cells. 4. In addition, oPRL counteracted the corticosterone-induced suppression of net ACTH-stimulated corticosterone production of hypox rat and intact domestic fowl cells, but not intact rat cells. 5. The potency of oPRL with domestic fowl cells was 4 times that with hypox rat cells. 6. Furthermore, in domestic fowl cells, the effect of oPRL was Ca2+-dependent.

  4. Pivotal roles of alpha-melanocyte-stimulating hormone and the melanocortin 4 receptor in leptin stimulation of prolactin secretion in rats.

    PubMed

    Watanobe, Hajime; Schiöth, Helgi B; Izumi, Junkichi

    2003-04-01

    Leptin, the obese gene product, was reported to stimulate prolactin (PRL) secretion, but the neuroendocrine mechanism underlying this hormonal response is largely unknown. Thus, in this study we examined the involvement of several important PRL regulators in the leptin-induced PRL secretion in male rats. Compared with the values in normally fed rats, food deprivation for 3 days significantly decreased both PRL and leptin levels in the plasma. These changes were reverted to normal by a 3-day constant infusion of 75 microg/kg/day of leptin to the fasted rats, while 225 microg/kg/day of leptin further elevated both PRL and leptin levels. These four groups of animals were used for the following experiments. Results of dopamine and serotonin turnover studies in the brain and the pituitary indicated that neither of these biogenic amines plays a primary role in mediating leptin's effects on PRL. Repeated intracerebroventricular injections over 72 h of neutralizing antibodies against vasoactive intestinal peptide, PRL-releasing peptide, or beta-endorphin, did not significantly suppress the leptin actions. However, both the blockade of the melanocortin (MC) 4 receptor (R) and the immunoquenching of brain alpha-melanocyte-stimulating hormone (alpha-MSH) completely abolished the leptin-induced PRL release, and the stimulation of the MC4-R, but not the MC3-R, significantly elevated PRL levels in the fasted rats. These results suggest that alpha-MSH, a cleaved peptide from pro-opiomelanocortin of which synthesis is stimulated by leptin, may be the pivotal neuropeptide in the brain mediating the leptin's stimulatory influence on PRL secretion. It was also suggested that the MC4-R may be the primary subtype of the MC-Rs mediating this action of alpha-MSH.

  5. Expression of autocrine prolactin and the short isoform of prolactin receptor are associated with inflammatory response and apoptosis in monocytes stimulated with Mycobacterium bovis proteins.

    PubMed

    López-Rincón, Gonzalo; Mancilla, Raúl; Pereira-Suárez, Ana L; Martínez-Neri, Priscila A; Ochoa-Zarzosa, Alejandra; Muñoz-Valle, José Francisco; Estrada-Chávez, Ciro

    2015-06-01

    Increased levels of prolactin (PRL) have recently been associated with carcinogenesis and the exacerbation of autoimmune diseases, and might be involved in the progression of tuberculosis (TB). To investigate the relationship between PRL and prolactin receptor (PRLr) expression with inflammatory response and apoptosis in monocytes, we used THP-1 cells stimulated with antigens of the Mycobacterium bovis AN5 strain culture filtrate protein (CFP-M. bovis). Western blot (WB), real-time Polymerase chain reaction (PCR), and immunocytochemistry were performed to identify both PRL and PRLr molecules. PRL bioactivity and proinflammatory cytokine detection were assessed. The results showed that PRL and PRLr messenger RNA (mRNA) were synthesized in THP-1 monocytes induced with CFP-M. bovis at peaks of 176- and 404-fold, respectively. PRL forms of 60 and 80kDa and PRLr isoforms of 40, 50, and 65kDa were also identified as time-dependent, while 60-kDa PRL, as well as 40-, and 50-kDa PRLr, were found as soluble forms in culture media and later in the nucleus of THP-1 monocytes. PRL of 60kDa released by monocytes exhibited bioactivity in Nb2 cells, and both synthesized PRL and synthesized PRLr were related with nitrite and proinflammatory cytokine levels proapoptotic activity in CFP-M. bovis-induced monocytes. Our results suggest the overexpression of a full-autocrine loop of PRL and PRLr in monocytes that enhances the inflammatory response and apoptosis after priming with M. bovis antigens.

  6. The in vitro effect of prolactin on the growth, motility and expression of prolactin receptors in larvae of Toxocara canis.

    PubMed

    Chávez-Güitrón, L E; Morales-Montor, J; Muñoz-Guzmán, M A; Nava-Castro, K E; Ramírez-Álvarez, H; Moreno-Méndoza, N A; Hernández-Cervantes, R; Alba-Hurtado, F

    2016-07-15

    The in vitro effect of prolactin (PRL) on the growth and motility of Toxocara canis larvae was assessed. Additionally, the expression and location of prolactin receptors (PRL-Rs) were determined in the larvae. Larvae of T. canis were incubated with different concentrations of PRL for different periods of time. The stimulated larvae accelerated their enlargement and increased their motility. The mean percentage of PRL-R+ cells in non-stimulated larvae, measured by flow cytometry was 7.3±0.3%. Compared with non-stimulated larvae, the mean fluorescence intensity (p<0.05) increased in larvae incubated with 40ng/mL of PRL for 10 days. A 465-bp length fragment was amplified from larvae gDNA by PCR. The sequence of this fragment showed 99% similarity with the gene fragment that codes for the PRL-R of the domestic dog. A high concentration of PRL-Rs was immune-located in the posterior region of the larval intestine; therefore, the intestinal cells in this region were most likely the targets for this hormone. Based on these results, PRL-Rs were identified in T. canis larvae, and the in vitro stimulation with PRL increased the number of these receptors, accelerated the growth and modified the activity of larvae. All of the above suggest that T. canis larvae are evolutionarily adapted to recognize the PRL of their definitive host and furthermore might explain the reactivation of tissue-arrested larvae during the gestation of bitches, which does not occur in gestating females of other species.

  7. Relationship between prolactin, reproductive experience, and parental care in a biparental songbird, the zebra finch (Taeniopygia guttata).

    PubMed

    Smiley, Kristina O; Adkins-Regan, Elizabeth

    2016-06-01

    Hormonal systems have long been thought to play an important role in stimulating the onset of parental behavior, a critical component of reproductive success in a variety of taxa. Elevations in the peptide hormone prolactin (PRL) have been repeatedly positively correlated with the onset and maintenance of parental care across vertebrate species. A causal role for PRL in parental care has been established in several mammalian species, but less evidence for a causal role of PRL and parental care exists in birds. The zebra finch, a socially monogamous, biparental songbird, is an exceptionally useful animal model to study parental care and other close social relationships. Both sexes share parental care equally, exhibit the same parental behaviors, and show a marked improvement in breeding success with experience. We hypothesize that PRL is critically involved in the expression of zebra finch parental care and predict that circulating PRL levels will increase with breeding experience. To begin testing this, we measured plasma PRL concentrations in 14 male-female zebra finch pairs (N=28) across two breeding cycles, using a repeated measures design. PRL was measured in the birds' first, reproductively inexperienced, breeding cycle beginning at courtship and extending through chick fledging. PRL was measured again during the birds' second, reproductively experienced, breeding cycle, beginning with egg laying until chick fledging. We found that plasma PRL is significantly elevated from non-breeding concentrations during late incubation and early post-hatch care and that this elevation is greater in the reproductively experienced cycle compared to the inexperienced cycle. Findings of this study will be used to inform hypotheses and predictions for future experimental manipulations of PRL during parental care.

  8. Cysteamine inhibition of prolactin immunoassayability and secretion: studies with aminothiophenols and other analogs

    SciTech Connect

    Jacobs, L.S.; Lorenson, M.Y.

    1984-09-01

    Analogs of the aminothiol cysteamine (CySH) have been studied to clarify the structural features required for exertion of inhibitory effects on PRL. The inhibited functions examined were the detectability of PRL by RIA and the release of PRL from suspensions of isolated secretory granules. The influence on GH assayability and release was also tested. The aromatic compounds 2-aminothiophenol, 3-aminothiophenol, and 4-aminothiophenol shared with CySH the ability to inhibit PRL assayability and release, but were all more potent. Derivatization of the thiol, as in 4-aminothioanisole, was associated with a substantial loss of inhibitory potency, whereas derivatization of the primary amine, as in N-dimethylaminoethanethiol, had no influence. Thiols such as mercaptoethanol, cysteine, glutathione, and others without nearby amino groups were stimulators of PRL assayability and release. The inhibitory effects of the aminothiols were highly pH dependent, being marked at pH 5.5, 6.5, and 7.5, but modest or marginal at 8.5. After CySH exposure, inhibition was reversible in part by extraction of samples with reduced glutathione or at pH 10.5. Though CySH and 4-aminothiophenol induced changes in the electrophoretic migration of granule PRL, similar changes occurred in the migration of standard purified hormone despite the known absence of immunochemical effects. There was close quantitative correlation between the potency of a compound to inhibit PRL assayability and its potency to inhibit PRL release. It was conclude that the inhibitory aminothiol action on PRL requires the thiol rather than the sulfide form and involves a reversible interaction which diminishes the immunochemical recognition of granule PRL. This change also results in diminished secretion.

  9. Prolactin mediates neuroprotection against excitotoxicity in primary cell cultures of hippocampal neurons via its receptor.

    PubMed

    Vergara-Castañeda, E; Grattan, D R; Pasantes-Morales, H; Pérez-Domínguez, M; Cabrera-Reyes, E A; Morales, T; Cerbón, M

    2016-04-01

    Recently it has been reported that prolactin (PRL) exerts a neuroprotective effect against excitotoxicity in hippocampus in the rat in vivo models. However, the exact mechanism by which PRL mediates this effect is not completely understood. The aim of our study was to assess whether prolactin exerts neuroprotection against excitotoxicity in an in vitro model using primary cell cultures of hippocampal neurons, and to determine whether this effect is mediated via the prolactin receptor (PRLR). Primary cell cultures of rat hippocampal neurons were used in all experiments, gene expression was evaluated by RT-qPCR, and protein expression was assessed by Western blot analysis and immunocytochemistry. Cell viability was assessed by using the MTT method. The results demonstrated that PRL treatment of neurons from primary cultures did not modify cell viability, but that it exerted a neuroprotective effect, with cells treated with PRL showing a significant increase of viability after glutamate (Glu)--induced excitotoxicity as compared with neurons treated with Glu alone. Cultured neurons expressed mRNA for both PRL and its receptor (PRLR), and both PRL and PRLR expression levels changed after the excitotoxic insult. Interestingly, the PRLR protein was detected as two main isoforms of 100 and 40 kDa as compared with that expressed in hypothalamic cells, which was present only as a 30 kDa variant. On the other hand, PRL was not detected in neuron cultures, either by western blot or by immunohistochemistry. Neuroprotection induced by PRL was significantly blocked by specific oligonucleotides against PRLR, thus suggesting that the PRL role is mediated by its receptor expressed in these neurons. The overall results indicated that PRL induces neuroprotection in neurons from primary cell cultures.

  10. Failure of maintained hyperprolactinemia to improve lactational performance in late puerperium.

    PubMed

    Barguño, J M; del Pozo, E; Cruz, M; Figueras, J

    1988-04-01

    Although stimulation of PRL secretion in the early postpartum period has been found to improve lactational performance, the effect of chronic maintenance of elevated plasma PRL levels on milk production is not known. In a randomized design, 66 lactating women were assigned to receive either a placebo (n = 32) or the dopamine antagonist sulpiride (n = 34; 100 mg, three times daily), for 4 days, followed by 50 mg, three times daily, for a 90-day period). Their basal and 30 min postsuckling plasma PRL levels as well as the weights of their infants were measured 1, 4, 15, 30, 60, and 90 days postpartum. Forty-one women (20 sulpiride-treated and 21 placebo-treated) completed the study. Compared with the placebo group, which had the expected postpartum plasma PRL decline, the sulpiride-treated women maintained significantly elevated basal plasma PRL values up to the 90th postpartum day. In contrast, the postsuckling plasma PRL level was significantly diminished in the latter group, and on day 90 was practically absent. On day 15, weight gain was significantly greater in the infants whose mothers received sulpiride, but later, no differences were detectable between groups of infants despite the disparity in PRL levels in their mothers. We conclude that enhancement of PRL secretion in the early postpartum period may transiently increase milk production, but chronic hyperprolactinemia has no effect on lactational performance. The plasma PRL response to suckling is not essential for the maintenance of milk secretion. Instead, basal plasma PRL levels and neurogenic reflexes may be more instrumental in maintaining established lactation.

  11. Lipopolysaccharide induces the expression of an autocrine prolactin loop enhancing inflammatory response in monocytes

    PubMed Central

    2013-01-01

    Background Prolactin from pituitary gland helps maintain homeostasis but it is also released in immune cells where its function is not completely understood. Pleiotropic functions of prolactin (PRL) might be mediated by different isoforms of its receptor (PRLr). Methods The aim of this study was to investigate the relationship between the eventual synthesis of PRL and PRLr isoforms with the inflammatory response in monocytes. We used THP-1 and monocytes isolated from healthy subjects stimulated with lipopolysaccharide (LPS). Western blot, real time PCR and immunocytochemistry were performed to identify both molecules. The bioactivity of the PRL was assessed using a bioassay and ELISA to detect pro inflammatory cytokines. Results PRLr mRNA and PRL mRNA were synthesized in THP-1 monocytes activated with LPS with peaks of 300-fold and 130-fold, respectively. The long (100 kDa) and the intermediate (50 kDa) isoforms of PRLr and big PRL (60 kDa) were time-dependent upregulated for monocytes stimulated with LPS. This expression was confirmed in monocytes from healthy subjects. The PRLr intermediate isoform and the big PRL were found soluble in the culture media and later in the nucleus in THP-1 monocytes stimulated with LPS. Big PRL released by monocytes showed bioactivity in Nb2 Cells, and both PRL and PRLr, synthesized by monocytes were related with levels of nitrites and proinflammatory citokines. Conclusions Our results suggest the expression of a full-autocrine loop of PRL enhances the inflammatory response in activated monocytes. This response mediated by big PRL may contribute to the eradication of potential pathogens during innate immune response in monocytes but may also contribute to inflammatory disorders. PMID:23731754

  12. Prolactin variants in ram adenohypophyses vary with season

    NASA Technical Reports Server (NTRS)

    Stroud, C. M.; Deaver, D. R.; Peters, J. L.; Loeper, D. C.; Toth, B. E.; Derr, J. A.; Hymer, W. C.

    1992-01-01

    Secretion of PRL in sheep is affected by photoperiod being highest during the spring and summer, lowest in fall and winter. The objectives of this study were to determine if 1) the production of variant forms of PRL, and 2) immuno- and bioactivities of PRL (iPRL and bPRL) differ during times of the year selected to represent periods of low, transitional and high PRL secretion. Twelve mature rams were maintained on pasture and killed in October, December, and April (n = 4/month). Individual pituitary glands were dispersed, cells obtained, and fixed for immunocytochemical flow cytometry, extracted with 0.01 N NaHCO3 or cultured in serum-free, defined media. The Mr of PRL extracted from cells immediately following dispersion ranged from 14-140K, with significantly more bands greater than 40K being detected from rams sacrificed in December than from those killed in October and April (P less than 0.01). No bands of PRL greater than 25K were observed when samples were reduced with beta-mercaptoethanol prior to electrophoresis, indicating that the high Mr forms were disulfide-linked aggregates. Culture media from October and April contained variants of PRL that ranged from 22-40K but those greater than 25K were generally not observed from cells harvested during December. Extracts of cells after 24 h in culture contained fewer high Mr species during December than had been present in initial extracts from that month. In contrast, during April more high Mr intracellular forms were present after culture than had been detected prior to culture during that month. The percentage of lactotrophs averaged 50.0 +/- 2.5, 47.4 +/- 5.7, and 59.4 +/- 5.5 for October, December, and April, respectively. Initial lactotroph content (pg/lactotroph) of iPRL was higher (P = 0.06) in April (46.0 +/- 17.0) when compared to October and December (8.0 +/- 2.0 and 20.0 +/- 10.0, respectively). In contrast, the bPRL content of initial extracts was higher (P = 0.05) in December (267.0 +/- 68.0) than

  13. The effects of novel and newly approved antipsychotics on serum prolactin levels: a comprehensive review.

    PubMed

    Peuskens, J; Pani, L; Detraux, J; De Hert, M

    2014-05-01

    Since the 1970s, clinicians have increasingly become more familiar with hyperprolactinemia (HPRL) as a common adverse effect of antipsychotic medication, which remains the cornerstone of pharmacological treatment for patients with schizophrenia. Although treatment with second-generation antipsychotics (SGAs) as a group is, compared with use of the first-generation antipsychotics, associated with lower prolactin (PRL) plasma levels, the detailed effects on plasma PRL levels for each of these compounds in reports often remain incomplete or inaccurate. Moreover, at this moment, no review has been published about the effect of the newly approved antipsychotics asenapine, iloperidone and lurasidone on PRL levels. The objective of this review is to describe PRL physiology; PRL measurement; diagnosis, causes, consequences and mechanisms of HPRL; incidence figures of (new-onset) HPRL with SGAs and newly approved antipsychotics in adolescent and adult patients; and revisit lingering questions regarding this hormone. A literature search, using the MEDLINE database (1966-December 2013), was conducted to identify relevant publications to report on the state of the art of HPRL and to summarize the available evidence with respect to the propensity of the SGAs and the newly approved antipsychotics to elevate PRL levels. Our review shows that although HPRL usually is defined as a sustained level of PRL above the laboratory upper limit of normal, limit values show some degree of variability in clinical reports, making the interpretation and comparison of data across studies difficult. Moreover, many reports do not provide much or any data detailing the measurement of PRL. Although the highest rates of HPRL are consistently reported in association with amisulpride, risperidone and paliperidone, while aripiprazole and quetiapine have the most favorable profile with respect to this outcome, all SGAs can induce PRL elevations, especially at the beginning of treatment, and have the

  14. New developments on the galactopoietic role of prolactin in dairy ruminants.

    PubMed

    Lacasse, P; Lollivier, V; Dessauge, F; Bruckmaier, R M; Ollier, S; Boutinaud, M

    2012-08-01

    In most mammals, prolactin (PRL) is essential for maintaining lactation and its suppression strongly inhibits lactation. However, the involvement of PRL in the control of ruminant lactation is less clear because inconsistent effects on milk yield have been observed with short-term suppression of PRL by bromocriptine. By contrast, in vitro studies have provided evidence that PRL helps to maintain the differentiation state and act as a survival factor for mammary epithelial cells. Therefore, a series of experiments were conducted to assess the galactopoietic role of PRL. In a first experiment, daily injections of the PRL inhibitor quinagolide reduced milking-induced PRL release and induced a faster decline in milk production. Milk production was correlated with PRL released at milking. Quinagolide reduced mammary cell activity, survival, and proliferation. During the last week of treatments, differential milking (1× vs 2×) was applied. The inhibition of milk production by quinagolide was maintained in the udder half that was milked 2× but not in the udder half milked 1×, suggesting that the response to PRL is modulated at the gland level. In a second experiment, cows were injected with quinagolide, quinagolide + injection of bovine PRL at milking time, or water. As in the first experiment, quinagolide reduced milk, protein, and lactose yields. Although PRL injections at milking time were not sufficient to restore milk yield, they tended to increase milk protein and lactose yields and increased the viability of milk-purified mammary epithelial cells. Recently, we investigated the use of quinagolide at drying off. Treating late-lactation cows with quinagolide decreased milk production within the first day of treatment and induced faster increases in somatic cells and bovine serum albumin content in mammary secretions after drying off, which indicates an acceleration of mammary gland involution. In conclusion, these data, combined with data from other studies

  15. Prolactin and estrogen enhance the activity of activating protein 1 in breast cancer cells: role of extracellularly regulated kinase 1/2-mediated signals to c-fos.

    PubMed

    Gutzman, Jennifer H; Nikolai, Sarah E; Rugowski, Debra E; Watters, Jyoti J; Schuler, Linda A

    2005-07-01

    Despite the important roles of both prolactin (PRL) and 17beta-estradiol (E2) in normal mammary development as well as in breast cancer, and coexpression of the estrogen receptor (ER) and PRL receptor in many mammary tumors, the interactions between PRL and E2 in breast cancer have not been well studied. The activating protein 1 (AP-1) transcription factor, a known regulator of processes essential for normal growth and development as well as carcinogenesis, is a potential site for cross-talk between these hormones in breast cancer cells. Here we demonstrate that PRL and E2 cooperatively enhance the activity of AP-1 in MCF-7-derived cells. In addition to the acute PRL-induced ERK1/2 activation, PRL and E2 also individually elicited delayed, sustained rises in levels of phosphorylated p38 and especially ERK1/2. Together, these hormones increased the dynamic phosphorylation of ERK1/2 and c-Fos, and induced c-fos promoter activity. Synergistic activation of the transcription factor, Elk-1, reflected the PRL-E2 interaction at ERK1/2 and is a likely mechanism for activation of the c-fos promoter via the serum response element. The enhanced AP-1 activity resulting from the interaction of these hormones may increase expression of many target genes that are critical for oncogenesis and may contribute to neoplastic progression.

  16. Effects of prolactin and experimental handling on liver, fat body and ovary lipid contents and their daily variations in Rana esculenta (L.).

    PubMed

    Sotowska-Brochocka, J; Jaklewicz, S

    1984-01-01

    Three groups of females of R. esculenta were kept under constant temperature and photoperiod conditions (L:D = 12:12). One group consisted of intact frogs, while the remainder were given saline or prolactin (PRL) injections 6 hours after light onset. After 5 days of such treatment examination was made every 6 hours over a 24-hour period of lipid content in the liver, fat bodies (FBs) and ovaries and the level and composition of plasma lipids. Both the experimental handling and PRL treatment caused in animals a decrease in weight of the liver and mobilization of lipid metabolism, inducing a shift in lipids and a change in their distribution within the organs examined. In animals injected with saline lipids were transported chiefly to FBs, whereas in frogs given PRL the whole, combined lipid content in these organs decreased considerably, suggesting that they had been transported to the tissues and that their catabolism had been intensified. It is suggested also that PRL has sparing effect on the ovarian lipid pool. In both groups, especially in frogs given PRL, there was a marked increase in plasma lipid concentration and the contents in percentages of its different classes. Increase in concentration of phospholipids (3X) and cholesterol (10X) in animals given PRL is particularly distinct. Both experimental handling and PRL administration affected the pattern of diurnal fluctuations in the lipid content of the organs examined.

  17. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy.

    PubMed

    Fukuoka, Hidenori; Cooper, Odelia; Mizutani, Jun; Tong, Yunguang; Ren, Song-Guang; Bannykh, Serguei; Melmed, Shlomo

    2011-01-01

    Dopamine agonist resistance or intolerance is encountered in approximately 20% of prolactinoma patients. Because human epidermal growth factor receptor 2 (HER2)/ErbB2 is overexpressed in prolactinomas and ErbB receptor ligands regulate prolactin (PRL) gene expression, we tested the role of HER2/ErbB2 in prolactinoma hormone regulation and adenoma cell proliferation to assess the rationale for targeting this receptor for prolactinoma therapy. As we showed prolactinoma HER2 overexpression, we generated constitutively active HER2-stable GH3 cell transfectants (HER2CA). PRL mRNA levels were induced approximately 250-fold and PRL secretion was enhanced 100-fold in HER2CA cells, which also exhibited increased proliferation. Lapatinib, a dual tyrosine kinase inhibitor (TKI) of both epidermal growth factor receptor (EGFR)/ErbB1 and HER2, blocked receptor signaling, and suppressed PRL expression more than gefitinib, a TKI of EGFR/ErbB1. Lapatinib also suppressed colony formation in soft agar more than gefitinib. Oral lapatinib treatment caused tumor shrinkage and serum PRL suppression both in HER2CA transfectant-inoculated Wistar-Furth rats and in estrogen-induced Fischer344 rat prolactinomas. In cultured human cells derived from resected prolactinoma tissue, lapatinib suppressed both PRL mRNA expression and secretion. These results demonstrate that prolactinoma HER2 potently induces PRL and regulates experimental prolactinoma cell proliferation. Because pituitary HER2 signaling is abrogated by TKIs, this receptor could be an effective target for prolactinoma therapy.

  18. Environmental influences on prolactin cell development in the cyprinodont fish, Cynolebias whitei.

    PubMed

    Ruijter, J M; van Kemenade, J A; Wendelaar Bonga, S E

    1984-01-01

    A combined immunocytochemical and morphometric study on the development of the prolactin (PRL) cells of the annual cyprinodont Cynolebias whitei, transferred as newly hatched larvae to water with different salinities and/or Ca2+-concentrations, was carried out. The percentage of the pituitary volume occupied by PRL cells and the affinity of PRL cells for immunocytochemical staining were used as criteria for their activity. Exposure of the larvae for one day to salt water (260 mOsm/kg) led to a significant reduction in the pituitary volume occupied by PRL cells, indicating an osmoregulatory function of PRL shortly after hatching. In fish reared in diluted artificial seawater (70 and 260 mOsm/kg) or Na+-enriched fresh water the development of PRL cells was significantly retarded, but such an effect was not observed in fish placed in Ca2+-enriched fresh water. These experiments show that in C. whitei the development and activity of PRL cells are influenced by changes in environmental osmolarity and not by changes in ambient Ca2+-concentration.

  19. Plasticity of hypothalamic dopamine neurons during lactation results in dissociation of electrical activity and release.

    PubMed

    Romanò, Nicola; Yip, Siew H; Hodson, David J; Guillou, Anne; Parnaudeau, Sébastien; Kirk, Siobhan; Tronche, François; Bonnefont, Xavier; Le Tissier, Paul; Bunn, Stephen J; Grattan, Dave R; Mollard, Patrice; Martin, Agnès O

    2013-03-06

    Tuberoinfundibular dopamine (TIDA) neurons are the central regulators of prolactin (PRL) secretion. Their extensive functional plasticity allows a change from low PRL secretion in the non-pregnant state to the condition of hyperprolactinemia that characterizes lactation. To allow this rise in PRL, TIDA neurons are thought to become unresponsive to PRL at lactation and functionally silenced. Here we show that, contrary to expectations, the electrical properties of the system were not modified during lactation and that the neurons remained electrically responsive to a PRL stimulus, with PRL inducing an acute increase in their firing rate during lactation that was identical to that seen in non-pregnant mice. Furthermore, we show a long-term organization of TIDA neuron electrical activity with an harmonization of their firing rates, which remains intact during lactation. However, PRL-induced secretion of dopamine (DA) at the median eminence was strongly blunted during lactation, at least in part attributable to lack of phosphorylation of tyrosine hydroxylase, the key enzyme involved in DA synthesis. We therefore conclude that lactation, rather than involving electrical silencing of TIDA neurons, represents a condition of decoupling between electrical activity at the cell body and DA secretion at the median eminence.

  20. L-DOPA attenuates prolactin secretion in response to isolation stress in Holstein steers.

    PubMed

    Kasuya, Etsuko; Yayou, Ken-ichi; Sutoh, Madoka

    2013-07-01

    To clarify endocrine responses to psychological stressors in cattle, the effects of isolation from familiar peers on plasma prolactin (PRL) and cortisol (CORT) concentrations, and the effect of 3,4-dihydroxy-L-phenylalanine (L-DOPA), a precursor of dopamine (DA), on stress-induced PRL secretion were determined in Holstein steers. First, the potency of peripheral L-DOPA administration on attenuation of central DA levels was confirmed. Cerebrospinal fluid (CSF) collected from a chronic cannula in the third ventricle and plasma were sampled 1 h before and 3 h after intravenous injection of L-DOPA (100 mg/head). DA concentrations in CSF increased just after L-DOPA injection with subsequent decrease in PRL secretion. Injection of L-DOPA increased CORT secretion. Second, one experimental steer was isolated in its stall by removing its peers for 2 h with or without- pre-injection of L-DOPA. The concentration of PRL was elevated by isolation treatment, whereas the effect of isolation on CORT concentration could not be detected. The increase in PRL concentration after isolation was abolished by pre-injection of L-DOPA. These results suggest that PRL responds to isolation and that DA neurons in the central nervous system may regulate stress-induced PRL secretion in steers.

  1. Serum prolactin and dehydroepiandrosterone concentrations during the summer and winter hair growth cycles of mink (Mustela vison).

    PubMed

    Rose, J; Kennedy, M; Johnston, B; Foster, W

    1998-11-01

    We investigated the relationship between serum concentrations of prolactin (PRL) and dehydroepiandrosterone (DHEA) during initiation and development of summer and winter hair growth (anagen) cycles in mink. In the spring, haloperidol (HAL) increased PRL concentrations and induced summer anagen earlier than controls, whereas melatonin (MEL) inhibited PRL secretion and completely blocked summer anagen. In the fall, HAL increased PRL concentrations, inducing anagen at an earlier time than controls, although the resulting fur was abnormal being almost devoid of underhair fibers. Exogenous MEL during the fall reduced PRL concentrations, initiating winter anagen 4 weeks earlier than controls. Adrenalectomy (ADX) induced earlier onset of summer and winter anagen and neutralized the inhibitory effects of HAL in the fall and MEL in the spring. No change in serum DHEA concentrations was observed during the onset of summer or winter anagen in any group although MEL increased DHEA levels from 27 March through 5 June relative to HAL-treated mink. We conclude that changes in serum levels of DHEA and PRL are not requisite to onset of summer or winter anagen in mink. It is possible that metabolites of DHEA and/or PRL may still affect other aspects of the hair growth cycle.

  2. Evidence that the growth hormone receptor mediates differentiation and development of the mammary gland.

    PubMed

    Feldman, M; Ruan, W; Cunningham, B C; Wells, J A; Kleinberg, D L

    1993-10-01

    We have shown that nonlactogenic rat (r) GH is far more potent than rPRL in inducing rat mammary development. To determine the relative roles of GH and PRL in mammary development and their mechanisms of action, we have compared the abilities of a group of native and mutant GHs, PRLs, and placental lactogens (PLs) to induce mammary development, bind to GH receptors, and activate lactogenic receptors. Mammary development was assessed histologically by counting terminal end buds and alveolar structures in glands from sexually immature, hypophysectomized, castrated, estradiol-treated rats. Hormones were implanted, in Elvax pellets, into the lumbar mammary gland. Significant increases in terminal end buds (P < 0.03) over internal control values were obtained with rGH, recombinant human GH (rhGH), rbGH, and one of two mutant rhGHs. These four hormones were also found to bind to GH receptors with high affinity. In contrast, little development occurred with hPRL, rPRL, rhPL, ovine PRL, mutant forms of rhPRL and rhPL, and a mutant of rhGH altered to reduce binding to GH and PRL receptors. All of these substances are more than 50-fold reduced in binding to the GH receptor, yet can bind and activate lactogenic receptors. Thus, only those natural or mutant pituitary or placental hormones with high binding affinity to GH receptors induce mammary development, suggesting that GH receptors play a central role in this process.

  3. Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

    PubMed Central

    Flores-Fernández, Rocio; Blanco-Favela, Francisco; Fuentes-Pananá, Ezequiel M.; Chávez-Sánchez, Luis; Gorocica-Rosete, Patricia; Pizaña-Venegas, Alberto; Chávez-Rueda, Adriana Karina

    2016-01-01

    Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease. PMID:27314053

  4. Mechanism of action of cysteamine in depleting prolactin immunoreactivity

    SciTech Connect

    Sagar, S.M.; Millard, W.J.; Martin, J.B.; Murchison, S.C.

    1985-08-01

    The thiol reagent cysteamine (CSH) depletes anterior pituitary cells of immunoreactive PRL both in vivo and in vitro. The authors examined the hypothesis that CSH affects either the solubility or immunoreactivity of PRL through a mechanism involving thiol-disulfide exchange. Adult female rats were treated with either CSH (300 mg/kg, sc) or an equimolar dose of ethanolamine as a control. Anterior pituitary glands were extracted in 0.1 M sodium borate buffer, pH 9.0. Treatment of pituitary extracts with beta-mercaptoethanol (BME) destroys the immunoreactivity of PRL. However, extraction in the presence of reduced glutathione or CSH of pituitaries of rats treated with CSH restores immunoreactive PRL to control levels. Extracts were also subjected to polyacrylamide gel electrophoresis (PAGE). On gels of pituitary extracts of CSH-treated rats, the band that comigrates with purified PRL is diminished compared to that in ethanolamine-treated controls. However, extraction of the pituitaries in sodium dodecyl sulfate-containing buffer followed by chemical reduction with BME restores the PRL band. Therefore, CSH acts on PRL through a thiol-related mechanism to yield a product that is poorly soluble in aqueous buffer at pH 9 and is poorly immunoreactive. Dispersed anterior pituitary cells in tissue culture were incubated with L-(TVS)methionine to radiolabel newly synthesized peptides. PAGE followed by autoradiography confirmed the above results obtained in vivo.

  5. High expression of prolactin receptor is associated with cell survival in cervical cancer cells

    PubMed Central

    2013-01-01

    Background The altered expression of prolactin (PRL) and its receptor (PRLR) has been implicated in breast and other types of cancer. There are few studies that have focused on the analysis of PRL/PRLR in cervical cancer where the development of neoplastic lesions is influenced by the variation of the hormonal status. The aim of this study was to evaluate the expression of PRL/PRLR and the effect of PRL treatment on cell proliferation and apoptosis in cervical cancer cell lines. Results High expression of multiple PRLR forms and PRLvariants of 60–80 kDa were observed in cervical cancer cell lines compared with non-tumorigenic keratinocytes evaluated by Western blot, immunofluorecence and real time PCR. Treatment with PRL (200 ng/ml) increased cell proliferation in HeLa cells determined by the MTT assay at day 3 and after 1 day a protective effect against etoposide induced apoptosis in HeLa, SiHa and C-33A cervical cancer cell lines analyzed by the TUNEL assay. Conclusions Our data suggests that PRL/PRLR signaling could act as an important survival factor for cervical cancer. The use of an effective PRL antagonist may provide a better therapeutic intervention in cervical cancer. PMID:24148306

  6. Prolactin, Oxytocin, and the development of paternal behavior across the first six months of fatherhood

    PubMed Central

    Gordon, Ilanit; Zagoory-Sharon, Orna; Leckman, James F.; Feldman, Ruth

    2011-01-01

    Animal studies have implicated the neuropeptides Prolactin (PRL) and Oxytocin (OT) in processes of maternal bonding and PRL has similarly been shown to play a role in the neurophysiology of fatherhood. Yet, very little is known on the involvement of PRL and OT in human fathering. Forty-three fathers and their firstborn infant were seen twice: in the second and sixth postpartum months. Paternal plasma PRL and OT were sampled at both time-points and analyzed with ELISA methods. At six months fathers were videotaped interacting with their child in social and exploratory play contexts and interactions were micro-analyzed for father–infant Affect Synchrony and father facilitation of child toy exploration. PRL and OT showed high individual stability across time and were correlated at the second observation. PRL was related to father– infant Coordinated Exploratory Play in the toy context whereas OT was associated with father–infant Affect Synchrony in the social context. Results point to the role of PRL and OT in the development of human fathering and underscore their differential relations with patterns of paternal care. PMID:20399783

  7. Effect of prolactin on carcinoembryonic antigen-specific cytotoxic T lymphocyte response induced by dendritic cells.

    PubMed

    Matera, L; Beltramo, E; Martinuzzi, E; Buttiglieri, S

    2004-08-01

    The cytokine hormone prolactin (PRL) has been shown previously to modulate native cellular responses and maturation of antigen-presenting cells. Here we have addressed its effect on the antigen-specific response of cytotoxic T lymphocytes (CTL). CTL were generated from HLA-A2 lymphocytes after three rounds of stimulation with autologous dendritic cells loaded with HLA-A2-restricted carcinoembrionic antigen (CEA) Cap-1 (YLSGANLNL) peptide. Selected cultures were expanded on cytokine-supplemented feeder-layers, enriched for CD8+ lymphocytes and analysed for PRL-receptor (PRL-R) expression and PRL responsiveness. Resting CD8+ lymphocytes were negative for PRL-R, whereas antigen-activated CD8+ lymphocytes derived from long-term cultures were highly positive. Results of a 51Cr release assay showed CTL killing of CEA-loaded, but not unloaded, T2 cell line and the CEA-positive gastric carcinoma cell line KATO, but not of the CEA-negative T leukaemia cell line Jurkat. Interferon (IFN)-gamma release, evaluated in an ELISPOT assay against CEA-loaded T2, was enhanced (P < 0.05) by concentrations of PRL (12-25 ng/ml) very close to the physiological levels (6-20 ng/ml), but was decreased (P < 0.05) by high concentrations (200 ng/ml). Pre-incubation of the stimulators with the anti-MHC class I MoAb W6.32 induced a 40-60% decrease of the PRL-boosted IFN-gamma release, thus proving the MHC restriction of the lymphocyte response. Cytotoxicity against CEA-loaded T2 and KATO cell lines was also increased by 12-25 ng (P < 0.05) and decreased (P < 0.05) by 200 ng PRL. Pre-incubation of CTL with an antibody specific for the PRL-R almost completely abrogated this effect.

  8. Effects of Hypergravity Exposure on Prolactin Levels in Pre-parturient , Parturient and Lactating Rat Dams

    NASA Technical Reports Server (NTRS)

    Baer. Lisa A.; Wade, Charles E.; Ronca, April E.; Sun, Sid (Technical Monitor)

    2001-01-01

    We analyzed the effects of 2.0-g, 1.75-g and 1.5-g hypergravity exposure on plasma concentrations of the lactotrophic hormone, prolactin (PRL), in female rats on pre-parturient (Gestation Day 20), parturient (Post-natal day 0) and lactating (P10) days. PRL levels have been found to be reduced in rat dams around the time of birth following exposure to gravitational loads varying from 2.16 to 3.14-g (Megory et. al., Aviation, Space and Environs 1129-1135, 1984). It has also been reported that at these high gravitational loads, neonatal mortality has been extremely high, suggesting a possible interaction between dam PRL concentration and neonatal outcome. We have previously reported no significant differences in PRL levels of parturient (PO) and lactating (P6 & P 15) dams when exposed to 1.5-g hypergravity, but did observe a slight elevation of PRL on PO and P 15, with a decrease on P6. In the present study, time-bred pregnant dams were exposed to either continuous 2.0-g, 1.75-g or 1.5-g centrifugation, beginning on Gestational day (G) 11 of the rats' 22-day pregnancy. We observed no significant differences in PRL concentrations between SC and any of the HG conditions. On G20 and PO, PRL concentrations of the 2.0-g and 1.5-g groups were slightly elevated as compared to SC. Similar to what we previously reported. PRL secretion was elevated in both HG and SC conditions on the day of birth relative to later during lactation, but on P10 it appeared to be reduced in HG relative to SC dams. These findings suggests that hypergravity slightly elevates plasma concentration of PRL in pre-parturient and lactating rat dams, with effects most pronounced during the periparturitional period and in a direction opposite to that observed following microgravity exposure.

  9. Integrating oculomotor and perceptual training to induce a pseudofovea: A model system for studying central vision loss

    PubMed Central

    Liu, Rong; Kwon, MiYoung

    2016-01-01

    People with a central scotoma often adopt an eccentric retinal location (Preferred Retinal Locus, PRL) for fixation. Here, we proposed a novel training paradigm as a model system to study the nature of the PRL formation and its impacts on visual function. The training paradigm was designed to effectively induce a PRL at any intended retinal location by integrating oculomotor control and pattern recognition. Using a gaze-contingent display, a simulated central scotoma was induced in eight normally sighted subjects. A subject's entire peripheral visual field was blurred, except for a small circular aperture with location randomly assigned to each subject (to the left, right, above, or below the scotoma). Under this viewing condition, subjects performed a demanding oculomotor and visual recognition task. Various visual functions were tested before and after training at both PRL and nonPRL locations. After 6–10 hr of the training, all subjects formed their PRL within the clear window. Both oculomotor control and visual recognition performance significantly improved. Moreover, there was considerable improvement at PRL location in high-level function, such as trigram letter-recognition, reading, and spatial attention, but not in low-level function, such as acuity and contrast sensitivity. Our results demonstrated that within a relatively short time, a PRL could be induced at any intended retinal location in normally-sighted subjects with a simulated scotoma. Our training paradigm might not only hold promise as a model system to study the dynamic nature of the PRL formation, but also serve as a rehabilitation regimen for individuals with central vision loss. PMID:27089065

  10. Effect of the prolactin-release inhibitor quinagolide on lactating dairy cows.

    PubMed

    Lacasse, P; Lollivier, V; Bruckmaier, R M; Boisclair, Y R; Wagner, G F; Boutinaud, M

    2011-03-01

    In most mammals, prolactin (PRL) is essential for maintaining lactation, and yet the short-term suppression of PRL during established lactation by bromocriptine has produced inconsistent effects on milk yield in cows and goats. To assess the effect of the long-term inhibition of PRL release in lactating dairy cows, 5 Holstein cows in early lactation received daily intramuscular injections of 1mg of the PRL-release inhibitor quinagolide for 9 wk. Four control cows received the vehicle (water) only. During the last week of the treatments, one udder half was milked once a day (1×) and the other twice a day (2×). Blood samples were harvested at milking in wk -1, 1, 4, and 8. The daily injections of quinagolide reduced milking-induced PRL release but not the basal PRL concentration. Quinagolide induced a faster decline in milk production, which was about 5.3 kg/d lower in the quinagolide-treated cows during the last 4 wk of treatment. During wk 9, the inhibition of milk production by quinagolide was maintained in the udder half that was milked 2× but not in the half milked 1×. Milk production was significantly correlated with the quantity of PRL released at milking. Quinagolide did not affect the release of oxytocin at milking. Serum concentration of insulin-like growth factor-1 was not affected by treatment or correlated with milk production. Serum concentrations of leptin and the calciotropic hormone stanniocalcin were not affected by the treatment. In conclusion, the chronic administration of the PRL-release inhibitor quinagolide decreases milk production in dairy cows. The effect is likely the result of the reduced release of milking-induced PRL and is modulated at the level of the gland by milking frequency.

  11. Antiapoptotic effects of erythropoietin in differentiated neuroblastoma SH-SY5Y cells require activation of both the STAT5 and AKT signaling pathways.

    PubMed

    Um, Moonkyoung; Lodish, Harvey F

    2006-03-03

    The hematopoietic cytokine erythropoietin (Epo) prevents neuronal death during ischemic events in the brain and in neurodegenerative diseases, presumably through its antiapoptotic effects. To explore the role of different signaling pathways in Epo-mediated antiapoptotic effects in differentiated human neuroblastoma SH-SY5Y cells, we employed a prolactin receptor (PrlR)/erythropoietin receptor (EpoR) chimera system, in which binding of prolactin (Prl) to the extracellular domain activates EpoR signaling in the cytosol. On induction of apoptosis by staurosporine, Prl supports survival of the SH-SY5Y cells expressing the wild-type PrlR/EpoR chimera. In these cells Prl treatment strongly activates the STAT5, AKT, and MAPK signaling pathways and induces weak activation of the p65 NF-kappaB factor. Selective mutation of the eight tyrosine residues of the EpoR cytoplasmic domain results in impaired or absent activation of either STAT5 (mutation of Tyr(343)) or AKT (mutation of Tyr(479)) or both (mutation of all eight tyrosine residues). Most interestingly, Prl treatment does not prevent apoptosis in cells expressing mutant PrlR/EpoR chimeras in which either the STAT5 or the AKT signaling pathways are not activated. In contrast, ERK 1/2 is fully activated by all mutant PrlR/EpoR chimeras, comparable with the level seen with the wild-type PrlR/EpoR chimera, implying that activation of the MAPK signaling pathway per se is not sufficient for antiapoptotic activity. Therefore, the antiapoptotic effects of Epo in neuronal cells require the combinatorial activation of multiple signaling pathways, including STAT5, AKT, and potentially MAPK as well, in a manner similar to that observed in hematopoietic cells.

  12. Effects of prolactin on lipid biosynthesis and protein kinase C in mouse mammary gland and NB sub 2 node lymphoma cells

    SciTech Connect

    Waters, S.B.

    1989-01-01

    In cultured mouse mammary gland explants derived from 12-14 day pregnant mice, prolactin (PRL) stimulates an increased rate of incorporation of ({sup 14}C)acetate and ({sup 3}H)glucose into triglycerides. The effect is significant between 4-6 hours after addition of PRL. Enzymes likely to be rate-limiting to this process include acetyl CoA carboxylase (ACC), fatty acid synthetase, acetyl CoA synthetase, and/or pyruvate dehydrogenase (PDH). It is possible that early perturbations of phospholipid (PL) metabolism may represent the initial cellular effects of PRL. Consequently the effect of PRL on the incorporation of several precursors into PLs was determined. Employing ({sup 14}C)acetate as a substrate, PRL stimulates its incorporation into phosphatidylcholine, as early as 1-2 hours, and phosphatidylinositol, phosphatidylserine and phosphatidylethanolamine by 2-4 hours. ({sup 3}H)Glycerol incorporation into triglycerides was significantly enhanced by PRL between 4-6 hours, but not into PLs until after 16 hours. Similarly, PRL did not enhance incorporation of ({sup 32}P)O{sub 4}, ({sup 3}H)choline, ({sup 3}H)inositol or ({sup 3}H)seine into PLs until 14-16 hours after addition to culture. 12-O-tetradeconyl-phorbol-13-acetate (TPA) was found to increase ({sup 3}H)uridine incorporation into RNA, and ({sup 3}H)leucine incorporation into caseins in a PRL-like manner. In addition, PRL stimulates a transient, time-dependent translocation of PKC to the particulate fraction of mammary gland explants.

  13. Prolactin modulates cytokine production induced by culture filtrate proteins of M. bovis through different signaling mechanisms in THP1 cells.

    PubMed

    Martínez-Neri, Priscila A; López-Rincón, Gonzalo; Mancilla-Jiménez, Raúl; del Toro-Arreola, Susana; Muñoz-Valle, José Francisco; Fafutis-Morris, Mary; Bueno-Topete, Miriam Ruth; Estrada-Chávez, Ciro; Pereira-Suárez, Ana Laura

    2015-01-01

    The immunomodulatory functions of prolactin (PRL) are well recognized. Augmented PRL plasma levels were observed in patients with advanced tuberculosis (TB). Recently, we have reported that LPS and Mycobacterium bovis (M. bovis) induced differential expression of PRL receptor (PRLR) isoforms in THP-1 cells and bovine macrophages, respectively. The aim of this work was to determine whether PRL should be considered as a potential modulator of the signaling pathways and cytokine synthesis, induced by culture filtrate protein (CFP) from M. bovis in THP-1 monocytes. The THP-1 cells were stimulated with PRL (20ng/mL), M. bovis CFP (50μg/mL). PRLR as well as phosphorylated STAT3, STAT5, Akt1/2/3, ERK1/2 and p38 expression were evaluated by Western blot. IL1-β, TNF-α, IL-6, IL-12, IL-8, and IL-10 concentrations were measured by ELISA. Our results demonstrated that the expression pattern of PRLR short isoforms is induced by M. bovis CFP. M bovis CFP induced phosphorylation of Akt2, ERK1/2, p38, STAT3, and STAT5 pathways. In turn, PRL only activated the JAK2/STAT3-5 signaling pathway. However, when combined both stimuli, PRL significantly increased STAT3-5 phosphorylation and downregulated Akt2, ERK1/2, and p38 phosphorylation. As expected, M. bovis CFP induced substantial amounts of IL1-β, IL-6, TNF-α, IL-8, IL-12, and IL-10. However, the PRL costimulation considerably decreased IL1-β, TNF-α, and IL-12 secretion, and increased IL-10 production. This results suggest that up-regulation of IL-10 by PRL might be modulating the pro-inflammatory response against mycobacterial antigens through the MAPK pathway.

  14. Direct effects of catecholamines, thyrotropin-releasing hormone, and somatostatin on growth hormone and prolactin secretion from adenomatous and nonadenomatous human pituitary cells in culture.

    PubMed Central

    Ishibashi, M; Yamaji, T

    1984-01-01

    To determine the mechanism and the site of action of catecholamines as well as hormones including thyrotropin-releasing hormone (TRH)1 and somatostatin on pituitary hormone release in patients with acromegaly and in normal subjects, the effects of these substances on growth hormone (GH) and prolactin (PRL) secretion from adenomatous and nonadenomatous human pituitary cells in culture were examined. When dopamine (0.01-0.1 microM) or bromocriptine (0.01-0.1 microM) was added to the culture media, a significant inhibition of GH and PRL secretion from adenoma cells from acromegalic patients was observed. This inhibition was blocked by D2 receptor blockade with metoclopramide or sulpiride, but not by D1 receptor blockade. Similarly, dopamine suppressed GH and PRL release by nonadenomatous pituitary cells in a dose-dependent manner, which was again blocked by D2 receptor blockade. The minimum effective concentration of dopamine required for a significant inhibition of PRL secretion (0.01 microM) was lower than that for GH release (0.1 microM). Norepinephrine, likewise, caused a suppression of PRL secretion from adenomatous and nonadenomatous pituitary cells. This effect was blocked by sulpiride, phentolamine, however, was ineffective. When TRH was added to the media, both GH and PRL secretion were enhanced in adenoma cells, while only the stimulation of PRL release was observed in nonadenomatous pituitary cells. Coincubation of TRH and dopamine resulted in variable effects on GH and PRL secretion. Somatostatin consistently lowered GH and PRL secretion in both adenomatous and nonadenomatous pituitary cells and completely blocked the TRH-induced stimulation of GH and PRL secretion from adenoma cells. Opioid peptides (1 microM) failed to affect hormone release. These results suggest that no qualitative difference in GH and PRL responses to dopaminergic agonists or to somatostatin exists between adenoma cells of acromegalic patients and normal pituitary cells, and that the

  15. Prolactin Receptor Coupling to Jak-Stat Pathways in Breast Cancer

    DTIC Science & Technology

    2007-07-01

    receptors (PRLR) have been considered selective activators of tyrosine kinase Jak2 but not Jak1, Jak3 or Tyk2. We now report marked PRL-induced tyrosine...been considered selective activators of tyrosine kinase Jak2 but not Jak1, Jak3 or Tyk2. We now report marked PRL-induced tyrosine phosphorylation...other members of the Janus kinase family, Jak1, Jak3 or Tyk2 (2-5). Upon PRL-induced receptor aggregation, activated Jak2 in turn phosphorylates

  16. [Study on preferred retinal locus].

    PubMed

    Dai, Bing-Fa; Hu, Jian-Min; Xu, Duan-Lian

    2012-03-01

    Preferred retinal locus (PRL) is always found in the age-related macular degeneration and other macular damages in patients with low vision, and it is a very important anatomic position in patients with central vision impairment to achieve the rehabilitation. In recent years, the training of preferred retinal locus (PRL) has become a research hotspot of low vision rehabilitation, it can clearly improve functional vision and quality of life. The authors reviewed relevant literatures, and summarized the definition, position, characteristics, training and clinical implications of the PRL.

  17. Concurrent production of adrenocorticotropin and prolactin from two distinct cell lines in a single pituitary adenoma: a detailed immunohistochemical analysis.

    PubMed

    Sherry, S H; Guay, A T; Lee, A K; Hedley Whyte, E T; Federman, M; Freidberg, S R; Woolf, P D

    1982-11-01

    A pituitary tumor from a patient with severe Cushing's disease and marked hyperprolactinemia was extensively studied by immunohistochemical techniques. Tissues from two separate areas of the adenoma were found to contain similar cell proportions of PRL as well as ACTH and related peptides (beta-lipotropin, beta-endorphin, and alpha MSH). The tumor was composed of approximately 70% immunoreactive PRL cells and 5% ACTH-containing cells. Double immunostaining revealed that PRL or ACTH and related peptides were found in two distinct populations of tumor cells. These results document for the first time inappropriate synthesis and secretion of an unusual combination of pituitary hormones from a mixed pituitary adenoma.

  18. Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas.

    PubMed

    Jaquet, P; Ouafik, L; Saveanu, A; Gunz, G; Fina, F; Dufour, H; Culler, M D; Moreau, J P; Enjalbert, A

    1999-09-01

    Recently, it was demonstrated that somatostatin analogs preferential for the SSTR5 subtype suppress PRL release from prolactinoma cell cultures by 30-40%. These data supported the idea of somatostatin receptor subtype-specific control of PRL secretion in such tumors. The present study examines the quantitative profile of SSTRs messenger ribonucleic acid (mRNA) in 10 PRL-secreting tumors and correlates the expression with the ability of native somatostatins (SS14 and SS28), SSTR2 preferential analogs (octreotide and BIM-23197), and the SSTR5 preferential analog BIM-23268 to suppress PRL secretion. RT-PCR quantitative analysis showed a large predominance of SSTR5 mRNA [5648 +/- 1918 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] vs. SSTR2 mRNA (148 +/- 83 pg/pg GAPDH). The SSTR1 transcript was also highly expressed in prolactinomas (1296 +/- 669 pg/pg GAPDH). SSTR5 mRNA expression correlated with PRL inhibition induced by both SRIF14 and SRIF28. Among the different analogs tested, only BIM-23268 produced inhibition of PRL release similar to that achieved with the native peptides. Its EC50 for PRL suppression was 0.28 +/- 0.10 nmol/L. No additive effects on PRL suppression were achieved by cotreatment of the tumor cells with SSTR2 and SSTR5 preferential analogs. In the same tumor cell cultures, quinagolide, a potent dopamine agonist, produced a dose-dependent inhibition of PRL with an EC50 at least 10 times lower than that of BIM-23268. Coincubation of quinagolide and BIM-23268, particularly in tumor cells resistant to dopamine agonist treatment, did not produce additive effects on PRL suppression. In conclusion, prolactinomas have a specific pattern of SSTR subtype mRNA expression (SSTR5 and SSTR1). SSTR5 expression is correlated to PRL regulation. These inhibitory effects are superimposable, at a higher concentration, to those of the dopamine agonists, but are not additive, particularly in the adenomas resistant to dopaminergic suppression of PRL release.

  19. Prolactin decrease and shift to a normal-like isoform profile during treatment with quinagolide in a patient affected by an invasive prolactinoma.

    PubMed

    Guido, R; Valenti, S; Foppiani, L; De Martini, D; Cossu, M; Giusti, M

    1997-05-01

    Prolactin (PRL) circulates as multiple molecular weight variants: glycosylated phosphorylated, deamidated and sulphated forms. The profiles of the forms, as determined by isoelectrofocusing (IEF), differ in physiological and pathological conditions. The case of a 72-year-old woman affected by an invasive prolactinoma is described. The patient had undergone surgical treatment followed by radiotherapy at the age of 71 years. Bromocriptine therapy followed (up to 10 mg/die), but the PRL levels were still extremely high (over 13,000 micrograms/l as determined by IRMA, after dilution). We therefore treated the patient with quinagolide, at increasing dosages, from 150 micrograms/die on day 0 to 600 micrograms/die on day 220. This treatment progressively lowered PRL to 23.2 micrograms/l. In addition to a decrease in PRL levels, a progressive change in the IEF profile was also noted. Indeed, on day 0, the PRL isoforms were very acidic and during treatment they progressively shifted toward a more basic range. For purpose of comparison PRL profiles were also determined in 8 women with pathological hyperprolactinaemia (group A, aged 16-50 years, PRL levels: 25.1-170.4 micrograms/l), in 6 normal women (group B, aged 25-29 years, PRL levels: 3.4-7.9 micrograms/l) and in 5 normal women during a TRH test (group C, aged 17-52 years, PRL levels: 2.7-10.3 micrograms/l). The profiles observed in group A had a single major peak at isoelectric point (pI) 6.5, while the group B and C profiles were more heterogeneous displaying multiple minor peaks, the majority of the molecules being in a more basic range (pI 6.9 for group B and pI 7.5 for group C). During treatment, the profiles of our subject at first resembled those of group A; subsequently, when the PRL levels had normalised, the profile resembled those noted in group B. Altered (immature?, more glycosilated?, less bioactive?) PRL molecules could be secreted by the tumour. These data show that quinagolide successfully reduced PRL

  20. Physical randomness sources for loophole-free Bell tests

    NASA Astrophysics Data System (ADS)

    Mitchell, Morgan W.

    2016-05-01

    We describe the strategy and physics used to select unpredictable measurement settings in the loophole-free Bell tests reported in [Hensen et al. Nature 2015, Giustina et al. PRL 2015, and Shalm et al. PRL 2015]. We demonstrate direct measurements of laser phase diffusion, a process driven by spontaneous emission, rigorous bounds on the effect of other, less-trusted contributions, and exponential predictability reduction by randomness extraction. As required for the cited experiments, we show the six-sigma bound for the predictability of the basis choices is below 0.001%. C. Abellan et al. PRL 2015.

  1. Scholarly Research Program Delivery Order 0011: Concept Design for a 1 MW Generator Based on a Permanent Magnet Rotor (Turbine Driven)

    DTIC Science & Technology

    2007-11-02

    prl 0.196 apEnd 1.000 Pend 0.000 Lme 0.260 in u_LKG 0.000 f_Lkg 0.950...20.212 in^2 Aghp 20.761 in^2 Rghp 1.062E+05 At/Wb Pm0 2.531 uWb/At Xrl 1.000 prl 0.196 apEnd ...20.761 in^2 Rghp 1.062E+05 At/Wb Pm0 2.610 uWb/At Xrl 1.000 prl 0.190 apEnd 1.000

  2. Cost Implications of the Broad Area Maritime Surveillance Unmanned Aircraft System for the Navy Flying Hour Program and Operation and Maintenance Budget

    DTIC Science & Technology

    2010-12-01

    shown in Table 28. 58 Aircraft Type PRE Costs $FY10 (Million) PRL Costs $FY10 (Million) Fire Scout $16.1 $4.0 SH -60B $0.9 $1.3 SH - 60F $1.0 $1.5...complexity of new aircraft systems, evident in the PRE and PRL cost estimates for new manned aircraft systems in development such as the F-35, P- 8, SH ...60S and SH -60R (OPNAV N432 analyst, personal communication, August 20, 2010). A comparison of the Fire Scout and SH -60 T/M/S PRL and PRE costs is

  3. Maternal exposure to atrazine during lactation suppresses suckling-induced prolactin release and results in prostatitis in the adult offspring.

    PubMed

    Stoker, T E; Robinette, C L; Cooper, R L

    1999-11-01

    The availability of prolactin (PRL) to the neonatal brain is known to affect the development of the tuberoinfundibular (TIDA) neurons and, as a consequence, lead to alterations in subsequent PRL regulation. Without early lactational exposure to PRL (derived from the dam's milk), TIDA neuronal growth is impaired and elevated PRL levels are present in the prepubertal male. These observations, combined with the finding that alterations in PRL secretion (i.e., hyperprolactinemia) in the adult male rat have been implicated in the development of prostatitis, led us to hypothesize that early lactational exposure to agents that suppress suckling-induced PRL release would lead to a disruption in TIDA development, altered PRL regulation, and subsequent prostatitis in the male offspring. To test this hypothesis, suckling-induced PRL release was measured in Wistar dams treated twice daily with the herbicide atrazine (ATR, by gavage, on PND 1-4 at 0, 6.25, 12.5, 25, and 50 mg/kg body weight), or twice daily with the dopamine receptor agonist bromocriptine (BROM, sc, at 0.052, 0.104, 0.208, and 0.417 mg/kg); BROM is known to suppress PRL release. Similarly, atrazine has also been reported to suppress PRL in adult females. Serum PRL was measured on PND 3 using a serial sampling technique and indwelling cardiac catheters. A significant rise in serum PRL release was noted in all control females within 10 min of the initiation of suckling. Fifty-mg/kg ATR inhibited suckling-induced PRL release in all females, whereas 25 and 12.5 mg/kg ATR inhibited this measure in some dams and had no discernible effect in others. The 6.25 mg/kg dose of ATR was without effect. BROM, used here as a positive control, also inhibited suckling-induced PRL release at doses of 0.104 to 0.417 mg/kg, with no effect at 0.052 mg/kg. To examine the effect of postnatal ATR and BROM on the incidence and severity of inflammation (INF) of the lateral prostate of the offspring, adult males were examined at 90 and

  4. The role of sex and sex-related hormones in cognition, mood and well-being in older men and women.

    PubMed

    Castanho, Teresa Costa; Moreira, Pedro Silva; Portugal-Nunes, Carlos; Novais, Ashley; Costa, Patrício Soares; Palha, Joana Almeida; Sousa, Nuno; Santos, Nadine Correia

    2014-12-01

    Alterations in hormone levels during aging impact on cognition and mood. Serum concentration levels of testosterone (TT), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS) and prolactin (PRL) were assessed in 120 community-dwellers (51+ years of age, males and females), in a cross-sectional approach. Performance clusters based on executive functioning (GENEXEC), memory (MEM), mood and well-being were obtained. In males, higher PRL levels associated with worse cognitive performance, lower well-being, and higher scores in depression scales, and lower E2 with poorer cognition and higher depressive mood. DHEAS positively associated with GENEXEC and MEM. Nutritional status significantly associated with PRL (positively) and with DHEAS (negatively). Findings indicate that besides the more exhaustively studied E2 and TT, variations in the levels of sex-related hormones such as PRL, FSH, LH and DHEAS are of interest for the mental health aging profile particularly in men.

  5. Changes in the nuclear uptake and retention of /sup 3/H-estrogen in gonadotrophs and lactotrophs as a function of age

    SciTech Connect

    Nogami, H.; Yoshimura, F.; Herbert, D.C.; Aufdemorte, T.B.; Gates, G.A.; Holt, G.R.; Sheridan, P.J.

    1985-07-01

    A quantitative autoradiographic immunocytochemical study was performed in which the nuclear uptake and retention of /sup 3/H-estradiol (/sup 3/H-E2) by luteinizing hormone (LH) and prolactin (PRL) cells was examined in 19-21-year-old baboons. /sup 3/H-E2 concentrating cells were found in all of the three lobes of the pituitary in varying percentages. Approximately 80% of PRL cells and nearly 100% of LH cells were labeled. A count of the number of silver grains over nuclei revealed a marked variation of the accumulation of /sup 3/H-E2 by LH cells and to a lesser extent in PRL cells. These results suggest functional heterogeneity among LH and PRL cells. The present results are discussed in relation to the physiological state of old animals.

  6. [Hyperprolactinemia: causes, diagnosis, and treatment].

    PubMed

    Karasek, Michał; Pawlikowski, Marek; Lewiński, Andrzej

    2006-01-01

    The basic data on hyperprolactinemia (i.e. an excess of PRL above a reference laboratory's upper limits), the most common endocrine disorder of the hypothalamic-pituitary axis are given in this review. The following issues are discussed: regulation of prolactin (Prl) secretion, definition of hyperprolactinemia, its etiology and pathogenesis as well as its symptoms, diagnosis, and treatment (including medical and surgical therapy). It should be stressed that finding of elevated PRL serum concentrations constitute the beginning of diagnostic procedure and, after exclusion of physiologic, pharmacologic, and other organic causes of increased PRL levels, should be followed by detailed diagnosis including MRI. In patients in whom hyperprolactinemia has been confirmed the treatment with dopamine agonists (with prevalence of cabergoline, followed by quinagoline) is currently considered first-choice therapy. Surgery should be performed only in the patients resistant or intolerant to these agents, or in patients who refuse long-term therapy.

  7. Learning and Memory Improvement through Chemistry: Dream or Reality in the Offing?

    ERIC Educational Resources Information Center

    Hansl, Nikolaus R.; Hansl, Adele B.

    1979-01-01

    Reports on PRL-8-53, an experimental drug that will boost the chemical system in the brain called the cholinergic system and thereby improve one's ability to retrieve information from a preexisting information pool. (Author/IRT)

  8. Bulls grazing Kentucky 31 tall fescue exhibit impaired growth, semen quality, and decreased semen freezing potential

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Serum prolactin (PRL) and testosterone concentrations, body weight, body composition, semen quality, and semen freezing potential for bulls grazing the toxic tall fescue (Lolium arundinaceum [Schreb.] Darbysh. ¼ Schedonorous arundinaceum [Schreb.] Dumort.) cultivar Kentucky 31 (E+) compared with a n...

  9. Effect on prolactin secretion of Echinacea purpurea, hypericum perforatum and Eleutherococcus senticosus.

    PubMed

    Di Carlo, G; Pacilio, M; Capasso, R; Di Carlo, R

    2005-09-01

    It has been recently reported that prolactin (PRL) plays an important role in immune system regulation. In this study we investigated the activity of three natural drugs with immunomodulatory activity: Echinacea purpurea (EP), Hypericum perforatum (HP) and Eleutherococcus senticosus (ES) on PRL production. Male rats were orally treated with two different doses (30 and 100 mg/kg) of extract of these drugs for 3 or 15 days. A 3-day treatment was not able to modify PRL serum levels, whereas a 15-day treatment with EP and HP at the higher dose significantly inhibits PRL production. A treatment with ES was always ineffective. A possible mechanism for this effect could be that both HP and EP extracts display a direct dopaminergic activity, although an involvement of the GABA-ergic system cannot be excluded.

  10. Correlation and comparison of Nb/sub 2/ lymphoma cell bioassay with radioimmunoassay for human prolactin

    SciTech Connect

    Subramanian, M.G.; Spirtos, N.J.; Moghissi, K.S.; Magyar, D.M.; Hayes, M.F.; Gala, R.R.

    1984-12-01

    Serum samples from groups of men and women with normal and elevated prolactin (PRL) levels were assayed by radioimmunoassay (RIA) and by Nb/sub 2/ lymphoma cell bioassay (BA) for the presence of PRL. Because the Nb/sub 2/ lymphoma cells respond to both PRL and growth hormone, BA for PRL activity was carried out before and after neutralization of growth hormone in the serum samples. There were excellent correlations between RIA and BA both in euprolactinemic and hyperprolactinemic subjects. On an absolute basis, RIA and BA values were similar in the euprolactinemic group (6.6 +/- 0.8 versus 6.2 +/- 1.0), whereas in the hyperprolactinemic group, RIA values were significantly higher than the BA results. The two assay systems also appeared to correlate better in women who were hyperprolactinemic, with obvious menstrual cycle disturbances, than in hyperprolactinemic women without menstrual cycle disturbances.

  11. Discovery of the improved antagonistic prolactin variants by library screening.

    PubMed

    Liu, Yun; Gong, Wei; Breinholt, Jens; Nørskov-Lauritsen, Leif; Zhang, Jinchao; Ma, Qinhong; Chen, Jianhe; Panina, Svetlana; Guo, Wei; Li, Tengkun; Zhang, Jingyuan; Kong, Meng; Liu, Zibing; Mao, Jingjing; Christensen, Leif; Hu, Sean; Wang, Lingyun

    2011-11-01

    Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.

  12. Growth hormone augments superoxide anion secretion of human neutrophils by binding to the prolactin receptor.

    PubMed Central

    Fu, Y K; Arkins, S; Fuh, G; Cunningham, B C; Wells, J A; Fong, S; Cronin, M J; Dantzer, R; Kelley, K W

    1992-01-01

    Recombinant human growth hormone (HuGH) and human prolactin (HuPRL), but not GH of bovine or porcine origin, prime human neutrophils for enhanced superoxide anion (O2-) secretion. Since HuGH, but not GH of other species, effectively binds to the HuPRL receptor (HuPRL-R), we used a group of HuGH variants created by site-directed mutagenesis to identify the receptor on human neutrophils responsible for HuGH priming. A monoclonal antibody (MAb) directed against the HuPRL-R completely abrogated O2- secretion by neutrophils incubated with either HuGH or HuPRL, whereas a MAb to the HuGH-R had no effect. The HuGH variant K172A/F176A, which has reduced affinity for both the HuGH-binding protein (BP) and the HuPRL-BP, was unable to prime human neutrophils. This indicates that priming is initiated by a ligand-receptor interaction, the affinity of which is near that defined for receptors for PRL and GH. Another HuGH variant, K168A/E174A, which has relatively low affinity for the HuPRL-BP but slightly increased affinity for the HuGH-BP, had much reduced ability to prime neutrophils. In contrast, HuGH variant E56D/R64M, which has a similar affinity as wild-type HuGH for the HuPRL-BP but a lower affinity for the HuGH-BP, primed neutrophils as effectively as the wild-type HuGH. Finally, binding of HuGH to the HuPRL-BP but not to the HuGH-BP has been shown to be zinc dependent, and priming of neutrophils by HuGH was also responsive to zinc. Collectively, these data directly couple the binding of HuGH to the HuPRL-R with one aspect of functional activation of human target cells. Images PMID:1310696

  13. Role of abnormal anterior pituitary hormones-growth hormone and prolactin in active systemic lupus erythematosus

    PubMed Central

    Zhu, Xiaohua; Xu, Jinhua; Li, Shujuan; Huang, Wen; Li, Feng

    2015-01-01

    Background: The role of anterior pituitary hormones in systemic lupus erythematosus (SLE) remains controversial. Aims and Objectives: We determined the expression levels of human growth hormone (GH), prolactin (PRL), and their receptors in subjects presenting with SLE, and modulation of disease severity. Materials and methods: Forty-seven subjects and ten healthy controls were assessed for possible association between SLE disease activity and levels of serum PRL, GH and thyrotropin-releasing hormone (TRH). In peripheral blood mononuclear cells (PBMC), specific binding and mRNA expression of receptors for GH (GHR), and PRL (PRLR) were determined by receptor-ligand binding assay (RLBA) and RT-PCR. PBMC of recruited subjects were treated with hPRL and rhGH to assess IgG production and antibodies against dsDNA. Results: In active SLE subjects we found elevated PRL and GH levels. Study subject PBMCs displayed augmented GHR and PRLR protein and mRNA expression. Study subjects also showed a positive correlation in serum PRL levels and specific antibodies against dsDNA, SLE disease activity index (SLEDAI), and proteinuria. However, a negative correlation was found between serum PRL levels and complement component C3. We found a positive correlation between specific binding rates of PRLR and GHR and both SLE activity and dsDNA antibody titers. Enhanced IgG and anti-dsDNA secretion was observed in cultured PBMC stimulated by PRL or GH with/without PHA, PWM, IL-2 or IL-10. In active SLE, a close association was found between augmented PRL and GH levels, expression and specific binding activities of PRLR and GHR, and changes in the specific titer of anti-dsDNA. Conclusion: Anterior pituitary hormones play an important role in the pathogenesis of SLE. High levels of growth hormone (GH) and prolactin (PRL) play a role in pathogenesis of SLE, which is correlated with SLE disease activity and antibodies against dsDNA. The mechanism of GH and PRL in SLE was complicated and should

  14. Growth hormone and prolactin responses to bolus and sustained infusions of GRH-1-40-OH in man.

    PubMed

    Goldman, J A; Molitch, M E; Thorner, M O; Vale, W; Rivier, J; Reichlin, S

    1987-08-01

    To determine whether GRH stimulates PRL secretion we studied the effects of iv bolus injections and prolonged infusions of GRH 1-40-OH on PRL and GH serum levels in normal volunteers. Eight patients with acromegaly, two of whom had elevated basal levels of PRL, were also tested with single bolus injections. Six normal subjects given 3.3 micrograms/kg bolus injections of GRH showed a mean increment of GH of 22.0 +/- 1.7 ng/ml (mean +/- SE). A small rise in PRL was noted in 5 of the 6 subjects (mean peak level of 6.4 +/- 1.9 ng/ml vs basal level of 3.3 +/- 0.4 ng/ml, p less than 0.05). During the continuous intusion of GRH (10 ng/kg/min), GH levels rose gradually from a mean baseline of 1.1 +/- 0.1 ng/ml to a mean peak of 30.0 +/- 7.2 ng/ml at about 2 h and then slowly declined to a nadir of 4.2 +/- 0.4 ng/ml at 330 min. PRL levels did not rise significantly during the infusion. To determine whether the decline in GH levels in the face of continued infusion was due to loss of GH responsiveness, a 3.3 micrograms/kg bolus of GRH was given during the nadir at 330 min; this GH increment was significantly less than that obtained by the GRH bolus injection without the infusion (12.9 +/- 3.5 ng/ml vs 22.0 +/- 1.7 ng/ml, p less than 0.05). The PRL response to the GRH bolus was the same during the infusion of GRH as before. In each of 8 acromegalic patients (including two who had initially elevated basal PRL levels) GRH led to an increase in both GH and PRL levels. PRL and GH levels spontaneously fluctuated in parallel in 4 acromegalic cases studied with repeated samples over 6 h during placebo administration. These experiments show that GRH has significant, though weak, PRF effect in normals and that it is more potent PRF in acromegalic patients. Furthermore, the effects on GH and PRL of a sustained infusion of GRH for 5 1/2 h are both qualitatively and quantitatively different. These results suggest that the GRH effect is exerted either on different pituitary receptors for

  15. Immunohistochemical detection of glycoprotein hormone alpha subunit in somatoprolactinic and pure somatotroph adenomas.

    PubMed

    Vantyghem, M C; Cortet, C; Bauters, C; Gevaert, M H; Dewailly, D; Lefebvre, J; Mazzucca, M

    1998-01-01

    Glycoprotein hormone alpha subunit (alpha SU) is expressed in nearly all thyreotroph adenomas and most gonadotrophinomas, but is less well documented in plurisecreting adenomas. We therefore examined the immunohistochemical (IHC) expression of alpha SU in a generally accepted model of plurisecreting adenomas (somatoprolactinic type) by comparison to a series of pure monosecreting somatotroph tumors. Fifty patients (32 females, 18 males) aged 15 to 68 years with clinical and/or biological acromegaly requiring adenomectomy were studied. Forty-five had clinical acromegaly and 5 had isolated amenorrhea and/or galactorrhea syndromes. Forty-eight of the 49 patients who had baseline assessments of plasma GH had a mean concentration of 5 ng/ml or more (normal value < 5). Fifteen of the 46 patients who had baseline measurements of plasma PRL had a prolactinemia value greater than 20 ng/ml (normal value < 20) but below 100 ng/ml, except for one patient. All the adenomas studied were positive by GH immunohistochemistry; 21 were immunostained by an antiPRL antibody and formed the "somatoprolactinic" (GH-PRL) group. Five of these 21 patients were male. The 12 female patients younger than 50 years had amenorrhea or galactorrhea, and one male patient complained of impotence. Eleven patients (9 females, 2 males) in this GH-PRL group had hyperprolactinemia. Sixteen of these GH-PRL adenomas were immunolabeled by alpha SU antiserum. The remaining 29 adenomas, which were immunonegative with the PRL antibody and formed the "somatotroph adenoma" (GH) group, were more frequent in male patients (13/29; 45%) compared to GH-PRL group. Eight amenorrhea or galactorrhea syndromes occurred among the 14 women younger than 50 years, 3 of whom had hyperprolactinemia. Thirteen of these 29 adenomas (45%) were immunopositive with alpha SU antibody. Compared to the GH group, the GH-PRL group had a significant higher frequency of amenorrhea and/or galactorrhea syndromes among women under 50 years (100

  16. Reproductive experience reduces circulating 17beta-estradiol and prolactin levels during proestrus and alters estrogen sensitivity in female rats.

    PubMed

    Bridges, Robert S; Byrnes, Elizabeth M

    2006-05-01

    The reproductive experiences of pregnancy, parturition, and lactation affect a range of neural and endocrine processes after the end of lactation. In women, previous parity results in reduced circulating prolactin (PRL) and androgen levels years after giving birth. Reductions in PRL secretion also occur in reproductively experienced, female rats. In the present study we examined the status and regulation of estradiol (E(2)) and PRL during the reproductive cycle after reproductive experience. These hormones regulate one another and have been implicated in a number of disease and aging processes. Using a rat model, the patterns of E(2) and PRL secretion, pituitary PRL content, and estrogen receptor alpha expression were characterized from 1200-1800 h on proestrus in age-matched, primiparous and nulliparous animals. The possible effect of parity on estrogen sensitivity was then examined by challenging nonlactating, ovariectomized, age-matched, multiparous and nulliparous rats with estradiol benzoate (EB; 0, 1, 5, 25, and 125 microg/kg) and measuring PRL responses 24 and 48 h later. Previous parity resulted in modest, yet significant, reductions in E(2) and PRL levels on proestrus, a limited increase in pituitary estrogen receptor alpha expression, and a significant shift in estrogen sensitivity, as measured by EB-induced PRL secretion. Nulliparous animals were more sensitive than multiparous rats to the two lower doses of EB, whereas multiparous animals were more responsive to the highest EB dose. These unique parity-induced alterations in the female's endocrine state that persist beyond lactation may impact a multitude of estrogen-mediated processes over the female's adult life span.

  17. Hyper-Prolactinemia in Men With Idiopathic Dilated Cardiomyopathy: Does It Have any Prognostic Implications?

    PubMed Central

    Naderi, Nasim; Bakhshandeh, Hooman; Ardeshiri, Maryam; Barzegari, Fatemeh; Amin, Ahmad; Taghavi, Sepideh; Maleki, Majid

    2014-01-01

    Background: Prolactin (PRL) has increasingly been recognized to play a stimulatory role in inflammatory response. Recently, studies have reported an increase in prolactin level among patients with chronic heart failure, however, there is conflicting data about its role as a prognostic factor in these patients. Objectives: We aimed to measure PRL level in male patients with idiopathic dilated cardiomyopathy (IDC) and its relationship with some prognostic factors. Patients and Methods: Serum prolactin level was assessed in 33 men with a diagnosis of IDC, left ventricle ejection fraction (LVEF) less than 35% on standard medical therapy for heart failure and New York Heart Association class II-III. Serum NT-Pro BNP (N terminal pro brain natriuretic peptide), hs-CRP (High sensitive C reactive protein) and six-minute walk test (6MWT) were also measured. Our secondary endpoints were mortality, transplantation and hospitalization due to acute heart failure and all patients were followed for one year. Results: The mean age was 33 ± 7 years (24-45 years) and the mean LVEF was 23% ± 6.5. The mean PRL level was 16 ± 7.7 ng/mL (95% confidence interval: 13.3-18.7 ng/mL), which was significantly higher than normal reference values (4.04-15 ng/mL) (P < 0.0001). There was no correlation between PRL levels and pro BNP, hs-CRP or 6MWT test, however, the serum PRL level was slightly higher among patients who died or were hospitalized or transplanted. Conclusions: Considering our study results, prognostic implication of PRL should be questioned. However, it seems that the significant increase in serum PRL in the study population needs more consideration and may have its own pathophysiologic importance. Further studies are recommended for better addressing the role of PRL in chronic heart failure patients. PMID:25478544

  18. Prolactin Signaling Stimulates Invasion via Na(+)/H(+) Exchanger NHE1 in T47D Human Breast Cancer Cells.

    PubMed

    Pedraz-Cuesta, Elena; Fredsted, Jacob; Jensen, Helene H; Bornebusch, Annika; Nejsum, Lene N; Kragelund, Birthe B; Pedersen, Stine F

    2016-07-01

    Prolactin (PRL) and its receptor (PRLR) are implicated in breast cancer invasiveness, although their exact roles remain controversial. The Na(+)/H(+) exchanger (NHE1) plays essential roles in cancer cell motility and invasiveness, but the PRLR and NHE1 have not previously been linked. Here we show that in T47D human breast cancer cells, which express high levels of PRLR and NHE1, exposure to PRL led to the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5), Akt, and ERK1/2 signaling and the rapid formation of peripheral membrane ruffles, known to be associated with cell motility. NHE1 was present in small ruffles prior to PRL treatment and was further recruited to the larger, more dynamic ruffles induced by PRL exposure. In PRL-induced ruffles, NHE1 colocalized with activated Akt, ERK1/2, and the ERK effector p90Ribosomal S kinase (p90RSK), known regulators of NHE1 activity. Stimulation of T47D cells with PRL augmented p90RSK activation, Ser703-phosphorylation of NHE1, NHE1-dependent intracellular pH recovery, pericellular acidification, and NHE1-dependent invasiveness. NHE1 activity and localization to ruffles were attenuated by the inhibition of Akt and/or ERK1/2. In contrast, noncancerous MCF10A breast epithelial cells expressed NHE1 and PRLR at lower levels than T47D cells, and their stimulation with PRL induced neither NHE1 activation nor NHE1-dependent invasiveness. In conclusion, we show for the first time that PRLR activation stimulates breast cancer cell invasiveness via the activation of NHE1. We propose that PRL-induced NHE1 activation and the resulting NHE1-dependent invasiveness may contribute to the metastatic behavior of human breast cancer cells.

  19. Prolactin and Human Ovarian Cancer

    DTIC Science & Technology

    2009-09-01

    Edery, Nadine Binart, and Paul A. Kelly. Prolactin (PRL) and its receptor: Actions, Signal transduction pathways and Phenotypes Observed in PRL receptor...development and tumorigenesis. J Mammary Gland Biol Neoplasia 2001, 6:115– 127 6. JF Trott , RC Hovey, S Koduri, and BK Vonderhaar. Alternative...Jean-Baptiste Jomain and Paul A. Kelly. Development of Prolactin Receptor Antagonists: Same Goal, Different Ways. Recent Patents on Endocrine

  20. Comparing the fixational and functional preferred retinal location in a pointing task.

    PubMed

    Sullivan, Brian; Walker, Laura

    2015-11-01

    Patients with central vision loss (CVL) typically adopt eccentric viewing strategies using a preferred retinal locus (PRL) in peripheral retina. Clinically, the PRL is defined monocularly as the area of peripheral retina used to fixate small stimuli. It is not clear if this fixational PRL describes the same portion of peripheral retina used during dynamic binocular eye-hand coordination tasks. We studied this question with four participants each with a unique CVL history. Using a scanning laser ophthalmoscope, we measured participants' monocular visual fields and the location and stability of their fixational PRLs. Participants' monocular and binocular visual fields were also evaluated using a computer monitor and eye tracker. Lastly, eye-hand coordination was tested over several trials where participants pointed to and touched a small target on a touchscreen monitor. Trials were blocked and carried out monocularly and binocularly, with a target appearing at 5° or 15° from screen center, in one of 8 locations. During pointing, our participants often exhibited long movement durations, an increased number of eye movements and impaired accuracy, especially in monocular conditions. However, these compensatory changes in behavior did not consistently worsen when loci beyond the fixational PRL were used. While fixational PRL size, location and fixation stability provide a necessary description of behavior, they are not sufficient to capture the pointing PRL used in this task. Generally, patients use a larger portion of peripheral retina than one might expect from measures of the fixational PRL alone, when pointing to a salient target without time constraints. While the fixational and pointing PRLs often overlap, the fixational PRL does not predict the large area of peripheral retina that can be used.

  1. Induction (or stimulatin) of prolactin and growth hormone production in a rat pituitary tumor cell line by bromodeoxyuridine

    SciTech Connect

    Cohen, H.; Andre, J.; Grenot, C.; Guillaumot, P.; Pascal, O.

    1982-02-01

    Under basal conditions, a rat pituitary tumor cell line (C/sub 3/ 11RAP) does not secrete any detectable PRL, FSH, and LH, and secretes only minute amounts of GH (27.1 +/- 0.5 ng/10/sup 6/ cells . 24 h), as evaluated by RIA. Bromodeoxyuridine (BrdUrd) added to the culture medium induced the accumulation of PRL into cells and medium, increased that of GH, but did not induce that of LH or FSH. The amount of radioimmunoassayable PRL and GH accumulated in the medium, increased after a lag period of 15 days and was drug concentration dependent. Maximal accumulation was 232.9 +/- 36.8 and 493.6 +/- 41.5 ng/10/sup 6/ cells . 24 h for PRL and GH, respectively, at 50 ..mu..g/ml BrdUrd. In the presence of BrdUrd (greater than or equal to20 ..mu..g/ml), the cells grew more slowly and were more strongly attached to the flasks. All of the effects induced by BrdUrd were reversible. PRL and GH were characterized by three methods: 1) radiocompetition with increasing dilution of samples; 2) Sephadex chromatography, followed by RIAs; and 3) sodium dodecyl sulfate-polyacrylamide gel electrophoresis done on the immunoprecipitate of the proteins secreted by cells incubated with (/sup 3/H)leucine. Chronic treatment with TRH (3 x 10/sup -6/ M) of cells grown without BrdUrd was unable to increase the production of GH or to induce that of PRL. On the other hand, after the same treatment of cells cultured in the presence of BrdUrd, the amounts of PRL accumulated in the culture medium or cells were increased 2- to 7-fold over unstimulated levels; under the same conditions, GH accumulation in the medium was also increased, but this augmentation was less than that of PRL.

  2. Comparing the fixational and functional preferred retinal location in a pointing task

    PubMed Central

    Sullivan, Brian; Walker, Laura

    2016-01-01

    Patients with central vision loss (CVL) typically adopt eccentric viewing strategies using a preferred retinal locus (PRL) in peripheral retina. Clinically, the PRL is defined monocularly as the area of peripheral retina used to fixate small stimuli. It is not clear if this fixational PRL describes the same portion of peripheral retina used during dynamic binocular eye-hand coordination tasks. We studied this question with four participants each with a unique CVL history. Using a scanning laser ophthalmoscope, we measured participants’ monocular visual fields and the location and stability of their fixational PRLs. Participants’ monocular and binocular visual fields were also evaluated using a computer monitor and eye tracker. Lastly, eye-hand coordination was tested over several trials where participants pointed to and touched a small target on a touchscreen monitor. Trials were blocked and carried out monocularly and binocularly, with a target appearing at 5° or 15° from screen center, in one of 8 locations. During pointing, our participants often exhibited long movement durations, an increased number of eye movements and impaired accuracy, especially in monocular conditions. However, these compensatory changes in behavior did not consistently worsen when loci beyond the fixational PRL were used. While fixational PRL size, location and fixation stability provide a necessary description of behavior, they are not sufficient to capture the pointing PRL used in this task. Generally, patients use a larger portion of peripheral retina than one might expect from measures of the fixational PRL alone, when pointing to a salient target without time constraints. While the fixational and pointing PRLs often overlap, the fixational PRL does not predict the large area of peripheral retina that can be used. PMID:26440864

  3. Salsolinol is present in the bovine posterior pituitary gland and stimulates the release of prolactin both in vivo and in vitro in ruminants.

    PubMed

    Hashizume, T; Shida, R; Suzuki, S; Nonaka, S; Yonezawa, C; Yamashita, T; Kasuya, E; Sutoh, M; Oláh, M; Székács, D; Nagy, G M

    2008-02-01

    The aims of the present study were to determine whether salsolinol (SAL), a dopamine-related compound, is present in the bovine posterior pituitary (PP) gland, and to clarify the effect of SAL on the secretion of prolactin (PRL) in ruminants. SAL was detected in extract of bovine PP gland using high-pressure liquid chromatography with electrochemical detection (HPLC-EC). A single intravenous (i.v.) injection of SAL (5 and 10mg/kg body weight) significantly and dose-dependently stimulated the release of PRL in goats (P<0.05). Plasma PRL levels reached a peak 10min after the injection, then gradually returned to basal values in 60-80min. The PRL-releasing pattern was similar to that in response to sulpiride (a dopamine receptor antagonist). The intracerebroventricular (i.c.v.) injection of 1mg of SAL had no significant effect on the release of PRL in calves, however, 5mg significantly stimulated the release (P<0.05) with peak values reached 30-40min after the injection. Moreover, SAL significantly stimulated the release of PRL from cultured bovine anterior pituitary cells at doses of 10(-6) and 10(-5)M, compared to control cells (P<0.05). Taken together, our data clearly show that SAL is present in extract of the PP gland of ruminants, and has PRL-releasing activity both in vivo and in vitro. Therefore, this endogenous compound is a strong candidate for the factor having PRL-releasing activity that has been previously detected in extract of the bovine PP gland.

  4. Immunological properties of prolactin and studies on a gonadotropin binding inhibitor

    SciTech Connect

    Chang, Y.S.

    1985-01-01

    The physiological role of prolactin in horses has not yet been well defined. With the availability of highly purified ePRL for inducing antibody formation in rabbits and for radiolabeling with Na/sup 125/I, a very sensitive (0.4-0.6 ng/ml) and highly specific homologous RIA for ePRL was developed. A heterologous RIA using /sup 125/I-labeled ovine PRL and anti-ePRL antiserum was also developed and compared to the homologous RIA for ePRL. Of the two systems, it is concluded that this homologous RIA system is more suitable and more reliable for measuring prolactin concentration in horse serum samples. Until now, biochemical information on PRL has not been available for reptilian species. Sea turtle (Chelonia mydas) prolactin was purified from pituitary extracts by selective precipitation, DEAE-cellulose chromatography and gel filtration. Similar to other species of PRL, sea turtle PRL is a 22,000-24,000 daltons protein and contains a high content of glutamic acid, aspartic acid, serine and leucine, the N-terminal amino acid residue. Gonadotropin (FSH) binding inhibitor was partially purified from sheep testes by ammonium sulfate fractionation and ion exchange chromatography. The FSH-BI (molecular weight: 50,000 daltons, estimated by gel filtration) contains a protein moiety necessary for binding inhibitory activity. The inhibition of the binding of /sup 125/I-labeled ovine FSH to its receptor by the FSH-BI is not competitive. Both in vivo and in vitro biological studies of FSH-BI preparations in rats indicated various effects on FSH and LH activities at the gonadal level. These findings suggest a physiological role for FSH-BI in the regulation of reproduction.

  5. Antagonism of Taxol Cytotoxicity by Prolactin: Implication for Patient Resistance to Chemotherapy

    DTIC Science & Technology

    2008-03-01

    neurochemical basis of schizophrenia. Recent theories , al- though not disputing a major role for dopamine, maintain that schizophrenia also involves...of human fetal hormones. III. Prolactin. J Clin Invest 56:155–164 261. Simon P, Decoster C, Brocas H, Schwers J, Vassart G 1986 Absence of human...molecular mimic of phosphorylated PRL, S179D- PRL. Endocrinology 144:5300–5307 382. Chen NY, Holle L, Li W, Peirce SK, Beck MT, Chen WY 2002 In vivo

  6. Prolactin Receptor Coupling to Jak-Stat Pathways in Breast Cancer

    DTIC Science & Technology

    2007-08-01

    PRL) signaling through the Jak2-Stat5 pathway has been well characterized and implicated for the normal growth , development, and differentiation of...Gordon Research Conference on Prolactin and Growth Hormone Family, Ventura CA, January 29-February 3, 2006. Poster Neilson LM, Zhu J, Xie J...Stat3 pathways on Jak1 raises the possibility that Jak1 represents a new and conditional branching point of the PRL receptor signaling network that

  7. Monte Carlo and Molecular Dynamics in the Multicanonical Ensemble: Connections between Wang-Landau Sampling and Metadynamics

    NASA Astrophysics Data System (ADS)

    Vogel, Thomas; Perez, Danny; Junghans, Christoph

    2014-03-01

    We show direct formal relationships between the Wang-Landau iteration [PRL 86, 2050 (2001)], metadynamics [PNAS 99, 12562 (2002)] and statistical temperature molecular dynamics [PRL 97, 050601 (2006)], the major Monte Carlo and molecular dynamics work horses for sampling from a generalized, multicanonical ensemble. We aim at helping to consolidate the developments in the different areas by indicating how methodological advancements can be transferred in a straightforward way, avoiding the parallel, largely independent, developments tracks observed in the past.

  8. Alpha-Estrogen and Progesterone Receptors Modulate Kisspeptin Effects on Prolactin: Role in Estradiol-Induced Prolactin Surge in Female Rats.

    PubMed

    Aquino, Nayara S S; Araujo-Lopes, Roberta; Henriques, Patricia C; Lopes, Felipe E F; Gusmao, Daniela O; Coimbra, Candido C; Franci, Celso R; Reis, Adelina M; Szawka, Raphael E

    2017-04-06

    Kisspeptin regulates prolactin (PRL) in an estradiol-dependent manner. We investigated the interaction between ovarian-steroid receptors and kisspeptin in the control of PRL secretion. Intracerebroventricular injections of kisspeptin-10 (Kp-10) or kisspeptin-234 (Kp-234) were performed in ovariectomized (OVX) rats under different hormonal treatments. Kp-10 increased PRL release and decreased 3,4-dihydroxyphenylacet acid (DOPAC) levels in the median eminence (ME) of OVX rats treated with estradiol (OVX+E), which was prevented by tamoxifen. Whereas these effects of Kp-10 were absent in OVX rats, they were replicated in OVX rats treated with selective agonist of estrogen receptor (ER)α, propylpyrazole triol (PPT), but not of ERβ, diarylpropionitrile (DPN). Furthermore, the Kp-10-induced increase in PRL was 2-fold higher in OVX+E rats further treated with progesterone (OVX+EP), which was associated with a reduced expression of both tyrosine hydroxylase (TH) and Ser40-phosphorylated TH in the ME. Kp-10 also reduced dopamine levels in the ME of OVX+EP rats, an effect blocked by the progesterone receptor (PR) antagonist, RU486. We also determined the effect of kisspeptin antagonism with Kp-234 on the estradiol-induced surges of PRL and luteinizing hormone (LH), using tail-tip blood sampling combined with ultrasensitive ELISA. Kp-234 impaired the early phase of the PRL surge and prevented the LH surge in OVX+E rats. Thus, we provide evidence for the first time that kisspeptin stimulation of PRL release requires ERα and is potentiated by progesterone via PR activation. Moreover, alongside its essential role in the LH surge, kisspeptin seems to play a role in the peak phase of the estradiol-induced PRL surge.

  9. A dopamine receptor d2-type agonist attenuates the ability of stress to alter sleep in mice.

    PubMed

    Jefferson, F; Ehlen, J C; Williams, N S; Montemarano, J J; Paul, K N

    2014-11-01

    Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between PRL secretion and REM sleep after restraint stress to determine whether: 1) the ability of stress to increase REM sleep is PRL-dependent, and 2) fluctuating PRL levels underlie sex differences in sleep responses to stress. Because dopamine D2 receptors in the pituitary gland are the primary regulator of PRL secretion, D2 receptor agonist, 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea (cabergoline), was used to attenuate PRL levels in mice before 1 hour of restraint stress. Mice were implanted with electroencephalographic/electromyographic recording electrodes and received an ip injection of either 0.3-mg/kg cabergoline or vehicle before a control procedure of 1 hour of sleep deprivation by gentle handling during the light phase. Six days after the control procedure, mice received cabergoline or vehicle 15 minutes before 1 hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on PRL and that sex differences in REM sleep amount may be driven by PRL.

  10. Hyperprolactinemia does not promote testicular recrudescence in photoregressed Siberian hamsters.

    PubMed

    Whitten, R D; Youngstrom, T G; Bartness, T J

    1993-07-01

    Serum prolactin (PRL) concentrations, as well as body, epididymal white adipose tissue (EWAT), and testes weights, decrease in Siberian hamsters (Phodopus sungorus sungorus) following short-photoperiod exposure. Previously, we have shown that lesions of the suprachiasmatic nucleus of the hypothalamus (SCNx) block regression of the testes and decreases in body weight and EWAT caused by short day-like, timed daily subcutaneous melatonin infusions in pinealectomized Siberian hamsters and elevate dramatically serum PRL concentrations. We also have shown that SCNx, as well as lesions of the paraventricular nucleus of the hypothalamus (PVNx) and an area immediately ventral to the PVN (subPVN), promote accelerated testicular recrudescence, increases in EWAT and body weights, and increases in serum PRL concentrations, in short-day (SD)-housed, photoregressed Siberian hamsters. The stimulation of the testes seen in these previous studies could have been due to the lesion-induced increases in serum PRL concentrations. Therefore, the purpose of the present experiment was to test whether experimentally induced hyperprolactinemia could stimulate testicular recrudescence. This was accomplished by giving photoregressed, SD-housed Siberian hamsters chronic subcutaneous infusions of ovine PRL (oPRL) to mimic either long-day- or lesion-induced serum concentrations of hamster prolactin (hPRL). No increase in testes, body, or EWAT weights were observed following 5 weeks of oPRL infusions in either group compared with their vehicle-infused counterparts. These data suggest that hyperprolactinemia was not solely responsible for the stimulation of testicular recrudescence in SCNx or PVNx photoregressed, or SCNx pinealectomized hamsters receiving timed melatonin infusions seen previously.

  11. Effects of the Janus Kinase Inhibitor, Tofacitinib, on Testicular Leydig Cell Hyperplasia and Adenoma in Rats, and on Prolactin Signaling in Cultured Primary Rat Leydig Cells.

    PubMed

    Chapin, Robert E; Ball, Douglas J; Radi, Zaher A; Kumpf, Steven W; Koza-Taylor, Petra H; Potter, David M; Mark Vogel, W

    2017-01-01

    Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity. Since prolactin signals through the JAK2 pathway, we hypothesized that these findings were off-target effects due to inhibition of PRL signaling via JAK2. The studies reported here were designed to investigate the interruption of PRL signaling pathways in Leydig cells. In isolated primary rat Leydig cells, PRL increased phosphorylated Signal Transducer and Activator of Transcription-5 protein, and mRNA levels for luteinizing hormone receptor. Tofacitinib, at concentrations observed in the rat carcinogenicity study, dose-dependently inhibited these effects. These observations illustrate a novel mechanism, the inhibition of prolactin signaling by which modulation of JAK activity can modulate PRL signaling pathways to induce Leydig cell tumors in rats. Since human Leydig cells lack this PRL dependence for normal function, these rodent tumors do not indicate a health risk to human patients.

  12. No association between oxytocin or prolactin gene variants and childhood-onset mood disorders

    PubMed Central

    Strauss, John S.; Freeman, Natalie L.; Shaikh, Sajid A.; Vetró, Ágnes; Kiss, Enikő; Kapornai, Krisztina; Daróczi, Gabriella; Rimay, Timea; Kothencné, Viola Osváth; Dombovári, Edit; Kaczvinszk, Emília; Tamás, Zsuzsa; Baji, Ildikó; Besny, Márta; Gádoros, Julia; DeLuca, Vincenzo; George, Charles J.; Dempster, Emma; Barr, Cathy L.; Kovacs, Maria; Kennedy, James L.

    2010-01-01

    Background Oxytocin (OXT) and prolactin (PRL) are neuropeptide hormones that interact with the serotonin system and are involved in the stress response and social affiliation. In human studies, serum OXT and PRL levels have been associated with depression and related phenotypes. Our purpose was to determine if single nucleotide polymorphisms (SNPs) at the loci for OXT, PRL and their receptors, OXTR and PRLR, were associated with childhood-onset mood disorders (COMD). Methods Using 678 families in a family-based association design, we genotyped sixteen SNPs at OXT, PRL, OXTR and PRLR to test for association with COMD. Results No significant associations were found for SNPs in the OXTR, PRL, or PRLR genes. Two of three SNPs 3' of the OXT gene were associated with COMD (p ≤ 0.02), significant after spectral decomposition, but were not significant after additionally correcting for the number of genes tested. Supplementary analyses of parent-of-origin and proband sex effects for OXT SNPs by Fisher’s Exact test were not significant after Bonferroni correction. Conclusions We have examined sixteen OXT and PRL system gene variants, with no evidence of statistically significant association after correction for multiple tests. PMID:20547007

  13. The m-chlorophenylpiperazine test in cluster headache: a study on central serotoninergic activity.

    PubMed

    Leone, M; Attanasio, A; Croci, D; Libro, G; Grazzi, L; D'Amico, D; Nespolo, A; Bussone, G

    1997-10-01

    The central serotoninergic agonist m-chlorophenylpiperazine (m-CPP) stimulates several 5HT receptor subtypes. It induces the release of both cortisol and prolactin (PRL). In this study we investigated central serotoninergic responsiveness in cluster headache by monitoring cortisol and PRL responses to m-CPP administration. Twenty-three patients with episodic cluster headache and 17 sex-matched and age-matched healthy subjects were studied. The cluster headache patients were tested during a cluster period, and none were receiving prophylaxis. A single oral dose of m-CPP, 0.5 mg/kg, was given at time 0. Blood samples were drawn at -30, 0, 30, 60, 90, 120, 150 and 180 min. PRL and cortisol levels were assayed in the samples. PRL and cortisol delta maxima (delta maximum = maximum response - baseline level at time 0/baseline level at time 0) were evaluated in each patient and mean values compared. Serum levels of m-CPP were detected by HPLC and correlated to hormonal responses. Reduced cortisol (p < 0.02) and increased PRL (p < 0.05) delta maxima were observed in cluster headache patients. Increased basal cortisol plasma levels (p < 0.05) and reduced basal PRL plasma levels (p = 0.06) also characterized cluster headache patients. This is the first study evaluating central serotoninergic responsiveness to m-CPP in cluster headache and these data suggest impaired central serotoninergic function in this pathology.

  14. Paradoxical effects of oxytocin and vasopressin on basal prolactin secretion and the estrogen-induced prolactin surge

    SciTech Connect

    Mai, Leemin ); Pan, Jenntser )

    1990-01-01

    The roles of oxytocin (OT) and vasopressin (AVP) on both basal and estrogen-induced prolactin (PRL) secretion were examined. Adult female Sprague-Dawley rats that were ovariectomized for 3 weeks and received estrogen treatment for 1 week were used. Intravenous administration of hormones and serial blood sampling were accomplished through indwelling intraatrial catheters which were implanted two days before. Plasma PRL levels were measured by radioimmunoassay. Oxytocin at a dose of 20 {mu}g/rat stimulated a moderate PRL release in the morning and lower doses were without effect. Vasopressin was most effective at a dose of 5 {mu}g/rat in stimulating PRL release, while consecutive injections of higher doses were less effective. In contrast, TRH, ranging from 1 to 8 {mu}g/rat, induced a dose-dependent increases in PRL secretion. Using the effective dosages determined from the morning studies, repeated injections of either OT, AVP or their specific antagonists MPOMeOVT were given hourly between 1300 to 1800h and blood samples were obtained hourly from 1100 to 1900h. It was found that either OT or AVP significantly reduced the afternoon PRL surge, while their antagonists were not as effective.

  15. Changes in mediobasal hypothalamic dopamine and GABA release: a possible mechanism underlying taurine-induced prolactin secretion.

    PubMed

    Arias, P; Jarry, H; Convertini, V; Ginzburg, M; Wuttke, W; Moguilevsky, J

    1998-01-01

    Taurine (Tau), a putative inhibitory amino acid neurotransmitter, has been shown to stimulate prolactin (PRL) release. Using ovariectomized, estrogen-replaced adult rats we investigated initially the effect of this amino acid, injected by different routes, on PRL secretion in vivo. Tau (100-500 mg/kg) had no effect on PRL release when given i.p.; 15 min after i.c.v. injection of Tau (3 mumoles), a significant increase in serum PRL levels was observed (78 +/- 9 ng/ml over basal levels, p < 0.01 vs. controls). In vitro (cultured anterior pituitary cells) PRL release was not affected by a 5 h incubation with Tau (10(-3)-10(-8) M). Basal dopamine (DA) or gamma-aminobutyric acid (GABA) output from superfused mediobasal hypothalamic fragments (MBH) was not affected by Tau (10(-3) M or 10(-5) M). However, during stimulation with KCl (50 mM), Tau (10(-3) M) significantly lowered DA release, and increased GABA output. It is concluded that Tau acts at a central level to increase PRL secretion, most probably by modulating the hypothalamic release of neurotransmitters controlling lactotroph function.

  16. Protective Effect of Prolactin against Methylmercury-Induced Mutagenicity and Cytotoxicity on Human Lymphocytes

    PubMed Central

    Silva-Pereira, Liz Carmem; da Rocha, Carlos Alberto Machado; Cunha, Luiz Raimundo Campos da Silva e; da Costa, Edmar Tavares; Guimarães, Ana Paula Araújo; Pontes, Thais Brilhante; Diniz, Domingos Luiz Wanderley Picanço; Leal, Mariana Ferreira; Moreira-Nunes, Caroline Aquino; Burbano, Rommel Rodríguez

    2014-01-01

    Mercury exhibits cytotoxic and mutagenic properties as a result of its effect on tubulin. This toxicity mechanism is related to the production of free radicals that can cause DNA damage. Methylmercury (MeHg) is one of the most toxic of the mercury compounds. It accumulates in the aquatic food chain, eventually reaching the human diet. Several studies have demonstrated that prolactin (PRL) may be differently affected by inorganic and organic mercury based on interference with various neurotransmitters involved in the regulation of PRL secretion. This study evaluated the cytoprotective effect of PRL on human lymphocytes exposed to MeHg in vitro, including observation of the kinetics of HL-60 cells (an acute myeloid leukemia lineage) treated with MeHg and PRL at different concentrations, with both treatments with the individual compounds and combined treatments. All treatments with MeHg produced a significant increase in the frequency of chromatid gaps, however, no significant difference was observed in the chromosomal breaks with any treatment. A dose-dependent increase in the mitotic index was observed for treatments with PRL, which also acts as a co-mitogenic factor, regulating proliferation by modulating the expression of genes that are essential for cell cycle progression and cytoskeleton organization. These properties contribute to the protective action of PRL against the cytotoxic and mutagenic effects of MeHg. PMID:25247425

  17. Short-Chain Fatty Acids Inhibit Growth Hormone and Prolactin Gene Transcription via cAMP/PKA/CREB Signaling Pathway in Dairy Cow Anterior Pituitary Cells

    PubMed Central

    Wang, Jian-Fa; Fu, Shou-Peng; Li, Su-Nan; Hu, Zhong-Ming; Xue, Wen-Jing; Li, Zhi-Qiang; Huang, Bing-Xu; Lv, Qing-Kang; Liu, Ju-Xiong; Wang, Wei

    2013-01-01

    Short-chain fatty acids (SCFAs) play a key role in altering carbohydrate and lipid metabolism, influence endocrine pancreas activity, and as a precursor of ruminant milk fat. However, the effect and detailed mechanisms by which SCFAs mediate bovine growth hormone (GH) and prolactin (PRL) gene transcription remain unclear. In this study, we detected the effects of SCFAs (acetate, propionate, and butyrate) on the activity of the cAMP/PKA/CREB signaling pathway, GH, PRL, and Pit-1 gene transcription in dairy cow anterior pituitary cells (DCAPCs). The results showed that SCFAs decreased intracellular cAMP levels and a subsequent reduction in PKA activity. Inhibition of PKA activity decreased CREB phosphorylation, thereby inhibiting GH and PRL gene transcription. Furthermore, PTX blocked SCFAs- inhibited cAMP/PKA/CREB signaling pathway. These data showed that the inhibition of GH and PRL gene transcription induced by SCFAs is mediated by Gi activation and that propionate is more potent than acetate and butyrate in inhibiting GH and PRL gene transcription. In conclusion, this study identifies a biochemical mechanism for the regulation of SCFAs on bovine GH and PRL gene transcription in DCAPCs, which may serve as one of the factors that regulate pituitary function in accordance with dietary intake. PMID:24177567

  18. Reorganization of visual processing in macular degeneration is not specific to the "preferred retinal locus".

    PubMed

    Dilks, Daniel D; Baker, Chris I; Peli, Eli; Kanwisher, Nancy

    2009-03-04

    Recent work has shown that foveal cortex, deprived of its normal bottom-up input as a result of macular degeneration (MD), begins responding to stimuli presented to a peripheral retinal location. However, these studies have only presented stimuli to the "preferred retinal location," or PRL, a spared part of the peripheral retina used by individuals with MD for fixating, face recognition, reading, and other visual tasks. Thus, previous research has not yet answered a question critical for understanding the mechanisms underlying this reorganization: Does formerly foveal cortex respond only to stimuli presented at the PRL, or does it also respond to other peripheral locations of similar eccentricity? If foveal cortex responds to stimuli at PRL because it is the long-term habitual use of this region as a functional fovea that drives the formerly foveal cortex to respond to stimuli presented at the PRL (the "use-dependent reorganization" hypothesis), then foveal cortex will not respond to stimuli presented at other locations. Alternatively, it may be that foveal cortex responds to any peripheral retinal input, independent of whether input at that retinal location has been chronically attended for months or years (the "use-independent reorganization" hypothesis). Using fMRI, we found clear activation of formerly foveal cortex to stimuli presented at either the PRL or an isoeccentric non-PRL location in two individuals with MD, supporting the use-independent reorganization hypothesis. This finding suggests that reorganization is driven by passive, not use-dependent mechanisms.

  19. Anti-proliferative effects of deflazacort on Nb2 cells as quantitated by formazan production.

    PubMed

    Adler, R A; Naumann, S A; Mansouri, A; Krieg, R J; Latta, K; Sanders, K M

    1994-01-01

    Prolactin and other lactogenic hormones are mitogenic for the rat T-cell lymphoma line, Nb2. Glucocorticoids have antiproliferative effects on these cells. A limiting feature of experiments utilizing the Nb2 line is their labor-intensive nature. We therefore adapted the commonly used MTT dye proliferation assay for the Nb2 cell line. While rPRL, hPRL, oPRL, hGH, bPL, and to a lesser extent bPRL stimulated the Nb2 cells, hormones without lactogenic activity, rGH and oGH did not. Human serum and rat sera from animals bearing a PRL-secreting tumor stimulated the Nb2 cells in parallel to standards. Glucocorticoids had anti-proliferative effects on Nb2 cells in the presence of half-maximal or maximal PRL doses, as measured by the MTT proliferation assay. It has been claimed that an oxazoline steroid, deflazacort, has anti-inflammatory effects in clinical studies with fewer of the deleterious side-effects common to glucocorticoids. We therefore compared the in vitro anti-proliferative effects of deflazacort with other glucocorticoids. Deflazacort's negative effect on Nb2 cell proliferation was similar to that of cortisol and prednisolone and less than that of dexamethasone. We conclude that the MTT proliferation assay can be used to study both mitogenic and anti-proliferative substances in Nb2 cells. In addition we found that deflazacort acts similarly in vitro to other glucocorticoids.

  20. Reversible weight gain and prolactin levels--long-term follow-up in childhood.

    PubMed

    Galluzzi, F; Salti, R; Stagi, S; La Cauza, F; Chiarelli, F

    2005-09-01

    In adult patients weight gain is a frequent complaint of hyperprolactinaemia and it has been associated with a high prevalence of obesity. Normalization of prolactin (PRL) levels result in weight loss. The nature of this link is poorly defined. In this report we describe a 14 year-old female with primary amenorrhea and persistent progressive weight gain. The patient's height, weight and BMI were 152 cm, 70 kg, and 30.3 kg/m2, respectively. Basal hormonal investigation showed normal free thyroxin, TSH, IGF-I, cortisol and ACTH values. Serum PRL level was very high (16,278 mIU/l; normal range 63-426 mIU/l). Magnetic resonance imaging scan showed the presence of a pituitary microadenoma. Treatment with the non-selective dopamine agonist pergolide caused a significant reduction of serum PRL concentration with a remarkable decrease of body weight. During follow-up, repeat MRI scan revealed disappearance of the microadenoma. The reduction of the daily dose of pergolide was associated with an increase of serum PRL with significant weight gain. A further reduction of body weight was subsequently observed with an increase of pergolide dosage. Serum PRL measurement may be useful as part of the endocrine work-up of obese children with a history of unexplained recent weight gain, especially if associated with pituitary-gonadal axis dysfunction. The relationship between PRL secretion and weight change needs to be examined in prospective larger studies.

  1. Comparison of plasma prolactin and CEA in monitoring patients with adenocarcinoma of colon and rectum.

    PubMed Central

    Bhatavdekar, J. M.; Patel, D. D.; Giri, D. D.; Karelia, N. H.; Vora, H. H.; Ghosh, N.; Shah, N. G.; Trivedi, S. N.; Balar, D. B.

    1992-01-01

    Plasma prolactin (PRL) and carcinoembryonic antigen (CEA) were measured by radioimmunoassay in 74 patients with adenocarcinoma of colon and rectum. The markers were correlated with disease stage, histological grade and progression/remission of disease. The circulating preoperative median PRL and CEA levels were significantly higher in colorectal cancer patients than in their respective controls. PRL was elevated in all Dukes stages and in all histological grades of the tumour whereas the rise in CEA was more pronounced in Dukes D. Out of 74 patients, 29% (21/74) developed recurrent disease and 31% (23/74) responded to the treatment. With regard to monitoring recurrence(s), the predictive value of PRL was 94% which was significantly greater than that of CEA which was only 62%. In patients who developed liver metastases PRL remained elevated whereas CEA showed more than 100-fold increase. Therefore, we feel that CEA is a better marker for monitoring patients who developed liver metastases. From our results, we suggest that PRL can be used as a better overall marker for detecting recurrence(s) in patients with colorectal adenocarcinoma. PMID:1419646

  2. A case of an ectopic prolactinoma.

    PubMed

    Simsir, Ilgin Yildirim; Kocabas, Gokcen Unal; Sahin, Serap Baydur; Erdogan, Mehmet; Cetinkalp, Sevki; Saygili, Fusun; Yilmaz, Candeger; Ozgen, Ahmet Gokhan

    2012-02-01

    A 34-year-old female presented to our clinic with a 1.5 year history of secondary amenorrhea and galactorrhea. Prolactin (PRL) level was found to be 151.89 ng/ml. Pituitary imaging was reported to be normal. An examination of the patient revealed that PRL level was still high so the dose of cabergoline was further increased and subsequently, bromocriptine was added to the treatment. There was no reduction in PRL levels in controls. A scanning was performed to look for an ectopic focus. Abdominal computerized tomography revealed a heterogenous mass lesion originating from the uterus. Octreotide scintigraphy was performed and we observed an involvement consistent with the mass in the uterus. The patient underwent abdominal total hysterectomy. PRL dropped to 0.4 ng/ml the next day after the operation. The pathology result was a low-grade malignant mesenchymal tumor. Prolactin was found to be immunohistochemically negative. However, galactorrhea disappeared postoperative and PRL levels are still low. Elevated levels of PRL, resistant to bromocriptine and cabergoline, rapidly returned to normal after hysterectomy, which obviously indicates that hyperprolactinemia was associated with the myoma of the uterus.

  3. Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis

    PubMed Central

    Adán, Norma; Guzmán-Morales, Jessica; Ledesma-Colunga, Maria G.; Perales-Canales, Sonia I.; Quintanar-Stéphano, Andrés; López-Barrera, Fernando; Méndez, Isabel; Moreno-Carranza, Bibiana; Triebel, Jakob; Binart, Nadine; Martínez de la Escalera, Gonzalo; Thebault, Stéphanie; Clapp, Carmen

    2013-01-01

    Chondrocytes are the only cells in cartilage, and their death by apoptosis contributes to cartilage loss in inflammatory joint diseases, such as rheumatoid arthritis (RA). A putative therapeutic intervention for RA is the inhibition of apoptosis-mediated cartilage degradation. The hormone prolactin (PRL) frequently increases in the circulation of patients with RA, but the role of hyperprolactinemia in disease activity is unclear. Here, we demonstrate that PRL inhibits the apoptosis of cultured chondrocytes in response to a mixture of proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) by preventing the induction of p53 and decreasing the BAX/BCL-2 ratio through a NO-independent, JAK2/STAT3–dependent pathway. Local treatment with PRL or increasing PRL circulating levels also prevented chondrocyte apoptosis evoked by injecting cytokines into the knee joints of rats, whereas the proapoptotic effect of cytokines was enhanced in PRL receptor–null (Prlr–/–) mice. Moreover, eliciting hyperprolactinemia in rats before or after inducing the adjuvant model of inflammatory arthritis reduced chondrocyte apoptosis, proinflammatory cytokine expression, pannus formation, bone erosion, joint swelling, and pain. These results reveal the protective effect of PRL against inflammation-induced chondrocyte apoptosis and the therapeutic potential of hyperprolactinemia to reduce permanent joint damage and inflammation in RA. PMID:23908112

  4. Overexpression of Protein Kinase Mζ in the Prelimbic Cortex Enhances the Formation of Long-Term Fear Memory

    PubMed Central

    Xue, Yan-Xue; Zhu, Zhen-Zhen; Han, Hai-Bin; Liu, Jian-Feng; Meng, Shi-Qiu; Chen, Chen; Yang, Jian-Li; Wu, Ping; Lu, Lin

    2015-01-01

    Neuroplasticity in the prefrontal cortex (PFC) after fear conditioning has been suggested to regulate the formation and expression of fear memory. Protein kinase Mζ (PKMζ), an isoform of protein kinase C with persistent activity, is involved in the formation and maintenance of memory. However, less is known about the role of PKMζ in the PFC in the formation of fear memory. We investigated whether the overexpression of PKMζ enhances the formation of auditory fear memory in rats. We found that microinfusion of lentiviral vector-expressing PKMζ into the prelimbic cortex (PrL) selectively enhanced the expression of PKMζ without influencing the expression of other isoforms of PKC. The overexpression of PKMζ in the PrL enhanced the formation of long-term fear memory without affecting short-term fear memory, whereas the overexpression of PKMζ in the infralimbic cortex had no effect on either short-term or long-term fear memory. The overexpression of PKMζ in the PrL had no effect on anxiety-like behavior or locomotor activity. We also found that PKMζ overexpression potentiated the fear conditioning-induced increase in the membrane levels of glutamate subunit 2 of AMPA receptors in the PrL. These results demonstrate that the overexpression of PKMζ in the PrL but not infralimbic cortex selectively enhanced the formation of long-term fear memory, and PKMζ in the PrL may be involved in the formation of fear memory. PMID:25722116

  5. Prolactin and aging: X-irradiated and estrogen-induced rat mammary tumorigenesis

    SciTech Connect

    Ito, A.; Naito, M.; Watanabe, H.; Yokoro, K.

    1984-07-01

    Both sexes of inbred WF rats at either 8 or 28-60 weeks of age were exposed to 200 rad whole-body radiation, 2.5 or 5.0 mg 17 beta-estradiol (E2), or both agents The female rats treated with E2 alone or with both X-rays and E2 at 8 weeks of age showed a high incidence of mammary carcinomas (MCA), a large increase in pituitary weight, and a rise in serum prolactin (PRL) levels. However, the same treatments to males did not induce MCA despite a moderate increase in both pituitary weight and serum PRL. Ovariectomy prior to E2 treatment failed to modify the occurrence of MCA or pituitary tumors. When X-rays and E2 were given to female rats at 28-60 weeks of age, pituitary weight, serum PRL levels, and the incidence of MCA were unaffected. When the E2 pellet was kept for the first 24 weeks and withdrawn during the last 12 weeks, the incidence of MCA, pituitary weight, and serum PRL was low. It was concluded that: 1) the pituitary glands of young female rats were susceptible to E2 treatment but were insensitive in older females, and 2) the occurrence of MCA in female rats appeared to be promoted by elevated PRL levels secreted by E2-induced pituitary tumors. Mammary tissue of male rats was less sensitive to PRL levels in the development of MCA.

  6. Growth hormone producing pituitary adenomas with concomitant hypersecretion of prolactin are particularly sensitive to photon irradiation.

    PubMed

    Werner, S; af Trampe, E; Palacios, P; Lax, I; Hall, K

    1985-09-01

    The effect of photon irradiation (50 Gy with a 3-field technique in fractionated doses) on growth hormone (GH), prolactin (PRL), and somatomedin A (SMA) was studied in 25 patients with acromegaly after previous unsuccessful surgery. In patients with concomitant hypersecretion of PRL, the GH reduction was 70 +/- 22% 1 year and 88 +/- 10% 3 years after radiotherapy. The corresponding reductions in patients with isolated GH hypersecretion were 42 +/- 25% and 60 +/- 22%. The reduction of GH levels was most notable the first year after radiotherapy in 16 patients and during the second year in 7 patients. Serum PRL decreased after radiotherapy in all patients with hyperprolactinemia, whereas PRL in normoprolactinemic patients showed inconsistent changes, including PRL increments in 8/12 patients. The effect of radiotherapy on GH and PRL was not correlated to the irradiation target volume or the cumulative radiation effect. SMA levels decreased after radiotherapy, but became normal only in 3 patients, all with pretreatment GH less than 5 micrograms/l. Radiotherapy, 3 years after treatment, appeared to be equivalent to the primary surgical intervention in reducing GH and SMA in patients with acromegaly due to advanced macroadenomas. Patients with concomitant hyperprolactinemia showed increased sensitivity to radiation compared to normoprolactinemic patients with acromegaly.

  7. Targeted overexpression of calcitonin in gonadotrophs of transgenic mice leads to chronic hypoprolactinemia.

    PubMed

    Yuan, Ren; Kulkarni, Trupti; Wei, Fu; Shah, Girish V

    2005-01-14

    It was previously shown that calcitonin-like pituitary peptide (pit-CT) is synthesized and secreted by gonadotrophs, and pit-CT inhibits PRL gene transcription and lactotroph cell proliferation. Present studies examined long-term consequences of pit-CT overexpression on the functioning of mouse anterior pituitary (AP) gland. Targeted overexpression of pit-CT in gonadotrophs of mouse pituitaries was achieved by generating mice overexpressing bovine luteinizing hormone (LH)-alpha subunit promoter-pit-CT cDNA transgene. Transgenic (pit-CT+) mice displayed chronic but selective overexpression of pit-CT in gonadotrophs. The mice also displayed a dramatic decline in PRL gene expression as assessed by PRL mRNA abundance, PRL immunohistochemistry (IHC) and serum PRL levels. LH secretion in pit-CT+ mice was also reduced, without any change in FSH secretion. Reproductive abnormalities such as prolonged estrous cycles, reduced pregnancy rate, delivery of smaller litters, increased neonatal mortality and deficient lactation were also observed. Administration of PRL during early pregnancy significantly increased the pregnancy rate and neonatal survival of newborns. These results demonstrate that overexpression of pit-CT leads to chronic hypoprolactinemia and reproductive dysfunction in female mice, and reinforces the possibility that gonadotroph-derived pit-CT is an important paracrine regulator of lactotroph function.

  8. β-Hydroxybutyric sodium salt inhibition of growth hormone and prolactin secretion via the cAMP/PKA/CREB and AMPK signaling pathways in dairy cow anterior pituitary cells.

    PubMed

    Fu, Shou-Peng; Wang, Wei; Liu, Bing-Run; Yang, Huan-Min; Ji, Hong; Yang, Zhan-Qing; Guo, Bin; Liu, Ju-Xiong; Wang, Jian-Fa

    2015-02-16

    β-hydroxybutyric acid (BHBA) regulates the synthesis and secretion of growth hormone (GH) and prolactin (PRL), but its mechanism is unknown. In this study, we detected the effects of BHBA on the activities of G protein signaling pathways, AMPK-α activity, GH, and PRL gene transcription, and GH and PRL secretion in dairy cow anterior pituitary cells (DCAPCs). The results showed that BHBA decreased intracellular cAMP levels and a subsequent reduction in protein kinase A (PKA) activity. Inhibition of PKA activity reduced cAMP response element-binding protein (CREB) phosphorylation, thereby inhibiting GH and PRL transcription and secretion. The effects of BHBA were attenuated by a specific Gαi inhibitor, pertussis toxin (PTX). In addition, intracellular BHBA uptake mediated by monocarboxylate transporter 1 (MCT1) could trigger AMPK signaling and result in the decrease in GH and PRL mRNA translation in DCAPCs cultured under low-glucose and non-glucose condition when compared with the high-glucose group. This study identifies a biochemical mechanism for the regulatory action of BHBA on GH and PRL gene transcription, translation, and secretion in DCAPCs, which may be one of the factors that regulate pituitary function during the transition period in dairy cows.

  9. Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.

    PubMed

    Taketa, Yoshikazu; Inoue, Kaoru; Takahashi, Miwa; Sakamoto, Yohei; Watanabe, Gen; Taya, Kazuyoshi; Yoshida, Midori

    2016-06-01

    Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.

  10. Fluoxetine, but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder.

    PubMed

    Meltzer, H; Bastani, B; Jayathilake, K; Maes, M

    1997-07-01

    It has been suggested that the clinical efficacy of chronic treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and perhaps all antidepressants is due to their ability to enhance serotonergic activity. The effects of chronic treatment with fluoxetine or tricyclic antidepressants on the L-5-hydroxytryptophan (200 mg, L-5-HTP; PO)-induced increases in plasma cortisol and prolactin (PRL) concentrations were studied in patients with major depression or obsessive compulsive disorder (OCD). Administration of L-5-HTP increased plasma cortisol and PRL levels in medicated and unmedicated patients with major depression or OCD. The L-5-HTP-induced cortisol and PRL responses were significantly higher in fluoxetine-treated than in tricyclic-treated or unmedicated major depressed patients. The latter two groups did not differ significantly in their cortisol or PRL responses to L-5-HTP. The L-5-HTP-induced increases in cortisol and PRL in fluoxetine-treated patients with major depression or OCD were not significantly different. The results suggest that fluoxetine, but not tricyclic antidepressants, potentiates 5-HT receptor-mediated stimulation of cortisol and PRL secretion in humans, consistent with available evidence that fluoxetine treatment, but not tricyclic antidepressants, increases central serotonergic activity in patients with MD or OCD by a presynaptic mechanism.

  11. Stimulation of food intake and weight gain in mature female rats by bovine prolactin and bovine growth hormone.

    PubMed

    Byatt, J C; Staten, N R; Salsgiver, W J; Kostelc, J G; Collier, R J

    1993-06-01

    Recombinant bovine prolactin (rbPRL) or bovine growth hormone (rbGH) was administered to mature female rats (10/treatment group) by daily subcutaneous injection for 10 days. Doses ranged from 7 to 5,000 micrograms/day (0.03-24 mg/kg body wt). Both rbPRL and rbGH increased body weight gain and food intake, but these parameters were increased at lower doses of rbPRL (7-63 micrograms/day) than rbGH (> 190 micrograms/day). Weight gain and food intake were maximally stimulated by 190 micrograms/day rbPRL, whereas maximal increased weight gain was obtained with the highest dose of rbGH (5,000 micrograms/day). Total carcass protein was increased by both hormones; however, protein as a percentage of body weight was unchanged. Similarly, neither rbPRL nor rbGH changed the percentage of carcass moisture. Percentage of body fat was increased by rbPRL but was decreased by rbGH. Weight of the gastrointestinal tract and kidneys was increased by both hormones, but increases were in proportion to body weight gain. These data confirm that ungulate prolactin is a hyperphagic agent in the female rat. In addition, they suggest that, while prolactin stimulates growth in mature female rats, this growth is probably not via a somatogenic mechanism.

  12. Intestinal mucosal changes and upregulated calcium transporter and FGF-23 expression during lactation: Contribution of lactogenic hormone prolactin.

    PubMed

    Wongdee, Kannikar; Teerapornpuntakit, Jarinthorn; Sripong, Chanakarn; Longkunan, Asma; Chankamngoen, Wasutorn; Keadsai, Chutiya; Kraidith, Kamonshanok; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2016-01-15

    As the principal lactogenic hormone, prolactin (PRL) not only induces lactogenesis but also enhances intestinal calcium absorption to supply calcium for milk production. How the intestinal epithelium res-ponses to PRL is poorly understood, but it is hypothesized to increase mucosal absorptive surface area and calcium transporter expression. Herein, lactating rats were found to have greater duodenal, jejunal and ileal villous heights as well as cecal crypt depths than age-matched nulliparous rats. Morphometric analyses in the duodenum and cecum showed that their mucosal adaptations were diminished by bromocriptine, an inhibitor of pituitary PRL release. PRL also upregulated calcium transporter expression (e.g., TRPV6 and PMCA1b) in the duodenum of lactating rats. Since excessive calcium absorption could be detrimental to lactating rats, local negative regulator of calcium absorption, e.g., fibroblast growth factor (FGF)-23, should be increased. Immunohistochemistry confirmed the upregulation of FGF-23 protein expression in the duodenal and cecal mucosae of lactating rats, consistent with the enhanced FGF-23 mRNA expression in Caco-2 cells. Bromocriptine abolished this lactation-induced FGF-23 expression. Additionally, FGF-23 could negate PRL-stimulated calcium transport across Caco-2 monolayer. In conclusion, PRL was responsible for the lactation-induced mucosal adaptations, which were associated with compensatory increase in FGF-23 expression probably to prevent calcium hyperabsorption.

  13. Prolactin mediates effects of chronic psychological stress on induction of fibrofatty cells in the heart

    PubMed Central

    Song, Jiangping; Wang, Mangyuan; Chen, Xiao; Liu, Li; Chen, Liang; Song, Zhizhao; Teng, Xiao; Xing, Yong; Chen, Kai; Zhao, Kun; Hou, Jianfeng; Yang, Pingchang

    2016-01-01

    Cardiocyte apoptosis plays an important role in the pathogenesis of heart diseases. The mechanism is unclear. It is reported that prolactin (PRL) is involved in cardiac disorders. This study aims to investigate the role of PRL in mediating the psychological stress-induced fibrofatty cell differentiation in the heart. In this study, BALB/c mice were treated with a 30-day restraint stress. The heart tissue was processed by paraffin embedding and hematoxylin and eosin. The expression of Sca1 in NIH3T3 cells was assessed by cell culture, flow cytometry and Western blotting. The results showed that chronic stress induced fibrofatty cells in the mouse heart and high serum PRL levels. The induction of fibrofatty cell was mimicked by administration with recombinant PRL. The stress also induced the expression of Sca1 in the mouse heart. Exposure of NIH3T3 cells (a fibroblast cell line) to PRL in the culture enhanced the expression of stem cell antigen-1 (Sca1), phosphorylation of signal transducer and activator of transcription 3 (STAT3) and expression of adipocyte-related protein molecules, including adiponectin, fatty acid binding protein (aP2), peroxisome proliferator activated receptor-g (PPARg) and CCAAT/enhancer binding protein (C/EBP)α, in the cells. We conclude that psychological stress-derived PRL induces fibroblasts to differentiate into fibrofatty cells in the heart. PMID:27158356

  14. Rat Prolactinoma cell growth regulation by Epidermal Growth Factor receptor ligands

    PubMed Central

    Vlotides, George; Siegel, Emily; Donangelo, Ines; Gutman, Shiri; Ren, Song-Guang; Melmed, Shlomo

    2008-01-01

    Epidermal growth factor (EGF) regulates pituitary development, hormone synthesis and cell proliferation. Although ErbB receptor family members are expressed in pituitary tumors, effects of EGF signaling on pituitary tumors are not known. Immunoprecipitation and Western blot confirmed EGFR and p185c-neu protein expression in GH3 lacto-somatotroph but not in ACTH-secreting AtT20 pituitary tumor cells. EGF (5 nM) selectively enhanced baseline (~ 4-fold) and serum-induced (> 6-fold) PRL mRNA levels, while gefitinib, an EGFR antagonist, suppressed serum-induced cell proliferation and Pttg1 expression, blocked PRL gene expression, and reversed EGF-mediated somatotroph-lactotroph phenotype switching. Downstream EGFR signaling by ERK, but not PI3K or PKC, mediated the gefitinib-response. Tumors in athymic mice implanted sc with GH3 cells resulted in weight gain accompanied by increased serum PRL, GH and IGF-I levels. Gefitinib decreased tumor volumes and peripheral hormone levels by ~ 30% and restored normal mouse body weight patterns. Mice treated with gefitinib exhibited decreased tumor tissue ERK1/2 phosphorylation and downregulated tumor PRL and Pttg1 mRNA abundance. These results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors. EGFR inhibitors could therefore be useful for control of PRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolactinomas undergoing rare malignant transformation. PMID:18676863

  15. Cysteamine-induced depletion of somatostatin and prolactin

    SciTech Connect

    Millard, W.J.; Sagar, S.M.; Martin, J.B.

    1985-06-01

    Cysteamine (2-aminoethanethiol (CSH), given in vivo or in vitro, rapidly but reversibly depletes immunoreactive somatostatin (irSS) in the central nervous system and gut as well as biological and immunological prolactin (PRL) activity in both the anterior pituitary and blood of the rat. This depletion of irSS and PRL is dose dependent and cannot be accounted for by release of either compound. Basal and potassium-stimulated SS release is reduced from hypothalamic tissue in vitro in CSH-treated animals. PRL secretion induced both pharmacologically and physiologically is abolished after CSH administration. Furthermore, CSH reduces cellular PRL content in a number of hyperprolactinemic states. The mechanism by which CSH reduces PRL levels is not clear, but it does not appear to act through the dopamine receptor nor does it alter the morphological structure of the lactotrope in normal animals. Most likely, CSH acts by interacting with the disulfide bonds of PRL, thus rendering the molecule both immunologically and biologically inactive.

  16. Persistent synchronized oscillations in prolactin gene promoter activity in living pituitary cells.

    PubMed

    McFerran, D W; Stirland, J A; Norris, A J; Khan, R A; Takasuka, N; Seymour, Z C; Gill, M S; Robertson, W R; Loudon, A S; Davis, J R; White, M R

    2001-07-01

    PRL gene expression in the anterior pituitary gland responds rapidly to different hormonal signals. We have investigated the long-term timing of transcriptional activation from the PRL, GH, and cytomegalovirus promoters in response to different stimulus duration, using real-time imaging of luciferase expression in living stably transfected GH3 cells. Long-term stimulation of serum-starved cells with 50% serum induced a homogeneous rise in PRL promoter activity, with subsequent heterogeneous fluctuations in luciferase activity in individual cells. When cells were subjected to a 2-h pulse of 50% serum, followed by serum-free medium, there were long-term (approximately 50 h) synchronized, homogeneous oscillations in PRL promoter activity. This response was PRL-specific, because in GH3 cells expressing luciferase from the GH or cytomegalovirus promoters, a serum pulse elicited no oscillations in luciferase expression after an initial transient response to serum. The PRL promoter may therefore be a template for an unstable transcription complex subject to stochastic regulation, allowing an oscillatory transcriptional response to physiological signals. This suggests that precise timing and coordination of cell responses to different signal-duration may represent a novel mechanism for coordinating long-term dynamic changes in transcription in cell populations.

  17. Prolactin: Friend or Foe in Central Nervous System Autoimmune Inflammation?

    PubMed Central

    Costanza, Massimo; Pedotti, Rosetta

    2016-01-01

    The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its crucial role in female reproduction and lactation has prompted great efforts to understand if PRL could represent a gender factor in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), the animal model for this disease. Extensive literature has documented a remarkable immune-stimulating potential for this hormone, indicating PRL as a disease-promoting factor in MS and EAE. However, recent work has pointed out that PRL is endowed with important neuroprotective and remyelinating properties and has encouraged a reinterpretation of the involvement of this hormone in MS. In this review we summarize both the protective functions that PRL exerts in central nervous system tissue as well as the inflammatory activity of this hormone in the context of autoimmune responses against myelin. Last, we draw future lines of research that might help to better clarify the impact of PRL on MS pathology. PMID:27918427

  18. Diurnal variations of prolactin in the plasma of maturing female rats bearing hypothalamic lesions.

    PubMed

    Alvarez, E O

    1979-03-01

    Previous evidence from our laboratory suggested a possible involvement of prolactin (PRL) in the induction of precocious puberty due to hypothalamic lesions in maturing female rats. In the present report the concentrations of PRL in plasma of lesioned and control rats were determined three times a day at three different periods of puberty. Lesions were produced in 20 day-old rats by a radiofrequency current in the anterior hypothalamic area (AHA). Intact littermates were used as control. Respectively 23, 25 and 28 day-old lesioned and control rats were bled at 08.00, 12.00 or 16.00 h. PRL levels, measured by RIA were determined from plasma aliquots. In control rats, elevated plasma PRL levels were found in the afternoon. Hypothalamic lesion induced a tendency to elevate tonically the PRL plasma concentrations which was evident at 16.00 h in 23 and 25 day-old rats and at 08.00 and 12.00 h in 28 day-old rats. The present results give additional support to our previous suggestion that PRL secretion is modified by the effect of lesions in the AHA.

  19. Tyrosyl Phosphorylated Serine-Threonine Kinase PAK1 is a Novel Regulator of Prolactin-Dependent Breast Cancer Cell Motility and Invasion

    PubMed Central

    Hammer, Alan

    2015-01-01

    Despite efforts to discover the cellular pathways regulating breast cancer metastasis, little is known as to how prolactin (PRL) cooperates with extracellular environment and cytoskeletal proteins to regulate breast cancer cell motility and invasion. We implicated serine-threonine kinase p21-activated kinase 1 (PAK1) as a novel target for PRL-activated Janus-kinase 2 (JAK2). JAK2-dependent PAK1 tyrosyl phosphorylation plays a critical role in regulation of both PAK1 kinase activity and scaffolding properties of PAK1. Tyrosyl phosphorylated PAK1 facilitates PRL-dependent motility via at least two mechanisms: formation of paxillin/GIT1/βPIX/pTyr-PAK1 complexes resulting in increased adhesion turnover and phosphorylation of actin-binding protein filamin A. Increased adhesion turnover is the basis for cell migration and phosphorylated filamin A stimulates the kinase activity of PAK1 and increases actin-regulating activity to facilitate cell motility. Tyrosyl phosphorylated PAK1 also stimulates invasion of breast cancer cells in response to PRL and three-dimensional (3D) collagen IV via transcription and secretion of MMP-1 and MMP-3 in a MAPK-dependent manner. These data illustrate the complex interaction between PRL and the cell microenvironment in breast cancer cells and suggest a pivotal role for PRL/PAK1 signaling in breast cancer metastasis. PMID:25472536

  20. Prolactin regulation of neonatal ovine uterine gland morphogenesis.

    PubMed

    Carpenter, Karen D; Gray, C Allison; Noel, Sekoni; Gertler, Arieh; Bazer, Fuller W; Spencer, Thomas E

    2003-01-01

    Uterine gland development or adenogenesis in the neonatal ovine uterus involves budding, proliferation, and branching morphogenesis of the glandular epithelium (GE) from the luminal epithelium (LE) between birth (postnatal day or PND 0) and PND 56. This critical developmental event is coincident with increases in serum PRL and expression of long and short PRL receptors specifically in the nascent and proliferating GE. In study one, ewes were treated with a placebo pellet as a control (CX) or a bromocryptine mesylate pellet from PNDs 0-56. On PND 56, the endometrium of bromocryptine mesylate ewes contained fewer glands, particularly in the stratum spongiosum that contained numerous coiled and branched glands in CX uteri. In study two, ewes were treated with saline as a CX or recombinant ovine PRL from PNDs 0-56. Treatment with PRL increased gland number and density on PND 14 and PND 56. In study three, expression of signal transducers and activators of transcription (STAT) 1, 3, and 5 proteins was detected in the developing glands from PNDs 7-56. In study four, Western blot analyses indicated that PRL increased levels of phosphorylated STATs 1 and 5, but not STAT 3, and phosphorylated ERK 1 and 2 MAPKs and c-Jun N-terminal kinase/stress-activated protein kinase proteins in explanted PND 28 ovine uteri. Collectively, results indicate that PRL regulates endometrial adenogenesis in the neonatal ovine uterus.

  1. ErbB Receptor-Driven Prolactinomas Respond to Targeted Lapatinib Treatment in Female Transgenic Mice

    PubMed Central

    Liu, Xiaohai; Kano, Maya; Araki, Takako; Cooper, Odelia; Fukuoka, Hidenori; Tone, Yukiko; Tone, Masahide

    2015-01-01

    As ErbB receptors are expressed in prolactinomas and exhibit downstream effects on prolactin (PRL) production and cell proliferation, we generated transgenic mice using a PRL enhancer/promoter expression system to restrict lactotroph-specific expression of human epidermal growth factor receptor (EGFR) or human EGFR2 (HER2). EGFR or HER2 transgenic mice developed prolactinomas between 13 and 15 months, and confocal immunofluorescence and Western blot analysis confirmed lactotroph-restricted PRL and EGFR or HER2 coexpression. Circulating PRL levels in EGFR and HER2 transgenic mice were increased 5- and 3.8-fold, respectively. Inhibiting EGFR or HER2 signaling with oral lapatinib (100 mg/kg), a dual tyrosine kinase inhibitor for both EGFR and HER2, suppressed circulating PRL by 72% and attenuated tumor PRL expression by 80% and also attenuated downstream tumor EGFR/HER2 signaling. This model demonstrates the role of ErbB receptors underlying prolactinoma tumorigenesis and the feasibility of targeting these receptors for translation to treatment of refractory prolactinomas. PMID:25375038

  2. Pulsatile growth hormone and prolactin: effects of (+) butaclamol, a dopamine receptor blocking agent.

    PubMed

    Willoughby, J O; Brazeau, P; Martin, J B

    1977-10-01

    Growth hormone (rGH) and prolactin (rPRL) secretory profiles were obtained before and after treatment with a dopamine receptor blocking agent, (+) butaclamol, in 10 male rats chronically implanted with right atrial cannulae. Mean rGH plasma concentrations, determined by planimetry, were reduced (202 +/- 20 ng/ml vs. 135 +/- 20ng/ml, P less than .01), but the basic configuration and periodicity of rGH secretory bursts were unaltered. Mean rPRL plasma concentrations were elevated (11.1 +/- 2.1 ng/ml vs 65.5 +/- 8.1 ng/ml, P less than .0005), but rPRL episodic secretion was still apparent. It is concluded that dopaminergic neurons have a minor role in facilitating episodic rGH secretion. Furthermore, persisting episodic rPRL secretion in rats administered a dopamine antagonist suggests that rPRL feedback inhibition does not inactivitate the neural mechanism generating episodic rPRL secretion.

  3. The dopamine antagonist domperidone increases prolactin concentration and enhances milk production in dairy cows.

    PubMed

    Lacasse, P; Ollier, S

    2015-11-01

    In previous studies, our team showed that the inhibition of prolactin (PRL) secretion by the dopamine agonist quinagolide reduces milk production in dairy cows. The objective of this study was to determine the effects of administration of a dopamine antagonist on basal and milking-induced PRL concentrations in blood and on milk production during positive energy balance and feed restriction in dairy cows. Eighteen mid-lactation Holstein cows received daily s.c. injections of either domperidone (300 mg, DOMP, n=9) or the vehicle, canola oil (CTL, n=9), for 5 wk. During wk 5, all cows were fed at 65% of their dry matter intake in the previous week. Blood and milk samples were collected before (for blood) and during (for milk) the a.m. milking thrice weekly from d -9 to 41 (8d after the last injection). In addition, blood samples were collected during the a.m. milking on d -1 (before the first injection), and on d 1, 28, and 34. Basal PRL concentration was similar in both groups before the start of the treatments. Domperidone injections caused a gradual increase in basal PRL concentration. Feed restriction reduced basal PRL concentration in both the CTL and DOMP cows, but PRL concentration remained higher in the DOMP cows. Prolactin concentration remained elevated in the DOMP cows 7d after the last injection. The milk concentration of PRL increased during the DOMP treatment, but the increase was smaller than that observed in serum. In the CTL cows, the milking-induced PRL release above the premilking concentration was similar on d -1, 1, and 28 but was reduced during feed restriction. In the DOMP cows, the milking-induced PRL release was similar on d -1 and 1 but was reduced on d 28 and 34. Milk production was similar for both groups before the treatments started but was greater in the DOMP cows during the treatment period, at 2.9 ± 0.6 and 2.4 ± 0.6 kg/d greater during wk 3 and 4 of treatment, respectively. Milk production declined in both groups during feed

  4. Prevalence of macroprolactinaemia in regularly menstruating women with non-toxic goitre or autoimmune thyroid disease

    PubMed Central

    2012-01-01

    Background The so called “big-big” prolactin (Prl), also known as macroprolactin is formed by Prl-immunoglobulin (Prl-IgG) complexes and may cause elevation of serum Prl concentrations measured by standard assays, potentially leading to unnecessary investigations and/or treatment. In our study, we have endeavoured to assess the prevalence of macroprolactinaemia in euthyroid, regularly menstruating women with thyroid disease, as well as to assess whether autoimmune thyroid disease may result in an increased prevalence of macroprolactinaemia. Material and methods We measured serum Prl in 182 regularly menstruating women aged 32.7 ± 7.5 years (mean ± SD, range 17–46 years) who attended endocrine clinic either for investigation of non-toxic goitre (n = 86, age 33.2 ± 7.8 years) or with autoimmune thyroid disease (n = 96, age 32.3 ± 7.2 years). Autoimmune thyroid disease was defined as raised titre of at least one anti-thyroid antibody [anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-Tg) and/or anti-TSH-receptor (anti-TSH-R) antibodies]. All women were clinically and biochemically euthyroid, either without or on treatment with L-thyroxine. In those with raised Prl (i.e., above 530 mIU/l) we ruled out the presence of macroprolactinaemia by polyethylene glycol (PEG) precipitation method. Results There was no significant age difference between women with and without autoimmune thyroid disease (p = 0.84). Raised Prl concentrations were found in 10 women with thyroid disease (5.5%), and of those a significant macroprolactinaemia (i.e., reduction of Prl concentrations of more than 60% after PEG precipitation) was found in 9 subjects (4.94%). There were no differences in the prevalence of macroprolactinaemia between women with autoimmune thyroid disease (4 out of 96), and without autoimmune thyroid disease (5 out of 86, p = 0.75). Conclusions Approximately one out of twenty women with regular menses is likely to have

  5. Dopamine transporters participate in the physiological regulation of prolactin.

    PubMed

    Demaria, J E; Nagy, G M; Lerant, A A; Fekete, M I; Levenson, C W; Freeman, M E

    2000-01-01

    Three populations of hypothalamic neuroendocrine dopaminergic (NEDA) neurons, arising from the arcuate and periventricular nuclei of the hypothalamus release dopamine (DA) that acts at the pituitary gland to regulate the secretion of PRL. It is generally accepted that NEDA neurons lack functional DA transporters (DATs), which are responsible for uptake of DA from the synaptic cleft into the presynaptic axon terminal. This study localized DATs to the hypothalamo-pituitary axis and evaluated the effect of DAT blockade on the hypothalamo-pituitary regulation of PRL. After 7 days of treatment with cocaine (a nonspecific amine transporter blocker) or mazindol (a specific DAT blocker), the relative abundance of PRL messenger RNA (mRNA) in the anterior lobe (AL) of OVX rats was significantly decreased, whereas the relative abundance of tyrosine hydroxylase mRNA in the hypothalamus was significantly increased. The effect of cocaine or mazindol administration on DA turnover and serum PRL concentration was examined in estradiol (E2)-treated OVX rats. E2 administration (i.v.) resulted in a significant increase in serum PRL within 4 h; however, cocaine or mazindol administration abolished the E2-induced increase of PRL. Cocaine or mazindol significantly increased the concentration of DA at the site of the axon terminals within the median eminence (ME), intermediate lobe (IL) and neural lobe (NL), indicating blockade of uptake. Because formation of DOPAC requires uptake of DA, concentrations of DOPAC in the ME, IL and NL decreased following treatment with either cocaine or mazindol. These data, together with the presence of immunopositive DAT in the ME, pituitary stalk, IL, and NL, suggest that a functional DAT system is present within all three populations of NEDA neurons. Moreover, similarity between the effects of cocaine and mazindol treatment indicate that blockade of the DAT, but not other amine transporters, is responsible for suppression of PRL gene expression and

  6. Mammotroph autoregulation: the differential roles of the 24K isoforms of prolactin.

    PubMed

    Ho, T W; Greenan, J R; Walker, A M

    1989-03-01

    In this study we have attempted to determine which of the secreted 24K isoforms was responsible for autocrine regulation of PRL secretion by comparing the isoforms synthesized and secreted by normal cells, which do autoregulate, with those synthesized and secreted by GH3 cells, which do not normally autoregulate. Comparable numbers of cells were washed free of serum and then extracted into Tris-buffered saline by sonication and detergent treatment. Proteins present in these cell extracts and in samples of culture medium were then precipitated with cold acetone (-20 C; 48 h) and subsequently dissolved in urea-lysis buffer for 2-dimensional (2-D) electrophoresis. The 2-D patterns for normal cells showed four 24K PRL isoforms inside the cells and three 24K PRL isoforms (designated 2, 3, and 3') secreted into the medium. The 2-D patterns for GH3 cells showed very little intracellular storage of PRL, but what was present was identified as 24K PRL isoform 2. The GH3 cells secreted large amounts of only 24K PRL isoform 2. Preparations of PRL containing only isoforms 1,2, and 3 (at a total radioimmunoassayable concentration of 5 micrograms/ml PRL) were capable of inducing autoregulation in GH3 cells, as evidence by decreased secretion of prelabeled intracellular PRL. Initiation of autoregulation in GH3 cells caused granulation and the intracellular production of isoform 3. Since a) a preparation containing isoforms 1, 2, and 3 was found to induce autoregulation in GH3 cells, b) isoform 1 is not a secreted form, and c) isoform 2 does not cause autoregulation (at least in GH3 cells), it is deduced that isoform 3 is an autocrine form of PRL. Since initiation of autoregulation in GH3 cells caused those cells to produce isoform 3, it is further deduced that the autoregulatory defect in GH3 cells lies in the actual lack of production of isoform 3 and not in an inherent inability of these cells to produce isoform 3.

  7. Effects of Neonatal Exposure to Estradiol on Prolactin Secretion and Activity of the Tubero-lnfundibular Dopamine System in Young Adulthood: Comparison with Neonatal Prolactin Deficiency*.

    PubMed

    Crowley, W R; Shah, G V; Watanobe, H; Grosvenor, C E

    1990-02-01

    Abstract Previous results from this laboratory indicate that female rats who consume milk deficient in prolactin (PRL) during the neonatal period subsequently display hyperprolactinemia, associated with decreased activity in the tubero-infundibular dopamine (DA) system and decreased lactotrope responsiveness to DA receptor stimulation. The present studies tested whether these neuroendocrine consequences of neonatal PRL deficiency can be mimicked by exposure of neonatal rats to estradiol. Female rats were injected sc with 1 mUg estradiol benzoate or oil vehicle on postpartum Days one to 3, while in other experiments, females were made neonatally deficient in PRL through treatment of their mothers with the DA agonist bromocriptine, a treatment that reduces the levels of PRL in milk. Females treated neonatally with estradiol benzoate, as well as offspring of the bromocriptine-treated mothers, displayed hyperprolactinemia as young adults, as compared to their respective vehicle-matched controls, and in both cases, this was abolished by ovariectomy, indicating dependence upon ovarian secretions. As reported previously in neonatal PRL-deficient females, neonatal estradiol benzoate-treated animals also exhibited reduced steady state levels and decreased turnover rates of DA in the median eminence when 35 days of age. DA levels and turnover rates in this region were still significantly reduced on postpartum Day 60. The DA agonist bromocriptine suppressed PRL release to a similar extent in cultured anterior pituitary cells from neonatal estrogen-treated and control rats, suggesting normal responsiveness of DA receptors on lactotrope cells in both groups. The present results confirm the ability of estradiol treatment or induction of a PRL deficiency during the early neonatal period to induce subsequent hyperprolactinemia in female rats, and further indicate that the hyperprolactinemic conditions resulting from either neonatal manipulation are dependent on the ovary and are

  8. Prolactin-Stimulated Activation of ERK1/2 Mitogen-Activated Protein Kinases is Controlled by PI3-Kinase/Rac/PAK Signaling Pathway in Breast Cancer Cells

    PubMed Central

    Aksamitiene, Edita; Achanta, Sirisha; Kolch, Walter; Kholodenko, Boris N.; Hoek, Jan B.; Kiyatkin, Anatoly

    2011-01-01

    There is strong evidence that deregulation of prolactin (PRL) signaling contributes to pathogenesis and chemoresistance of breast cancer. Therefore, understanding cross-talk between distinct signal transduction pathways triggered by activation of the prolactin receptor (PRL-R), is essential for elucidating the pathogenesis of metastatic breast cancer. In this study, we applied a sequential inhibitory analysis of various signaling intermediates to examine the hierarchy of protein interactions within the PRL signaling network and to evaluate the relative contributions of multiple signaling branches downstream of PRL-R to the activation of the extracellular signal-regulated kinases ERK1 and ERK2 in T47D and MCF-7 human breast cancer cells. Quantitative measurements of the phosphorylation/activation patterns of proteins showed that PRL simultaneously activated Src family kinases (SFKs) and the JAK/STAT, phosphoinositide-3 (PI3)-kinase/Akt and MAPK signaling pathways. The specific blockade or siRNA-mediated suppression of SFK/FAK, JAK2/STAT5, PI3-kinase/PDK1/Akt, Rac/PAK or Ras regulatory circuits revealed that (1) the PI3-kinase/Akt pathway is required for activation of the MAPK/ERK signaling cascade upon PRL stimulation; (2) PI3-kinase-mediated activation of the c-Raf-MEK1/2-ERK1/2 cascade occurs independent of signaling dowstream of STATs, Akt and PKC, but requires JAK2, SFKs and FAK activities; (3) activated PRL-R mainly utilizes the PI3-kinase-dependent Rac/PAK pathway rather than the canonical Shc/Grb2/SOS/Ras route to initiate and sustain ERK1/2 signaling. By interconnecting diverse signaling pathways PLR may enhance proliferation, survival, migration and invasiveness of breast cancer cells. PMID:21726627

  9. Gonadotropin-releasing hormone stimulates prolactin release from lactotrophs in photoperiodic species through a gonadotropin-independent mechanism.

    PubMed

    Henderson, Helen L; Hodson, David J; Gregory, Susan J; Townsend, Julie; Tortonese, Domingo J

    2008-02-01

    Previous studies have provided evidence for a paracrine interaction between pituitary gonadotrophs and lactotrophs. Here, we show that GnRH is able to stimulate prolactin (PRL) release in ovine primary pituitary cultures. This effect was observed during the breeding season (BS), but not during the nonbreeding season (NBS), and was abolished by the application of bromocriptine, a specific dopamine agonist. Interestingly, GnRH gained the ability to stimulate PRL release in NBS cultures following treatment with bromocriptine. In contrast, thyrotropin-releasing hormone, a potent secretagogue of PRL, stimulated PRL release during both the BS and NBS and significantly enhanced the PRL response to GnRH during the BS. These results provide evidence for a photoperiodically modulated functional interaction between the GnRH/gonadotropic and prolactin axes in the pituitary gland of a short day breeder. Moreover, the stimulation of PRL release by GnRH was shown not to be mediated by the gonadotropins, since immunocytochemical, Western blotting, and PCR studies failed to detect pituitary LH or FSH receptor protein and mRNA expressions. Similarly, no gonadotropin receptor expression was observed in the pituitary gland of the horse, a long day breeder. In contrast, S100 protein, a marker of folliculostellate cells, which are known to participate in paracrine mechanisms within this tissue, was detected throughout the pituitaries of both these seasonal breeders. Therefore, an alternative gonadotroph secretory product, a direct effect of GnRH on the lactotroph, or another cell type, such as the folliculostellate cell, may be involved in the PRL response to GnRH in these species.

  10. FOXO1A differentially regulates genes of decidualization.

    PubMed

    Buzzio, Oscar L; Lu, Zhenxiao; Miller, Curt D; Unterman, Terry G; Kim, J Julie

    2006-08-01

    The forkhead box O1A (FOXO1A) has been identified as one gene that is up-regulated early in the decidualization process. To further investigate the role of FOXO1A during this process, six genes, IGFBP1, PRL, TIMP3, LAMB1, CNR1, and DCN, shown to be up-regulated during decidualization, were chosen as potential targets of FOXO1A action. Treatment of human endometrial stromal cells with hormones (estradiol and medroxyprogesterone acetate) plus dibutyryl cAMP (H+dbcAMP) for 48 h increased expression of IGFBP1, PRL, TIMP3, CNR1, and DCN but not LAMB1, as measured by real-time PCR. Silencing of FOXO1A using small interfering RNA oligonucleotides decreased IGFBP1 and DCN levels and increased CNR1, TIMP3, and PRL levels. LAMB1 was not affected. When FOXO1A was overexpressed in human endometrial stromal cells, expression of IGFBP1, DCN, and PRL increased, whereas levels of TIMP3 and CNR1 decreased. Addition of H+dbcAMP caused an increased expression of IGFBP1, PRL, and DCN beyond that of FOXO1A alone. TIMP3 and CNR1 levels decreased even further in response to H+dbcAMP compared with FOXO1A alone. LAMB1, which was unresponsive to FOXO1A, decreased when H+dbcAMP was added. Overexpressing FOXO1A also caused a change in cell shape, in that the stromal fibroblasts acquired a rounded, epithelioid appearance. Finally, reporter studies showed that cotransfection of FOXO1A significantly increased PRL promoter activity but not TIMP3 promoter activity. Addition of H+dbcAMP resulted in a significant increase in PRL promoter activity and a significant decrease in TIMP3 promoter activity. In summary, this study demonstrates the versatile nature of FOXO1A in the regulation of a number of decidualization-specific genes.

  11. Role of Estrogen Response Element in the Human Prolactin Gene: Transcriptional Response and Timing.

    PubMed

    McNamara, Anne V; Adamson, Antony D; Dunham, Lee S S; Semprini, Sabrina; Spiller, David G; McNeilly, Alan S; Mullins, John J; Davis, Julian R E; White, Michael R H

    2016-02-01

    The use of bacterial artificial chromosome (BAC) reporter constructs in molecular physiology enables the inclusion of large sections of flanking DNA, likely to contain regulatory elements and enhancers regions that contribute to the transcriptional output of a gene. Using BAC recombineering, we have manipulated a 160-kb human prolactin luciferase (hPRL-Luc) BAC construct and mutated the previously defined proximal estrogen response element (ERE) located -1189 bp relative to the transcription start site, to assess its involvement in the estrogen responsiveness of the entire hPRL locus. We found that GH3 cell lines stably expressing Luc under control of the ERE-mutated hPRL promoter (ERE-Mut) displayed a dramatically reduced transcriptional response to 17β-estradiol (E2) treatment compared with cells expressing Luc from the wild-type (WT) ERE hPRL-Luc promoter (ERE-WT). The -1189 ERE controls not only the response to E2 treatment but also the acute transcriptional response to TNFα, which was abolished in ERE-Mut cells. ERE-WT cells displayed a biphasic transcriptional response after TNFα treatment, the acute phase of which was blocked after treatment with the estrogen receptor antagonist 4-hydroxy-tamoxifen. Unexpectedly, we show the oscillatory characteristics of hPRL promoter activity in individual living cells were unaffected by disruption of this crucial response element, real-time bioluminescence imaging showed that transcription cycles were maintained, with similar cycle lengths, in ERE-WT and ERE-Mut cells. These data suggest the -1189 ERE is the dominant response element involved in the hPRL transcriptional response to both E2 and TNFα and, crucially, that cycles of hPRL promoter activity are independent of estrogen receptor binding.

  12. Estrogen inhibits tuberoinfundibular dopaminergic neurons but does not cause irreversible damage.

    PubMed

    Morel, Gustavo R; Carón, Rubén W; Cónsole, Gloria M; Soaje, Marta; Sosa, Yolanda E; Rodríguez, Silvia S; Jahn, Graciela A; Goya, Rodolfo G

    2009-12-16

    Dopaminergic neurons of the hypothalamic tuberoinfundibular dopaminergic (TIDA) system exert a tonic inhibitory control on prolactin (PRL) secretion whereas estrogen, known to inhibit TIDA neuron function, has been postulated to be toxic to TIDA neurons when it is chronically high. In order to determine whether estrogen in high doses can cause permanent damage to TIDA function, we submitted young female rats to continue high doses of estrogen administered, either centrally (intrahypothalamic estrogen implants) or peripherally (subcutaneous estrogen implants or weekly intramuscular (i.m.) injections for 7 weeks), subsequently withdrawing the steroid and observing the evolution of lactotrophes, serum PRL and TIDA neurons. Serum PRL was measured by radioimmunoassay whereas tyrosine hydroxylase positive (TH+) neurons and PRL cells were morphometrically assessed in sections of fixed hypothalami and pituitaries, respectively. After 30 days, hypothalamic estrogen implants induced a significant increase in serum PRL, whereas TH+ neurons were not detectable in the arcuate-periventricular hypothalamic (ARC) region of estrogen-implanted rats. Removal of implants on day 30 restored TH expression in the ARC and brought serum PRL back to basal levels 30 days after estrogen withdrawal. Subcutaneous or i.m. administration of estrogen for 7 weeks induced a marked hyperprolactinemia. However, 30 weeks after estrogen withdrawal, TH neuron numbers in the ARC were back to normal and serum PRL returned to basal levels. After peripheral but not central estrogen withdrawal, pituitary weight and lactotrophic cell numbers remained slightly increased. Our data suggest that estrogen even at high doses, does not cause permanent damage to TIDA neurons.

  13. Regulation of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase expression and activity in the hypophysectomized rat ovary: Interactions between the stimulatory effect of human chorionic gonadotropin and the luteolytic effect of prolactin

    SciTech Connect

    Martel, C.; Labrie, C.; Dupont, E.; Couet, J.; Trudel, C.; Rheaume, E.; Simard, J.; Luu-The, V.; Pelletier, G.; Labrie, F. )

    1990-12-01

    The enzyme 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) catalyzes an obligatory step in the conversion of pregnenolone and other 5-ene-3 beta-hydroxysteroids into progesterone as well as precursors of all androgens and estrogens in the ovary. Since 3 beta-HSD is likely to be an important target for regulation by pituitary hormones, we have studied the effect of chronic treatment with LH (hCG), FSH, and PRL on ovarian 3 beta-HSD expression and activity in hypophysectomized adult female rats. Human CG (hCG) (10 IU, twice a day (bid)), ovine FSH (0.5 microgram, bid), and ovine PRL (1 mg, bid) were administered, singly or in combination, for a period of 10 days starting 15 days after hypophysectomy. In hypophysectomized rats, PRL exerted a potent inhibitory effect on all the parameters studied. In fact, PRL caused a 81% decrease in ovarian 3 beta-HSD mRNA content accompanied by a similar decrease in 3 beta-HSD activity and protein levels. In addition, ovarian weight decreased by 40% whereas serum progesterone fell dramatically from 1.92 nmol/liter to undetectable levels after treatment with PRL. Whereas hCG alone had only slight stimulatory effects on 3 beta-HSD mRNA, protein content and activity levels, treatment with the gonadotropin partially or completely reversed the potent inhibitory effects of oPRL on all the parameters measured. FSH, on the other hand, had no significant effect on 3 beta-HSD expression and activity. In situ hybridization experiments using the 35S-labeled rat ovary 3 beta-HSD cDNA probe show that the inhibitory effect of PRL is exerted primarily on luteal cell 3 beta-HSD expression and activity. On the other hand, it can be seen that hCG stimulates 3 beta-HSD mRNA accumulation in interstitial cells.

  14. LPXRFamide peptide stimulates growth hormone and prolactin gene expression during the spawning period in the grass puffer, a semi-lunar synchronized spawner.

    PubMed

    Shahjahan, Md; Doi, Hiroyuki; Ando, Hironori

    2016-02-01

    Gonadotropin-inhibitory hormone (GnIH) plays as a multifunctional neurohormone that controls reproduction in birds and mammals. LPXRFamide (LPXRFa) peptide, the fish ortholog of GnIH, has been shown to regulate the secretion of not only gonadotropin (GTH) but also growth hormone (GH) and prolactin (PRL), which are potentially important for gonadal function. To investigate the role of LPXRFa peptide on reproduction of the grass puffer, which spawns in semilunar cycles, we examined changes in the levels of gh and prl expression over the several months during the reproductive cycle, and the effects of goldfish LPXRFa peptide-1 (gfLPXRFa-1) on their expression were examined using primary pituitary cultures. The expression levels of both gh and prl showed significant changes during the reproductive cycle in both sexes with one peak in the spawning and pre-spawning periods for gh and prl, respectively. Particularly, gh showed substantial increase in expression in the spawning and post-spawning periods, indicative of its essentiality in the advanced stage of reproduction. gfLPXRFa-1 stimulated the expression of both gh and prl but there was a marked difference in response between them: gfLPXRFa-1 stimulated gh expression at a relatively low dose but little effect was observed on prl. Combined with the previous results of daily and circadian oscillations of lpxrfa expression, the present results suggest that LPXRFa peptide is important in the control of the cyclic reproduction by serving as a multifunctional hypophysiotropic factor that regulates the expression of gh and prl as well as GTH subunit genes.

  15. Effects of photoperiod on salsolinol-induced prolactin secretion in goats.

    PubMed

    Yaegashi, Tomoyoshi; Jin, Jin; Sawada, Tatsuru; Saito, Hayato; Fülöp, Ferenc; Nagy, György Miklos; Hashizume, Tsutomu

    2012-05-01

    The aim of the present study was to clarify the relation between salsolinol (SAL)-induced prolactin (PRL) release and photoperiod in goats. A single intravenous (i.v.) injection of SAL was given to adult female goats under short (8 h light, 16 h dark) or long (16 h light, 8 h dark) photoperiod conditions at two different ambient temperatures (20°C or 5°C), and the PRL-releasing response to SAL was compared to that of thyrotropin-releasing hormone (TRH) or a dopamine (DA) receptor antagonist, sulpiride. SAL, as well as TRH or sulpiride, stimulated the release of PRL promptly after each injection in both 8- and 16-h daily photoperiods at 20°C (P<0.05). The area under the response curve (AUC) of PRL for the 60-min period after injections of saline (controls), SAL, TRH and sulpiride in the 16-h daily photoperiod group was greater than each corresponding value in the 8-h daily photoperiod group (P<0.05). There were no significant differences in the AUC of PRL among the values produced after the injection of SAL, TRH and sulpiride in 16-h daily photoperiod group; however, the values produced after the injection of TRH were smallest among the three in the 8-h daily photoperiod group (P<0.05). The PRL-releasing responses to SAL, TRH and sulpiride under a short and long photoperiod condition at 5°C resembled those at 20°C. These results show that a long photoperiod highly enhances the PRL-releasing response to SAL as well as TRH or sulpiride in either medium or low ambient temperature in goats.

  16. Prolactin increases the synthesis of 7alpha-hydroxypregnenolone, a key factor for induction of locomotor activity, in breeding male Newts.

    PubMed

    Haraguchi, Shogo; Koyama, Teppei; Hasunuma, Itaru; Vaudry, Hubert; Tsutsui, Kazuyoshi

    2010-05-01

    We recently found that the Japanese red-bellied newt, Cynops pyrrhogaster, actively produces 7alpha-hydroxypregnenolone, a previously undescribed amphibian neurosteroid. 7alpha-Hydroxypregnenolone stimulates locomotor activity of male newts. Locomotor activity of male newts increases during the breeding period as in other wild animals, but the molecular mechanism for such a change in locomotor activity is poorly understood. Here we show that the adenohypophyseal hormone prolactin (PRL) stimulates 7alpha-hydroxypregnenolone synthesis in the brain, thus increasing locomotor activity of breeding male newts. In this study, cytochrome P450(7alpha) (CYP7B), a steroidogenic enzyme catalyzing the formation of 7alpha-hydroxypregnenolone, was first identified to analyze seasonal changes in 7alpha-hydroxypregnenolone synthesis. Only males exhibited marked seasonal changes in 7alpha-hydroxypregnenolone synthesis and CYP7B expression in the brain, with a maximum level in the spring breeding period when locomotor activity of males increases. Subsequently we identified PRL as a key component of the mechanism regulating 7alpha-hydroxypregnenolone synthesis. Hypophysectomy decreased 7alpha-hydroxypregnenolone synthesis in the male brain, whereas administration of PRL but not gonadotropins to hypophysectomized males caused a dose-dependent increase in 7alpha-hydroxypregnenolone synthesis. To analyze the mode of PRL action, CYP7B and the receptor for PRL were localized in the male brain. PRL receptor was expressed in the neurons expressing CYP7B in the magnocellular preoptic nucleus. Thus, PRL appears to act directly on neurosteroidogenic magnocellular preoptic nucleus neurons to regulate 7alpha-hydroxypregnenolone synthesis, thus inducing seasonal locomotor changes in male newts. This is the first report describing the regulation of neurosteroidogenesis in the brain by an adenohypophyseal hormone in any vertebrate.

  17. Prolactin: does it exert an up-modulation of the immune response in Trypanosoma cruzi-infected rats?

    PubMed

    Filipin, Marina Del Vecchio; Brazão, Vânia; Santello, Fabricia Helena; Caetano, Leony Cristina; Toldo, Míriam Paula Alonso; do Prado, José Clóvis

    2011-09-27

    During the course of infection by Trypanosoma cruzi, the host immune system is involved in distinct, complex interactions with the endocrine system, and prolactin (PRL) is one of several hormones involved in immunoregulation. Although intensive studies attempting to understand the mechanisms that underlie Chagas' disease have been undertaken, there are still some pieces missing from this complex puzzle. Because data are scarce concerning the role of PRL involvement in Chagas' disease and taking into account the existence of crosstalk between neuroendocrine hormones and the immune system, the current study evaluates a possible up-regulation of the cellular immune response triggered by PRL in T. cruzi-infected rats and the role of PRL in reversing immunosuppression caused by the parasitic infection. The data shown herein demonstrate that PRL induces the proliferation of T lymphocytes, coupled with an activation of macrophages and the production of nitric oxide (NO), leading to a reduction in the number of blood trypomastigotes during the peak of parasitemia. During the acute phase of T. cruzi infection, an enhancement of both CD3+CD4+ and CD3+CD8+ T cell populations were observed in infected groups, with the highest numbers of these T cell subsets found in the infected group treated with PRL. Because NO is a signaling molecule involved in a number of cellular interactions with components of the immune system and the neuroendocrine system, PRL can be considered an alternative hormone able to up-regulate the host's immune system, consequently lowering the pathological effects of a T. cruzi infection.

  18. Effects of heat acclimation on endurance capacity and prolactin response to exercise in the heat.

    PubMed

    Burk, Andres; Timpmann, Saima; Kreegipuu, Kairi; Tamm, Maria; Unt, Eve; Oöpik, Vahur

    2012-12-01

    We examined the effect of heat acclimation (HA) on endurance capacity and blood prolactin (PRL) response to moderate intensity exercise in the heat in young male subjects (n = 21). Three exercise tests (ET) were completed on a treadmill: H1 (walk at 60% VO(2)peak until exhaustion at 42°C), N (walk at 22°C; duration equal to H1) and H2 (walk until exhaustion at 42°C after a 10-day HA program). Heart rate (HR), skin (T (sk)) and core (T (c)) temperatures and body heat storage (HS) were measured. Blood samples were taken immediately before, during and immediately after each ET. HA resulted in lower HR, T (sk), T (c) and HS rate (P < 0.05) during ET, whereas endurance capacity increased from 88.6 ± 27.5 min in H1 to 162.0 ± 47.8 min in H2 (P < 0.001). Blood PRL concentration was lower (P < 0.05) during exercise in H2 compared to H1 but the peak PRL level observed at the time of exhaustion did not differ in the two trials. Blood PRL concentration at 60 min of exercise in H1 correlated with time to exhaustion in H1 (r = -0.497, P = 0.020) and H2 (r = -0.528, P = 0.014). In conclusion, HA slows down the increase in blood PRL concentration but does not reduce the peak PRL level occurring at the end of exhausting endurance exercise in the heat. Blood PRL response to exercise in the heat in non-heat-acclimated subjects is associated with their endurance capacity in the heat in a heat-acclimated state.

  19. [Frequency of increased thyrotropin in women with hyperprolactinemia].

    PubMed

    Carranza-Lira, Sebastián; Daza-Carrasco, María Luisa; Chán-Verdugo, Rosario

    2017-01-01

    Introducción: el hipotiroidismo se suele asociar con hiperprolactinemia (HPRL). Se buscó determinar la frecuencia de tirotropina (TSH) elevada en mujeres con HPRL. Métodos: estudio retrospectivo, observacional, abierto y no controlado que incluyó a todas las mujeres no embarazadas en quienes se detectó la prolactina (PRL) y la TSH del 1 de enero al 31 de diciembre de 2014. Resultados: se estudiaron 437 mujeres. Los diagnósticos que motivaron la solicitud de PRL fueron: infertilidad (31.7%), síndrome de ovarios poliquísticos (18.7%) y amenorrea (7.8%). En el grupo completo las concentraciones de TSH fueron 2.5 ± 2.7 µUl/mL y las de PRL 16.5 ± 13.2 ng/dL. Del total de pacientes, aquellas con PRL normal, 1.4% tuvo TSH baja, 76.6% TSH normal y 7.5% elevada, mientras que de aquellas con PRL elevada 0.7% tuvo TSH baja, 12.6% normal y 1.1% elevada. De las 374 pacientes que tenían PRL normal, 6 (1.6%) presentaron TSH disminuida, 335 (89.6%) TSH normal y 33 (8.8%) TSH elevada. De las 63 pacientes con PRL elevada, 3 (4.8%) presentaron TSH disminuida, 55 (87.3%) TSH normal y 5 (7.9%) TSH aumentada. Conclusión: no se logró documentar que la proporción de pa-cientes con TSH elevada fuera mayor en aquellas con HPRL.

  20. Prolactin as an Adjunct for Type 1 Diabetes Immunotherapy.

    PubMed

    Hyslop, Colin M; Tsai, Sue; Shrivastava, Vipul; Santamaria, Pere; Huang, Carol

    2016-01-01

    Type 1 diabetes is caused by autoimmune destruction of β-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune-mediated β-cell loss, residual β-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost β-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate β-cell proliferation and up-regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms. Here, we test the hypothesis that PRL can improve the efficacy of an immune modulator, the anticluster of differentiation 3 monoclonal antibody (aCD3), in inducing diabetes remission by up-regulating β-cell mass and function. Diabetic nonobese diabetic (NOD) mice were treated with a 5-day course of aCD3 with or without a concurrent 3-week course of PRL. We found that a higher proportion of diabetic mice treated with the aCD3 and PRL combined therapy achieved diabetes reversal than those treated with aCD3 alone. The aCD3 and PRL combined group had a higher β-cell proliferation rate, an increased β-cell fraction, larger islets, higher pancreatic insulin content, and greater glucose-stimulated insulin release. Lineage-tracing analysis found minimal contribution of β-cell neogenesis to the formation of new β-cells. Although we did not detect a significant difference in the number or proliferative capacity of T cells, we observed a higher proportion of insulitis-free islets in the aCD3 and PRL group. These results suggest that combining a growth factor with an immunotherapy may be an effective treatment paradigm for autoimmune diabetes.

  1. Terguride as a new anti-hyperprolactinemic agent: characterization in rats and dogs in comparison with bromocriptine.

    PubMed

    Mizokawa, T; Akai, T; Nakada, Y; Yamaguchi, M; Nakagawa, H; Hasan, S; Rettig, K J; Wachtel, H

    1993-11-01

    Terguride, a derivative of the ergot alkaloid, was characterized as a new anti-hyperprolactinemic agent in rats and dogs in comparison with bromocriptine. Terguride was found to bind selectively to the pituitary dopamine D2-receptors with a high affinity (Kd = 0.39 nM). In reserpinized rats, terguride at 0.03 mg/kg, p.o. significantly reduced the serum prolactin (PRL) level. The PRL lowering effect and the effective dose were longer lasting and about 30 times lower than those of bromocriptine, respectively. In rats bearing estrogen-induced pituitary prolactinoma, chronic terguride induced shrinkage of the prolactinoma as well as reduction of the high serum PRL level. In lactating rats, terguride (1.0 mg/kg, s.c.) reduced milk production in the mammary gland, whereas bromocriptine showed no significant effect up to 10 mg/kg, s.c. Terguride (10 mg/kg, p.o.) did not induce any stereotypy and hypermotility in reserpinized rats, while bromocriptine induced both stereotypy and hypermotility significantly at 10 mg/kg, p.o. In dogs, terguride, like bromocriptine, reduced the serum PRL level, but did not affect the serum levels of growth hormone and luteinizing hormone. In dogs, bromocriptine induced both emesis and PRL-lowering at almost the same dose, whereas emesis-inducing doses of terguride were about 100 times higher than the PRL-lowering dose. These results suggest that terguride as a dopamine D2-agonist is a potent inhibitor of PRL secretion with less neurotropic side effects compared to bromocriptine, and thus a useful drug for the treatment of galactorrhea and hyperprolactinemia including prolactinoma.

  2. Effect of iodination on human growth hormone and prolactin: characterized by bioassay, radioimmunoassay, radioreceptor assay, and electrophoresis

    SciTech Connect

    Hughes, J.P.; Tanaka, T.; Gout, P.W.; Beer, C.T.; Noble, R.L.; Friesen, H.G.

    1982-09-01

    Human GH (hGH) and PRL (hPRL) were iodinated using lactoperoxidase. The iodinated hormones were characterized by RIA, radioreceptor assay (RRA), and bioassay (BA) using the Nb2 Node lymphoma cell line. The proportion of tracer that could bind to rat liver membranes or rabbit antibodies was determined, and the distribution of iodinated hormones was examined using polyacrylamide gel electrophoresis. Excess antibody was capable of precipitating 87.9% of the radioactivity associated with the hGH tracer and 86.0% of the hPRL tracer. The maximal specific binding to a liver membrane preparation averaged 67.3% of the (/sup 125/I)iodo-hGH radioactivity and 48.8% of the (/sup 125/I)iodo-hPRL radioactivity. The respective BA and RRA activity estimates for (/sup 125/)iodo-hGH averaged 90% and 114% of the activity measured by the RIA. For (/sup 125/I)iodo-hPRL, the values were 75% by BA and 68% by RRA. The bioactivity profiles of iodinated hGH and hPRL shifted anodally on polyacrylamide gel electrophoresis in comparison to the bioactivity distribution of the respective uniodinated hormones. Iodine incorporation rather than oxidation appeared to be responsible for the shift. After electrophoresis, all eluates which contained significant radioactivity were active in the BA and RIA. Furthermore, specific activities calculated from the bioactive hormone and radioactivity in each electrophoretic segment agreed well with the average specific activity estimated from the amount of iodine incorporated into the protein peak upon gel filtration. These data suggest that hGH and hPRL to a major degree retain biological integrity after iodination.

  3. Effect of iodination on human growth hormone and prolactin: characterized by bioassay, radioimmunoassay, radioreceptor assay, and electrophoresis

    SciTech Connect

    Hughes, J.P.; Tanaka, T.; Gout, P.W.; Beer, C.T.; Noble, R.L.; Friesen, H.G.

    1982-09-01

    Human GH (hGH) and PRL (hPRL) were iodinated using lactoperoxidase. The iodinated hormones were characterized by RIA, radioreceptor assay (RRA), and bioassay (BA) using the Nb2 Node lymphoma cell line. The proportion of tracer that could bind to rat liver membranes or rabbit antibodies was determined, and the distribution of iodinated hormones was examined using polyacrylamide gel electrophoresis. Excess antibody was capable of precipitating 87.9% of the radioactivity associated with the hGH tracer and 86.0% of the hPRL tracer. The maximal specific binding to a liver membrane preparation averaged 67.3% of the (/sup 125/I)iodo-hGH radioactivity and 48.8% of the (/sup 125/I)iodo-hPRL radioactivity. The respective BA and RRA activity estimates for (/sup 125/I)iodo-hGH averaged 90% and 114% of the activity measured by the RIA. For (/sup 125/I)iodo-hPRL, the values were 75% by BA and 68% by RRA. The bioactivity profiles of iodinated hGH and hPRL shifted anodally on polyacrylamide gel electrophoresis in comparison to the bioactivity distribution of the respective uniodinated hormones. Iodine incorporation rather than oxidation appeared to be responsible for the shift. After electrophoresis, all eluates which contained significant radioactivity were active in the BA and RIA. Furthermore, specific activities calculated from the bioactive hormone and radioactivity in each electrophoretic segment agreed well with the average specific activity estimated from the amount of iodine incorporated into the protein peak upon gel filtration. These data suggest that hGH and hPRL to a major degree retain biological integrity after iodination.

  4. Effects of prolactin and growth hormone on strategies of hypoosmotic adaptation in a marine teleost, Sparus sarba.

    PubMed

    Kelly, S P; Chow, I N; Woo, N Y

    1999-01-01

    Silver seabream (Sparus sarba) held in seawater (33 per thousand) or acclimated to a hypoosmotic environment of 6 per thousand were given intraperitoneal injections of saline (0.8% NaCl), recombinant bream growth hormone (rbGH, 1 microg/g), or ovine prolactin (oPRL, 6microg/g) for 7 consecutive days. Serum Na+ levels were unaffected by hypoosmotic acclimation and rbGH and oPRL treatment. Treatment of seawater fish with oPRL resulted in hyperchloremia. In 6 per thousand, saline-treated fish exhibited elevated branchial chloride cell (CC) numbers and exposure indices, all of which were markedly reduced by oPRL. CC numbers and morphometrics were unaffected by oPRL in seawater fish. In contrast, rbGH treatment of seawater fish resulted in elevated CC numbers, apical area, and fractional area and, in 6 per thousand fish, elevated CC fractional area and exposure numbers. Branchial Na+-K+-ATPase activity reduced in saline-treated fish adapted to 6% but was unaffected by rbGH regardless of salinity. oPRL reduced activity in both seawater and 6 per thousand-adapted fish. Neither hypoosmotic adaptation nor oPRL had any effect on renal Na+-K+-ATPase activity whereas rbGH reduced activity in both 33 and 6 per thousand. Saline-treated fish adapted to 6 per thousand exhibited reduced Na+-K+-ATPase activity in most regions of the intestine. Treatment with rbGH did not change intestinal Na+-K+-ATPase activity of seawater fish but elevated activity in the anterior regions (esophagus and stomach) of 6 per thousand-adapted fish. Treatment with oPRL elevated Na+-K+-ATPase activity throughout the gastrointestinal tract of seawater fish and in the anterior reaches of 6 per thousand-adapted fish. The data indicated that the as yet uncharacterized osmoregulatory roles of PRL and GH in seabream may warrant further attention as the present study connoted differing responses to that of other teleosts studied.

  5. Seasonal changes of responses to gonadotropin-releasing hormone analog in expression of growth hormone/prolactin/somatolactin genes in the pituitary of masu salmon.

    PubMed

    Bhandari, Ramji Kumar; Taniyama, Shinya; Kitahashi, Takashi; Ando, Hironori; Yamauchi, Kohei; Zohar, Yonathan; Ueda, Hiroshi; Urano, Akihisa

    2003-01-01

    Gonadotropin-releasing hormone (GnRH) is considered to stimulate secretion of growth hormone (GH), prolactin (PRL), and somatolactin (SL) at particular stages of growth and sexual maturation in teleost fishes. We therefore examined seasonal variation in the pituitary levels of GH/PRL/SL mRNAs, and tried to clarify seasonal changes of responses to GnRH in expression of GH/PRL/SL genes, in the pituitaries of growing and maturing masu salmon (Oncorhynchus masou). Pituitary samples were monthly collected one week after implantation with GnRH analog (GnRHa). The levels of mRNAs encoding GH, PRL, and SL precursors in single pituitaries were determined by a real-time polymerase chain reaction method. The fork lengths and body weights of control and GnRHa-implanted fish of both sexes gradually increased and peaked out in September of 2-year-old (2+) when fish spawned. GnRHa implantation did not stimulate somatic growth, nor elevate gonadosomatic index (GSI) of 1+ and 2+ males, whereas it significantly increased GSI of 2+ females in late August to early September. The GnRHa-implanted 1+ males had higher levels of GH and PRL mRNAs in July, and SL mRNA from June to August than the control males. The levels of GH, PRL, and SL mRNAs in the control and GnRHa-implanted 1+ females, however, did not show any significant changes. Afterward, the PRL mRNA levels elevated in the control 2+ fish of both sexes in spring. GnRHa elevated the GH mRNA levels in both males and females in 2+ winter, and the PRL mRNA levels in females in early spring. Regardless of sex and GnRHa-implantation, the SL mRNA levels increased during sexual maturation. In growing and maturing masu salmon, expression of genes encoding GH, PRL, and SL in the pituitary is thus sensitive to GnRH in particular seasons probably in relation to physiological roles of the hormones.

  6. Antipsychotics: impact on prolactin levels.

    PubMed

    Goodnick, Paul J; Rodriguez, Lucero; Santana, Orlando

    2002-10-01

    Hyperprolactinaemia has been associated with a variety of side effects including amenorrhoea, galactorrhoea, sexual dysfunction, breast engorgement and osteoporosis. Since the mid-1970s, the impact of antipsychotics on human prolactin (hPrl) levels has been investigated. Baseline levels of hPrl were found to be similar in healthy controls and patients who were diagnosed as having schizophrenia. Short-term acute studies done after single parenteral or oral doses of phenothiazines found rapid two- to tenfold increases in hPrl. Similar increases were found in longer term studies that reported increases of three times in both men and women after 3 days that doubled again after several weeks of treatment. A study of longer term injectable fluphenazine enanthate found that elevation induced by a single injection lasted up to 28 days. The same results with significant increases have been reported with the butyrophenone, haloperidol. Substantial increases are found after single injections (up to nine times) and after weeks of treatment (up to three times sustained). Thus, early literature believed that there might be an association between these induced changes and response to therapy. However, prolactin is secreted by the anterior pituitary and is under inhibitory control of dopamine released from the tuberoinfundibular neurones. Thus, increases in prolactin are due to antipsychotic impact on tuberoinfundibular tract, one of four dopamine-related tracts. With the application of clozapine and other atypical antipsychotics, it was found that medications can successfully treat psychosis without increasing hPrl. In fact, early single-dose trails found clozapine to reduce hPrl by 16%. Later studies replicated this result and also found that up to 6 weeks of administration led to reductions in hPrl of up to 80%. Risperidone, however, has been found to persistently elevate hPrl in studies, despite its impact on other receptor sites. Olanzapine, quetiapine and ziprasidone have

  7. Evidence that growth hormone stimulates milk synthesis by direct action on the mammary gland and that prolactin exerts effects on milk secretion by maintenance of mammary deoxyribonucleic acid content and tight junction status.

    PubMed

    Flint, D J; Gardner, M

    1994-09-01

    Both PRL and GH play a role in maintaining lactation in the rat, although GH can only maintain pup weight gain at around 50% of the control value, whereas PRL can maintain weight gain close to 90% in the absence of GH. In this study we examined the effects of PRL and GH deficiency (using bromocriptine and an antiserum to rat GH) on milk yield and composition in lactating rats. Treatment with bromocriptine to suppress PRL secretion for 48 h led to a 57% decrease in milk yield with a concomitant decrease in milk protein and lactose yields, but no decrease in fat output. This led to the production of milk with a lower lactose concentration but increased concentrations of protein and particularly fat (increased 100%), which suggests that GH serves an auxiliary role by maintaining an energy-rich milk for the neonate when PRL secretion is reduced. This decrease in milk synthesis was accompanied by decreases in total mammary DNA content and increased milk sodium concentrations. The latter indicates the opening of tight junctions between mammary epithelial cells, which normally occurs during dedifferentiation and involution of the mammary gland. This suggests that PRL maintains milk synthesis at least in part by inhibiting epithelial cell loss and maintaining cellular differentiation. A deficiency in GH, by contrast, caused only a small decrease (24%) in milk yield and had no effect on the major constituents of milk or on milk sodium concentrations or total mammary DNA content. When animals were made deficient in both PRL and GH, however, there was a further marked decrease (88%) in milk volume along with the yields of all major milk constituents, confirming our previous findings that PRL and GH are the major regulators of milk synthesis. Recent studies have indicated that GH exerts direct effects on mammary gland growth, but its actions on milk secretion have been proposed to be mediated indirectly via insulin-like growth factor-I (IGF-I). We, therefore, inhibited

  8. Plasma levels of beta-endorphin, prolactin and gonadotropins in male athletes after an international nordic ski race.

    PubMed

    Mougin, C; Henriet, M T; Baulay, A; Haton, D; Berthelay, S; Gaillard, R C

    1988-01-01

    Plasma beta-endorphin, prolactin (PRL), FSH and LH were measured in 17 volunteer male subjects at rest and under the stress caused by a long-distance nordic ski race. The race induced increased levels of beta-endorphin and PRL in all skiers. The changes in PRL with exercise were significantly related to the changes in beta-endorphin (r = 0.69, p less than 0.001). Furthermore, the highly trained skiers training over 150 km.week-1 of nordic ski showed consistently higher post-exercise beta-endorphin and PRL levels than the moderately trained skiers who trained for 20 km.week-1. In addition the race induced slight falls in FSH and LH; however plasma gonadotropin levels did not show any correlation with plasma beta-endorphin concentrations and did not differ between the two groups of skiers. These results suggest that endogenous opioid peptides may modulate PRL secretion in heavy exercise, since they are of minor importance in the release of FSH and LH in such a situation. The observations also suggest that the degree of previous training and the exercise intensity do seem to be responsible for the hormonal changes.

  9. Analysis of the genetic effects of prolactin gene polymorphisms on chicken egg production.

    PubMed

    Li, Hui-Fang; Shu, Jing-Ting; Du, Yu-Feng; Shan, Yan-Ju; Chen, Kuan-Wei; Zhang, Xue-Yu; Han, Wei; Xu, Wen-Juan

    2013-01-01

    Chicken prolactin (PRL) is a physiological candidate gene for egg production. Variations of T8052C and G8113C in exon 5 of PRL gene may associate with chicken egg production. The objective of the study was to investigate the association of these two single nucleotide polymorphisms in PRL gene with egg production of Recessive White chickens and Qingyuan Partridge chickens. Genotyping was performed by polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The T8052C and G8113C of PRL were significantly associated with age at first egg (AFE) and total egg number at 300 days of age (EN 300). A significant association was also found between T8052C-G8113C haplotypes and AFE as well as EN300, the H2H3 was the most advantageous diplotype for egg production. We putatively drew the conclusion that these two SNPs in PRL gene as well as their haplotypes could be used as the potential molecular markers for egg production traits in chicken.

  10. Evolutionary aspects of growth hormones and prolactins and their receptors

    SciTech Connect

    Tarpey, J.F.

    1986-01-01

    The interactions of GH's, PRL's and PL's with receptors for GH and PRL were examined from a comparative and evolutionary viewpoint. The binding of /sup 125/I-bGH to membrane preparations from liver of representatives of the major classes of non-mammalian vertebrates was also studied. Only hepatic membranes from sturgeon and Gillichthys had significant bGH binding and were further characterized and compared with male rabbit liver membranes in terms of time, temperature, pH, and membrane concentration to optimize binding conditions. The binding of several members of the GH, PRL, PL family of hormones to GH receptors from liver of sturgeon, Gillichthys, rabbit, mouse and rat was investigated. in terms of hormonal specificity, the mammalian receptors and the sturgeon binding sites were similar, while Gillichthys receptors had a different pattern of hormonal specificity. The binding of /sup 125/I-oPRL to renal membranes of the turtle, Pseudemys scripta elegans, was characterized and compared to PRL binding sites of kidney membranes of the bullfrog, Rana catesbeiana, and the tiger salamander, Ambystoma tigrinum.

  11. Prolactin protects against the methamphetamine-induced cerebral vascular toxicity.

    PubMed

    Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Ali, Syed F; Gonzalez, Carmen

    2013-11-01

    Methamphetamine (Meth) is a highly addictive drug of abuse which alters the dopaminergic system and damages the blood-brain barrier (BBB), structure that protects the brain tissue from the circulating substances in the blood, keeping a low permeability through the presence of tight junctions (TJs) between endothelial cells. Meth increases BBB permeability by decreasing the TJs proteins claudin-5 and occludin and by decreasing the viability of endothelial cells. Individuals abused of Meth have increased blood concentrations of prolactin (PRL); hormone related with milk production, but able to increase the expression of TJs proteins and to decrease permeability on the mammary epithelium and brain endothelial cells. However, the effects of PRL on the permeability of the BBB in the presence of Meth have not been studied. Here, we report Meth-induced apoptosis and decreased cellular proliferation as well as the trans-endothelial electrical resistance (TEER), related to a decrease of claudin-5 and occludin in primary cultured bovine brain microvessel endothelial cells. The expression of the PRL receptor was not altered. Administration of PRL prevented a decrease in cellular proliferation, an increase in apoptosis and restored the TEER and TJs proteins to basal levels. This protection was absent at high Meth concentrations. These data suggest that PRL protects brain endothelial cells against the Meth-induced toxicity. Further investigation is required to study the mechanisms involved and to confirm these effects in vivo.

  12. Hypothyroidism decreases JAK/STAT signaling pathway in lactating rat mammary gland.

    PubMed

    Campo Verde Arboccó, Fiorella; Persia, Fabio Andres; Hapon, María Belén; Jahn, Graciela A

    2017-04-05

    Thyroid pathologies have deleterious effects on lactation. Especially hypothyroidism (HypoT) induces premature mammary involution at the end of lactation and decreases milk production and quality in mid lactation. Milk synthesis is controlled by JAK2/STAT5 signaling pathway and prolactin (PRL), which activates the pathway. In this work we analyzed the effect of chronic 6-propyl-2- thiouracil (PTU)-induced HypoT on PRL signaling pathway on mammary glands from rats on lactation (L) days 2, 7 and 14. HypoT decreased prolactin receptor expression, and expression and activation of Stat5a/b protein. Expression of members of the SOCS-CIS family, inhibitors of the JAK-STAT pathway, decreased in L2 and L7, possibly as a compensatory response of the mammary cells to maintain PRL responsiveness. However, on L14, the level of these inhibitors was normal and the transcription of α-lactoalbumin (lalba), a target gene of the PRL pathway, decreased by half. HypoT altered the transcriptional capacity of the cell and decreased mRNA levels of Prlr and Stat5b on L14. Stat5b gene has functional thyroid hormone response elements in the regulatory regions, that bind thyroid hormone receptor β (TRβ) differentially and in a thyroid hormone dependent manner. The overall decrease in the PRL signaling pathway and consequently in target gene (lalba) mRNA transcription explain the profound negative impact of HypoT on mammary function through lactation.

  13. A Common Phenotype Polymorphism in Mammalian Brains Defined by Concomitant Production of Prolactin and Growth Hormone

    PubMed Central

    Daude, Nathalie; Lee, Inyoul; Kim, Taek-Kyun; Janus, Christopher; Glaves, John Paul; Gapeshina, Hristina; Yang, Jing; Sykes, Brian D.; Carlson, George A.; Hood, Leroy E.; Westaway, David

    2016-01-01

    Pituitary Prolactin (PRL) and Growth Hormone (GH) are separately controlled and sub-serve different purposes. Surprisingly, we demonstrate that extra-pituitary expression in the adult mammalian central nervous system (CNS) is coordinated at mRNA and protein levels. However this was not a uniform effect within populations, such that wide inter-individual variation was superimposed on coordinate PRL/GH expression. Up to 44% of individuals in healthy cohorts of mice and rats showed protein levels above the norm and coordinated expression of PRL and GH transcripts above baseline occurred in the amygdala, frontal lobe and hippocampus of 10% of human subjects. High levels of PRL and GH present in post mortem tissue were often presaged by altered responses in fear conditioning and stress induced hyperthermia behavioral tests. Our data define a common phenotype polymorphism in healthy mammalian brains, and, given the pleiotropic effects known for circulating PRL and GH, further consequences of coordinated CNS over-expression may await discovery. PMID:26894278

  14. A randomized cross-over study comparing cabergoline and quinagolide in the treatment of hyperprolactinemic patients.

    PubMed

    De Luis, D A; Becerra, A; Lahera, M; Botella, J I; Valero; Varela, C

    2000-01-01

    Quinagolide (QUI) and cabergoline (CAB) are dopamine agonists recently introduced for the treatment of hyperprolactinemia. In the present study, these drugs have been compared in terms of effectiveness and tolerability. Twenty patients (18 females and 2 males) with hyperprolactinemia (8 with microprolactinomas, 6 with idiopathic hyperprolactinemia and 6 with empty sella turcica syndrome) were treated with oral QUI (75 microg once daily) and CAB (0,5 mg twice weekly), in a randomized cross-over trial with placebo between both drugs. Each drug was administered for 12 weeks, separated by other 12 weeks with placebo. PRL levels decreased with both drugs at 2 or 4 weeks of starting the treatment, without differences between both drugs at weeks 4, 8 and 12. At week 12, normal PRL levels (<20 ng/ml) were attained in 90% patients with CAB and only in 75% patients with QUI (p<0.05). After discontinuation of treatment, significant increase in serum PRL was higher after QUI withdrawal than after CAB. Clinical efficacy of both treatments was similar in terms of improvement amenorrhea, oligomenorrhea, galactorrhea, and impotence. All patients completed both cycles of treatment, and the most frequent side-effects were nausea, headache and dizziness, without significant differences between CAB (30%) and QUI (55%). Our study indicates that, at the doses employed here, CAB showed a high percentage of patients with normal PRL at the end of treatment and long-lasting efficacy in the levels of PRL. Clinical response and side-effects were similar in both drugs.

  15. Profiles of mRNA expression for prolactin, growth hormone, and somatolactin in Japanese eels, Anguilla japonica: The effect of salinity, silvering and seasonal change.

    PubMed

    Sudo, Ryusuke; Suetake, Hiroaki; Suzuki, Yuzuru; Aoyama, Jun; Tsukamoto, Katsumi

    2013-01-01

    For understanding the functions of the growth hormone (GH)/prolactin (PRL)/somatolactin (SL) family of hormones, we examined pituitary mRNA expression of these hormones in anguillid eels in relation to salinity difference, silvering, and seasonal change. Female Japanese eels (Anguilla japonica) were collected in the brackish Hamana Lake and its freshwater rivers from July to December. To clarify the effect of salinity, the habitat use history of the eels were determined using otolith microchemistry. Expression levels of mRNA of each hormone were determined using real time PCR. Although GH and PRL have been known to be osmoregulatory hormones, there were no consistent differences in expression levels of these hormones between different salinity habitats. In contrast, SL mRNA expression was higher in eels from freshwater rivers than from the brackish lake. GH mRNA expression clearly decreased during silvering, whereas PRL and SL mRNA expression did not change. We also showed that PRL mRNA and SL mRNA decreased in the brackish lake and PRL mRNA increased in freshwater rivers from autumn to early winter. These findings provide basic knowledge for a further understanding of the role of these hormones.

  16. Effects of photoperiod on the secretion of growth hormone and prolactin during nighttime in female goats.

    PubMed

    Jin, Jin; Yaegashi, Tomoyoshi; Hashizume, Tsutomu

    2013-02-01

    The aim of the present study was to clarify the effect of photoperiod on nighttime secretion of growth hormone (GH) in goats. Adult female goats were kept at 20°C with an 8 h or 16 h dark photoperiod, and secretory patterns of GH for 8 h in the dark period were examined with the profile of prolactin (PRL) secretion. GH was secreted in a pulsatile manner in the dark period. There were no significant differences in pulse frequency between the 8- and 16-h dark photoperiods; however, pulse amplitude tended to be greater in the group with the 16-h dark photoperiod (P = 0.1), and mean GH concentrations were significantly greater in the same photoperiod (P < 0.05). PRL secretion increased quickly after lights off under both photoperiods. The PRL-releasing responses were weaker in the 8-h than 16-h dark photoperiod. The secretory response to photoperiod was more obvious for PRL than GH. The present results show that a long dark photoperiod enhances the nighttime secretion of GH in female goats, although the response is not as obvious as that for PRL.

  17. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes.

    PubMed

    Stratakis, C A; Tichomirowa, M A; Boikos, S; Azevedo, M F; Lodish, M; Martari, M; Verma, S; Daly, A F; Raygada, M; Keil, M F; Papademetriou, J; Drori-Herishanu, L; Horvath, A; Tsang, K M; Nesterova, M; Franklin, S; Vanbellinghen, J-F; Bours, V; Salvatori, R; Beckers, A

    2010-11-01

    The prevalence of germline mutations in MEN1, AIP, PRKAR1A, CDKN1B and CDKN2CI is unknown among pediatric patients with pituitary adenomas (PA). In this study, we screened children with PA for mutations in these genes; somatic GNAS mutations were also studied in a limited number of growth hormone (GH) or prolactin (PRL)-secreting PA. We studied 74 and 6 patients with either isolated Cushing disease (CD) or GH- or PRL-secreting PA, respectively. We also screened four pediatric patients with CD, and four with GH/PRL-secreting tumors who had some syndromic features. There was one AIP mutation (p.Lys103Arg) among 74 CD patients. Two MEN1 mutations that occurred in patients with recurrent or difficult-to-treat disease were found among patients with CD. There was one MEN1 and three AIP mutations (p.Gln307ProfsX104, p.Pro114fsX, p.Lys241X) among pediatric patients with isolated GH- or PRL-secreting PA and one additional MEN1 mutation in a patient with positive family history. There were no mutations in the PRKAR1A, CDKN1B, CDKN2C or GNAS genes. Thus, germline AIP or MEN1 gene mutations are frequent among pediatric patients with GH- or PRL-secreting PA but are significantly rarer in pediatric CD; PRKAR1A mutations are not present in PA outside of Carney complex.

  18. Site-specific methylation of the rat prolactin and growth hormone promoters correlates with gene expression.

    PubMed Central

    Ngô, V; Gourdji, D; Laverrière, J N

    1996-01-01

    The methylation patterns of the rat prolactin (rPRL) (positions -440 to -20) and growth hormone (rGH) (positions -360 to -110) promoters were analyzed by bisulfite genomic sequencing. Two normal tissues, the anterior pituitary and the liver, and three rat pituitary GH3 cell lines that differ considerably in their abilities to express both genes were tested. High levels of rPRL gene expression were correlated with hypomethylation of the CpG dinucleotides located at positions -277 and -97, near or within positive cis-acting regulatory elements. For the nine CpG sites analyzed in the rGH promoter, an overall hypomethylation-expression coupling was also observed for the anterior pituitary, the liver, and two of the cell lines. The effect of DNA methylation was tested by measuring the transient expression of the chloramphenicol acetyltransferase reporter gene driven by a regionally methylated rPRL promoter. CpG methylation resulted in a decrease in the activity of the rPRL promoter which was proportional to the number of modified CpG sites. The extent of the inhibition was also found to be dependent on the position of methylated sites. Taken together, these data suggest that site-specific methylation may modulate the action of transcription factors that dictate the tissue-specific expression of the rPRL and rGH genes in vivo. PMID:8668139

  19. Pathological study of thyrotropin-secreting pituitary adenoma: plurihormonality and medical treatment.

    PubMed

    Teramoto, Akira; Sanno, Naoko; Tahara, Shigeyuki; Osamura, Yoshiyuki R

    2004-08-01

    Thyrotropin (TSH)-secreting adenomas are rare and, as most adenomas are large, invasive and difficult to cure by surgery only, many require additional medical treatment. Many TSH-secreting adenomas cosecrete growth hormone (GH) and/or prolactin (PRL). We evaluated the relationship between pathology and the effect of dopamine agonist bromocriptine and somatostatin analogue octreotide in 20 operated patients with TSH-secreting adenomas. The four men and 16 women ranged in age from 23 to 62 years; three had clinically overt acromegaly; two manifested galactorrhea-amenorrhea. Endocrinologically, elevated serum GH, and/or IGF-1 were observed in six patients and elevated serum PRL was observed in eight. Immunohistochemically, 16 of the 20 adenomas were positive for GH and/or PRL (GH-positive, n=13; PRL-positive, n=9). Pituitary-specific transcription factor Pit-1 was demonstrated in the nuclei of all adenoma cells. Octreotide tests showed suppression of serum TSH (<50%) in ten of 14 patients. Preoperative octreotide treatment effectively reduced serum TSH and tumor size in two patients. Electron micrographs of octreotide-treated TSH-secreting adenomas showed shrinkage of the cytoplasm and diffuse distribution of secretory granules. Our study suggests that cosecretion of GH and/or PRL from TSH-secreting adenoma has no correlation with response of tumor cells to medical treatment.

  20. Effect of hyperthyroidism on circulating prolactin and hypothalamic expression of tyrosine hydroxylase, prolactin signaling cascade members and estrogen and progesterone receptors during late pregnancy and lactation in the rat.

    PubMed

    Pennacchio, Gisela E; Neira, Flavia J; Soaje, Marta; Jahn, Graciela A; Valdez, Susana R

    2017-02-15

    Hyperthyroidism (HyperT) compromises pregnancy and lactation, hindering suckling-induced PRL release. We studied the effect of HyperT on hypothalamic mRNA (RT-qPCR) and protein (Western blot) expression of tyrosine hydroxylase (TH), PRL receptor (PRLR) and signaling pathway members, estrogen-α (ERα) and progesterone (PR) receptors on late pregnancy (days G19, 20 and 21) and early lactation (L2) in rats. HyperT advanced pre-partum PRL release, reduced circulating PRL on L2 and increased TH mRNA (G21 and L2), p-TH, PRLR mRNA, STAT5 protein (G19 and L2), PRLR protein (G21) and CIS protein (G19). PRs mRNAs and protein decreased on G19 but afterwards PRA mRNA (G20), PRB mRNA (G21) and PRA mRNA and protein (L2) increased. ERα protein increased on G19 and decreased on G20. Thus, the altered hypothalamic PRLR, STAT5, PR and ERα expression in hyperthyroid rats may induce elevated TH expression and activation, that consequently, elevate dopaminergic tone during lactation, blunting suckling-induced PRL release and litter growth.

  1. The association between antiphospholipid antibodies and pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature.

    PubMed

    Chighizola, C B; Andreoli, L; de Jesus, G Ramires; Banzato, A; Pons-Estel, G J; Erkan, D

    2015-08-01

    In a previous systematic literature search, we demonstrated that the frequencies of antiphospholipid antibodies (aPL) in general-population patients with pregnancy morbidity (PM), deep vein thrombosis (DVT), myocardial infarction (MI), and stroke (ST) are 6%, 10%, 11%, and 14%. To determine the association between aPL and clinical outcomes, we conducted a follow-up analysis of the 120 studies included in the original paper. Based on the analysis of 81 studies, a significant difference in the frequency of aPL criteria tests between patients and controls emerged considering all the outcomes together (10% versus 3%). In particular, a significant difference was reported for overall PM, pregnancy loss (PrL), late PrL, severe preeclampsia (PEC), ST, MI, and DVT. No difference emerged for early PrL, intrauterine growth restriction (IUGR), PEC, eclampsia (EC), and HELLP. A positive association was found in more than half of the studies for overall PrL, severe PEC, HELLP, ST, MI, and DVT and in less than half for early and late PrL, PEC, EC, and IUGR. The positive association between aPL and clinical outcomes included in the antiphospholipid syndrome classification criteria is not supported by every study, being particularly inconsistent for early PL, IUGR, PEC, EC, and HELLP.

  2. Expression of 17?-hydroxysteroid dehydrogenase and the effects of LH, FSH and prolactin on oestrone and 17?-oestradiol secretion in the endometrium of pigs during early pregnancy and the oestrous cycle.

    PubMed

    Wojciechowicz, B; Kotwica, G; Zglejc, K; Waszkiewicz, E; Franczak, A

    2016-03-07

    The endometrium of pregnant and cyclic pigs is a source of oestrone (E1) and 17β-oestradiol (E2). However, the roles of LH, FSH and prolactin (PRL) as regulators of endometrial steroidogenesis, and the presence of 17β-hydroxysteroid dehydrogenase (17β-HSD) in the porcine endometrium, remain unknown. Therefore, in the present study we examined 17β-HSD expression and the effects of LH, FSH and PRL on E1 and E2 release in vitro in endometrial explants harvested from gravid pigs on Days 10-11 (embryo migration within the uterus), 12-13 (maternal recognition of pregnancy) and 15-16 (beginning of implantation) and compared them with results obtained in non-gravid pigs. The results show that: (1) endometrial 17β-HSD activity was decreased on Days 15-16 in pregnant and cyclic pigs compared with the preceding days; (2) LH, FSH and PRL increased endometrial E1 secretion on Days 10-11 and 15-16 of pregnancy and on Days 12-13 and 15-16 of the oestrous cycle; and (3) LH, FSH and PRL increased endometrial E2 secretion on Days 15-16 of pregnancy and during the days studied in the oestrous cycle. In conclusion, data suggest that LH, FSH and PRL affect endometrial secretion of estrogens in pigs.

  3. Kidnapping of chicks in emperor penguins: a hormonal by-product?

    PubMed

    Angelier, Frédéric; Barbraud, Christophe; Lormée, Hervé; Prud'homme, François; Chastel, Olivier

    2006-04-01

    The function and causes of kidnapping juveniles are little understood because individuals sustain some breeding costs to rear an unrelated offspring. Here we focus on the proximal causes of this behaviour in emperor penguins (Aptenodytes forsteri), whose failed breeders often kidnap chicks. We experimentally tested the hypothesis that kidnapping behaviour was the result of high residual levels of prolactin (PRL), a hormone involved in parental behaviour. Penguins with artificially decreased PRL levels by bromocriptine administration kidnapped chicks less often than control penguins. Within the bromocriptine treated group, kidnapping behaviour was not totally suppressed and the probability of kidnapping a chick was positively correlated to PRL levels measured before treatment. During breeding, emperor penguins have to forage in remote ice-free areas. In these birds, PRL secretion is poorly influenced by chick stimuli and has probably evolved to maintain a willingness to return to the colony after a long absence at sea. Therefore, penguins that have lost their chick during a foraging trip still maintain high residual PRL levels and this, combined with colonial breeding, probably facilitates kidnapping. We suggest that kidnapping in non-cooperative systems may result from a hormonal byproduct of a reproductive adaptation to extreme conditions.

  4. Investigation of Prolactin Receptor Activation and Blockade Using Time-Resolved Fluorescence Resonance Energy Transfer

    PubMed Central

    Tallet, Estelle; Fernandez, Isabelle; Zhang, Chi; Salsac, Marion; Gregor, Nathalie; Ayoub, Mohammed Akli; Pin, Jean Philippe; Trinquet, Eric; Goffin, Vincent

    2011-01-01

    The prolactin receptor (PRLR) is emerging as a therapeutic target in oncology. Knowledge-based drug design led to the development of a pure PRLR antagonist (Del1-9-G129R-hPRL) that was recently shown to prevent PRL-induced mouse prostate tumorogenesis. In humans, the first gain-of-function mutation of the PRLR (PRLRI146L) was recently identified in breast tumor patients. At the molecular level, the actual mechanism of action of these two novel players in the PRL system remains elusive. In this study, we addressed whether constitutive PRLR activation (PRLRI146L) or PRLR blockade (antagonist) involved alteration of receptor oligomerization and/or of inter-chain distances compared to unstimulated and PRL-stimulated PRLR. Using a combination of various biochemical and spectroscopic approaches (co-IP, blue native electrophoresis, BRET1), we demonstrated that preformed PRLR homodimers are altered neither by PRL- or I146L-induced receptor triggering, nor by antagonist-mediated blockade. These findings were confirmed using a novel time-resolved fluorescence resonance energy transfer (TR-FRET) technology that allows monitoring distance changes between cell surface tagged receptors. This technology revealed that PRLR blockade or activation did not involve detectable distance changes between extracellular domains of receptor chains within the dimer. This study merges with our previous structural investigations suggesting that the mechanism of PRLR activation solely involves intermolecular contact adaptations leading to subtle intramolecular rearrangements. PMID:22649370

  5. Role of luteinizing hormone in luteotropic complex of pregnant hamster

    SciTech Connect

    Tamura, H.; Greenwald, G.S.

    1987-04-01

    Hamsters were hypophysectomized on day 4 of pregnancy and injected subcutaneously on days 4-7 with various combinations of 200 ..mu..g prolactin (Prl), 10 ..mu..g follicle-stimulating hormone (FSH), and 20 ..mu..g luteinizing hormone (LH) in polyvinylpyrrolidone (PVP) to decrease its rate of absorption or in saline. End points for luteal function on day 8 were maintenance of pregnancy, serum progesterone (P/sub 4/), luteal weight, and luteal binding for human chorionic gonadotropin, FSH, and Prl. After hypophysectomy, a drastic decline occurred in all parameters including an 89% decrease in luteal weight. Injection of Prl did not maintain pregnancy nor serum P/sub 4/ but partially maintained luteal weight and human chorionic gonadotropin binding sites per corpus luteum. The minimal luteotropic complex of Prl and FSH was effective in maintaining pregnancy and significantly increased serum P/sub 4/ and Prl and FSH receptors but not to control levels. Thus, the luteotropic activity of LH was only demonstrable when it was injected in a long-acting form; when delivered as a bolus, LH (saline) was luteolytic. P/sub 4/ and estradiol were measured by radioimmunoassay. Radioiodinated gonadotropins were prepared. The percentage of tracer reacting with an excess of receptor were 51% of /sup 125/I-FSH and 45.9% of /sup 125/I-hCG using whole homogenates of hamster ovaries.

  6. Hepatic prolactin binding is rapidly altered by endotoxin in lactating mice

    SciTech Connect

    Carr, J.K.; Keefer, L.M.; Cohen, J.C.

    1987-09-21

    Endotoxin or lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, produces profound physiologic changes in most mammals. The effects of LPS on ovine prolactin (oPRL) binding by hepatic membranes of lactating mice is explored in this report. Specific /sup 125/I-oPRL binding by liver membranes from LPS-responder C3HfB/HeN mice increased two-fold within fifteen minutes of the injection of LPS, while no change was observed in the non-responder C3H/HeJ mice. Specific /sup 125/I-insulin binding did not change. Scatchard analysis of equilibrium binding of oPRL to C3HfB/HeN liver membranes indicated that within fifteen minutes of LPS injection, a receptor of differing binding affinity appears and then disappears by one hour post-injection. The authors propose that these rapid alterations in the specific binding of oPRL by liver membranes from LPS-injected, lactating C3HfB/HeN mice are due to the transient creation or unmasking of a novel class of PRL receptor. 32 references, 6 figures.

  7. Tamoxifen inhibition of prolactin action in the mouse mammary gland.

    PubMed

    Biswas, R; Vonderhaar, B K

    1991-01-01

    Binding of lactogenic hormones to particulate and solubilized microsomal membranes isolated from mammary glands of lactating mice is inhibited by direct addition of 10(-10) M or greater concentrations of triphenylethylene antiestrogens [i.e. tamoxifen (TAM), 4-hydroxy-tamoxifen, and Nafoxidine] to the binding assays. Estradiol and other antiestrogens such as BPEA (-2-(4-tert-butyl-phenoxy) ethyl diethylamine hydrochloride, LY117018, and LY 156758 do not have this effect. The triphenylethylene antiestrogens bind to the membrane-associated antiestrogen binding sites (AEBS). Effectiveness of binding to the AEBS parallels the effectiveness of inhibition of the lactogen binding. The effect is selective in that binding of epidermal growth factor and insulin to these same membranes is unaffected by the antiestrogens. Binding of PRL to membranes prepared from the livers of the lactating mice is also unaffected. Both the PRL receptor and AEBS are primarily localized to the microsomal membrane fraction of cells. Maximal inhibition of PRL binding by TAM is observed in the light microsomes that contain plasma membranes. In addition to inhibition of PRL binding, TAM also prevents the PRL-induced accumulation of caseins by cultured mouse mammary explants. Thus it appears that the triphenylethylene antiestrogens, acting through the AEBS, act as antilactogens in the normal mammary gland.

  8. Prolactin and prolactin secretagogues reverse immunosuppression in mice treated with cysteamine, glucocorticoids, or cyclosporin-A.

    PubMed

    Bernton, E; Bryant, H; Holaday, J; Dave, J

    1992-12-01

    Suppression of prolactin (PRL) secretion with the dopamine agonist, bromocriptine, has been shown in rodents to diminish a variety of immunologic responses, including delayed type hypersensitivity, primary antibody response, T-cell dependent macrophage activation, and ex vivo T- and B-lymphocyte proliferation in response to mitogens. These same responses can be suppressed by endogenous or exogenous glucocorticosteroids and, in large measure, the immunosuppressant peptide cyclosporin A. The sulfhydryl reducing agent cysteamine (2-aminoethanethiol) is known to reduce pituitary and plasma prolactin levels. Treatment of mice with cysteamine at doses which suppressed circulating PRL levels resulted in suppression of ex vivo blastogenic responses of lymphocytes from treated mice. The T-cell-dependent primary IgM response to immunization with sheep red blood cells was also suppressed by cysteamine treatment. Treatment of mice with drugs stimulating the release of endogenous PRL, or with exogenous ovine PRL, was found to antagonize the suppression of lymphocyte proliferative responses to mitogens induced in mice by glucocorticoid or cyclosporin treatment. These data suggest that many drugs in common clinical use could have potential immunomodulatory actions due to suppression or stimulation of pituitary PRL secretion. Furthermore, lactogenic hormones appear to exert counterregulatory actions which may modify glucocorticosteroid actions on immune and other target issues.

  9. Depletion of bovine pituitary prolactin by cysteamine involves a thiol:disulfide mechanism

    SciTech Connect

    Lorenson, M.Y.; Jacobs, L.S.

    1984-10-01

    Cysteamine (2-aminoethanethiol (CySH)) reduces measurable PRL concentrations in vivo and in vitro. Since secretion is also inhibited, CySH may block conversion from a poorly assayable hormone storage form(s) to readily assayable, releasable PRL. This would represent a previously unrecognized mechanism for secretory regulation. We undertook the present study to identify the sites involved in the loss of measurable PRL (depletion) induced by cysteamine. The disulfide cystamine was ineffective on secretory granules unless combined with reduced glutathione, indicating the generation of the active CySH-thiol form. Pretreatment of granules with thiol-blocking agents resulted in dose-dependent enhancement of CySH inhibition, achieving nearly complete inhibition with 5 mM iodoacetamide. In contrast, pretreatment with reduced glutathione or dithiothreitol, respectively, impaired or abolished the CySH effect. These data suggest that the mechanism by which CySH causes PRL depletion is mediated by granule disulfides and the -SH of CySH. The regulation of thiol:disulfide equilibria appears to be an important determinant of the detectability of PRL storage forms and of their secretion.

  10. Distribution of hypothalamic vasoactive intestinal peptide immunoreactive neurons in the male native Thai chicken.

    PubMed

    Kamkrathok, Boonyarit; Sartsoongnoen, Natagarn; Prakobsaeng, Nattiya; Rozenboim, Israel; Porter, Tom E; Chaiseha, Yupaporn

    2016-08-01

    Avian prolactin (PRL) secretion is under stimulatory control by the PRL-releasing factor (PRF), vasoactive intestinal peptide (VIP). The neuroendocrine regulation of the avian reproductive system has been extensively studied in females. However, there are limited data in males. The aim of this study was to elucidate the VIPergic system and its relationship to PRL and testosterone (T) in the male native Thai chicken. The distributions of VIP-immunoreactive (-ir) neurons and fibers were determined by immunohistochemistry. Changes in VIP-ir neurons within the nucleus inferioris hypothalami (IH) and nucleus infundibuli hypothalami (IN) areas were compared across the reproductive stages. Plasma levels of PRL and T were determined by enzyme-linked immunosorbent assay and then compared across the reproductive stages. The results revealed that the highest accumulations of VIP-ir neurons were concentrated only within the IH-IN, and VIP-ir neurons were not detected within other hypothalamic nuclei. Within the IH-IN, VIP-ir neurons were low in premature and aging males and markedly increased in mature males. Changes in VIP-ir neurons within the IH-IN were directly mirrored with changes in PRL and T levels across the reproductive stages. These results suggested that VIP neurons in the IH-IN play a regulatory role in year-round reproductive activity in males. The present study also provides additional evidence that VIP is the PRF in non-seasonal, continuously breeding equatorial species.

  11. Induction of maternal behavior in adult female rats following chronic morphine exposure during puberty.

    PubMed

    Byrnes, Elizabeth M; Rigero, Beth A; Bridges, Robert S

    2003-12-01

    The peripubertal period in the female rat is the time when the stimulatory effects of opioids on prolactin (PRL) secretion develop. In the adult rat, the administration of chronic high-dose morphine has been shown to attenuate the ability of opiates to stimulate PRL secretion. One function of PRL in adult virgin rats is the induction of maternal behavior. The present study examined whether chronic high-dose morphine exposure during the peripubertal period alters PRL-mediated induction of maternal behavior in adult female rats. Two groups of juvenile female rats were administered increasing doses of morphine or vehicle (s.c.) from age 30 to 50 days. As adults, these females either remained intact, or were ovariectomized and treated with a PRL-dependent, steroid hormone regimen that stimulates a rapid onset of maternal behavior. All females were then exposed daily to rat foster pups to determine whether peripubertal morphine exposure affected their latencies to induce maternal behavior. Morphine treatment resulted in a delay in vaginal opening and a temporary reduction in the rate of weight gain; however, the rate of onset of maternal behavior was unaffected by peripubertal morphine treatment. Thus, chronic morphine exposure in the pubertal female did not impact the expression of pup-induced maternal care.

  12. Role of alpha 1- and alpha 2-adrenergic receptors in the growth hormone and prolactin response to insulin-induced hypoglycemia in man.

    PubMed

    Tatár, P; Vigas, M

    1984-09-01

    The effects of intravenous infusion of the nonselective alpha-adrenergic antagonist phentolamine or of the selective alpha 2-adrenergic antagonist yohimbine on growth hormone (GH), prolactin (PRL) and cortisol secretion during insulin-induced hypoglycemia were studied in 11 healthy young men. The GH response was blunted following each antagonist used, PRL secretion was higher after yohimbine and diminished after phentolamine when compared to controls. The plasma cortisol response was not influenced by either compound. In another series of experiments no effect of an oral administration of prazosin, a selective alpha 1-adrenergic antagonist, on the secretion of GH, PRL and cortisol was found in any of 7 subjects. Prazosin inhibited blood pressure increase during hypoglycemia and induced slight drowsiness and fatigue in the subjects. It is concluded that in man alpha-adrenergic stimulation of GH secretion during hypoglycemia is transmitted via alpha 2-receptors, PRL secretion is mediated via alpha 1-receptors, whereas inhibition of PRL release is mediated via alpha 2-receptors. In this experiment no effect of alpha 1- or alpha 2-blockade on cortisol response to hypoglycemia was seen.

  13. Modeling Island-Growth Capture Zone Distributions (CZD) with the Generalized Wigner Distribution (GWD): New Developments in Theory and Experiment

    NASA Astrophysics Data System (ADS)

    Pimpinelli, Alberto; Einstein, T. L.; González, Diego Luis; Sathiyanarayanan, Rajesh; Hamouda, Ajmi Bh.

    2011-03-01

    Earlier we showed [PRL 99, 226102 (2007)] that the CZD in growth could be well described by P (s) = asβ exp (-bs2) , where s is the CZ area divided by its average value. Painstaking simulations by Amar's [PRE 79, 011602 (2009)] and Evans's [PRL 104, 149601 (2010)] groups showed inadequacies in our mean field Fokker-Planck argument relating β to the critical nucleus size. We refine our derivation to retrieve their β ~ i + 2 [PRL 104, 149602 (2010)]. We discuss applications of this formula and methodology to experiments on Ge/Si(001) and on various organics on Si O2 , as well as to kinetic Monte Carlo studies homoepitaxial growth on Cu(100) with codeposited impurities of different sorts. In contrast to theory, there can be significant changes to β with coverage. Some experiments also show temperature dependence. Supported by NSF-MRSEC at UMD, Grant DMR 05-20471.

  14. Effects of hypophysectomy and substitution with growth hormone, prolactin, and thyroxine on growth and deposition in juvenile frogs, Xenopus laevis.

    PubMed

    Nybroe, O; Rosenkilde, P; Ryttersgaard, L

    1985-02-01

    Growth was studied in young metamorphosed frogs, Xenopus laevis, following hypophysectomy and substitution with mammalian growth hormone (bGH or pGH), mammalian prolactin (oPRL), and thyroxine. Hypophysectomy reduced growth (weight and length increase). GH and PRL proved equally efficient in restoring growth and in mobilizing energy stores (fat bodies and liver glycogen). No synergistic effects between GH and PRL could be observed. GH exerted its growth-promoting effects by increasing gross food conversion efficiency (weight increase/food intake), but did not stimulate appetite. Moderate GH doses given to a group of frogs in growth stagnation exerted moderate metabolic effects, and may have stimulated appetite in some animals, but did not increase body size significantly. Thyroxine was unable to promote growth, but increased mobilization of energy stores. Hypophysectomy and hormone substitution affected feeding behavior. The nature of the actions of pituitary somatotropic hormones and of thyroxine on growth and deposition is discussed.

  15. Thymic atrophy in acute experimental Chagas disease is associated with an imbalance of stress hormones.

    PubMed

    Lepletier, Ailin; de Frias Carvalho, Vinícius; Morrot, Alexandre; Savino, Wilson

    2012-07-01

    Disorders in the hypothalamic-pituitary-adrenal axis are associated with the pathogenesis of Trypanosoma cruzi infection. During the acute phase of this disease, increased levels of circulating glucocorticoids (GCs) correlate with thymic atrophy. Recently, we demonstrated that this phenomenon is paralleled by a decrease of prolactin (PRL) secretion, another stress hormone that seems to counteract many immunosuppressive effects of GCs. Both GCs and PRL are intrathymically produced and exhibit mutual antagonism through the activation of their respective receptors, GR, and PRLR. Considering that GCs induce apoptosis and inhibit double-positive (DP) thymocyte proliferation and that PRL administration prevents these effects, it seems plausible that a local imbalance of GR-PRLR crosstalk underlies the thymic involution occurring in acute T. cruzi infection. In this respect, preserving PRLR signaling seems to be crucial for protecting DP from GC-induced apoptosis.

  16. Plasma prolactin concentrations in lead exposed workers.

    PubMed

    Govoni, S; Battaini, F; Fernicola, C; Castelletti, L; Trabucchi, M

    1987-01-01

    Plasma Prolactin (Prl) Zinc protoporphyrin (Zpp) and blood lead concentrations (PbB) were measured in 76 exposed male workers. All of them were employed in small (not more than 30 persons) pewter factories and were randomly selected from those regularly controlled by the National Health Service, Occupational Health Unit of Brescia (USSL 41). Although all plasma Prl values were within the normal range, the mean value of the subgroup having Zpp and PbB higher than 40 micrograms/dl was significantly higher (+47%) than that observed in the group of workers having Zpp and PbB less than 40 micrograms/dl. The data indicate the possibility of a lead-induced Prl secretion dysfunction, probably mediated by a decrease in dopaminergic inhibitory control.

  17. The role of prolactin in fish reproduction.

    PubMed

    Whittington, Camilla M; Wilson, Anthony B

    2013-09-15

    Prolactin (PRL) has one of the broadest ranges of functions of any vertebrate hormone, and plays a critical role in regulating aspects of reproduction in widely divergent lineages. However, while PRL structure, mode of action and functions have been well-characterised in mammals, studies of other vertebrate lineages remain incomplete. As the most diverse group of vertebrates, fish offer a particularly valuable model system for the study of the evolution of reproductive endocrine function. Here, we review the current state of knowledge on the role of prolactin in fish reproduction, which extends to migration, reproductive development and cycling, brood care behaviour, pregnancy, and nutrient provisioning to young. We also highlight significant gaps in knowledge and advocate a specific bidirectional research methodology including both observational and manipulative experiments. Focusing research efforts towards the thorough characterisation of a restricted number of reproductively diverse fish models will help to provide the foundation necessary for a more explicitly evolutionary analysis of PRL function.

  18. Transformation of a Microprolactinoma into a Mixed Growth Hormone and Prolactin-Secreting Pituitary Adenoma

    PubMed Central

    Dessimoz, Cédric; Browaeys, Patrick; Maeder, Philippe; Lhermitte, Benoît; Pitteloud, Nelly; Momjian, Shahan; Pralong, François P.

    2012-01-01

    Combined prolactin (PRL) and growth hormone (GH) secretion by a single pituitary tumor can occur in approximately 5% of cases. However, in all previously reported patients, combined secretion of both hormones was present at the time of diagnosis. Here we describe a patient initially diagnosed with a pure prolactin-secreting microadenoma, who experienced the progressive apparition of symptomatic autonomous GH secretion while on intermittent long term dopamine agonist therapy. She was operated on, and immunohistochemical analysis of tumor tissue confirmed the diagnosis of pituitary adenoma with uniform co-staining of all cells for both GH and PRL. This patient represents the first documented occurrence of asynchronous development of combined GH and PRL secretion in a pituitary adenoma. Although pathogenic mechanisms implicated remain largely speculative, it emphasizes the need for long term hormonal follow up of patients harboring prolactinomas. PMID:22654846

  19. Relationship between glucocorticoids and prolactin during mammary gland stimulation in dairy cows.

    PubMed

    Ponchon, B; Zhao, X; Ollier, S; Lacasse, P

    2017-02-01

    The objectives of this study were to determine the role of glucocorticoids in the regulation of prolactin (PRL) release induced by mammary gland stimulation and to investigate whether the milk depression induced by glucocorticoids in dairy cows is due to a decrease in PRL release. In experiment 1, 8 dairy cows were used in a 4 × 4 Latin square design. Four hours after the morning milking, the cows received 1 of the following treatments: (1) a 5-min manual stimulation of the mammary gland; (2) an i.v. injection of 1 mg of dexamethasone; (3) 2 infusions of 2.5 g of metyrapone (an inhibitor of cortisol biosynthesis) in the omasum 4 and 2 h before a 5-min stimulation of the mammary gland; or (4) no treatment. Sixty minutes later, the mammary gland of each cow was stimulated for 5 min. Blood samples were collected from 20 min before to 120 min after the start of the treatment. When the mammary gland was stimulated twice in 60 min, less PRL and cortisol were released during the second stimulation. Metyrapone did not affect PRL or cortisol release. Dexamethasone decreased serum cortisol concentration but did not affect PRL concentration. In experiment 2, 16 cows were used in a crossover experimental design consisting of 2 experimental weeks separated by 1 resting week. During the first week, cows were treated as follows: (1) 4 cows were injected with 0.5 g of domperidone (a PRL secretagogue) in canola oil on d 1 and 2 and 20 mg of dexamethasone on d 1; (2) 4 cows were injected with 0.5 g of domperidone on d 1 and 2; (3) 4 cows were injected with canola oil on d 1 and 2 and with 20 mg of dexamethasone on d 1; and (4) 4 cows were injected with canola oil on d 1 and 2. During the second experimental week, the same 4 treatments were repeated, except the cows that did not receive dexamethasone in the first week received it on d 1 of the second week, and cows that did receive it in the first week did not receive it in the second week. On d 1 and 2 of each week, blood samples

  20. Are clock genes involved in altered circadian rhythms during space flight?

    NASA Astrophysics Data System (ADS)

    Egli, Marcel; Betram, Richard; Cogoli-Greuter, Marianne; Vadrucci, Sonia; Henggeler, Daniele

    2005-08-01

    Hormone secretion in mammals often displays circadian rhythms. These rhythms usually relay on internal "biological clocks", which adjusts to geophysical parameters like the light/dark cycle, temperature cycle, or gravity force, all functioning as time cues. In humans, synchronized external and internal rhythms are important for good performance. This study focuses on the effect of altered gravity on the rhythmic secretory pattern of prolactin (PRL), a hormone of the hypothalamic-pituitary system. Several studies have shown that space flight disturbs PRL secretion. Further, we will investigate the response of clock gene expression in the suprachiasmatic nucleus (SCN), the central circadian pacemaker implicated in the neural network for timed PRL secretion, under various gravitational fields. The results of this study will demonstrate the vulnerability of mammalian endocrine systems to changes in gravity and may help in the design of counter actions for stabilizing circadian rhythms during long-term manned space flight.

  1. Segmentation of x-ray images using Probabilistic Relaxation Labeling

    SciTech Connect

    Thai, T.Q.

    1991-01-01

    Segmentation is a process of separating objects of interest from their background or from other objects in an image. Without a suitable segmentation scheme, it is very difficult to detect contraband in X-rays images. In this paper, a Probabilistic Relaxation Labeling (PRL) segmentation scheme is presented and compared with other segmentation methods. PRL segmentation is an interative algorithm that labels each pixel in an image by cooperative use of two information sources: the pixel probability and the degree of certainty of its probability supported by the neighboring pixels. The practical implementation and results of the PRL segmentation on X-ray baggage images are also discussed and compared with other segmentation methods. 13 refs., 12 figs.

  2. Covalent coupling of bovine growth hormone to its receptor in bovine liver membranes.

    PubMed

    Badinga, L; Collier, R J; Thatcher, W W; Quintana, S J; Bazer, F W

    1987-07-01

    The structure of bovine somatotropin receptor was examined following covalent coupling of iodinated recombinant bovine growth hormone ([125I]rbGH) to bovine liver membrane receptors using ethylene glycol bis(succinimidyl succinate). Iodinated rbGH was incorporated into a complex of estimated Mr of 140,000 under reducing conditions. Excess unlabeled rbGH, but not bovine prolactin (bPRL), inhibited completely the incorporation of [125I]rbGH into the Mr = 140,000 species. In dairy bulls, the Mr = 140,000 complex was undetectable soon after birth but became predominant at 6 months of age. No evidence was found to support presence of bPRL receptors in steer liver membranes. Assuming a 1:1 stoichiometry of hormone binding to receptor, it appears that bGH binds to a major receptor subunit of Mr = 119,000 which does not recognize bPRL.

  3. Plasma concentrations of luteinising hormone, follicle stimulating hormone, androgen, growth hormone, prolactin, thyroxine and triiodothyronine during growth and sexual development in the cockerel.

    PubMed

    Sterling, R J; Sharp, P J; Klandorf, H; Harvey, S; Lea, R W

    1984-07-01

    Changes in concentrations of plasma luteinising hormone (LH), follicle stimulating hormone (FSH), androgen, growth hormone (GH), prolactin (Prl), thyroxine (T4) and triiodothyronine (T3) were measured during growth and sexual maturation in broiler cockerels reared in continuous light to 7 weeks and 14 h light/d thereafter. Concentrations of LH and FSH began to increase between 13 and 15 weeks, while those of androgens increased between 16 and 17 weeks. FSH concentration increased faster than that of LH. Concentrations of GH and Prl were high at 3 weeks; that of GH decreasing progressively between 3 and 14 weeks of age and thereafter remaining low, while that of Prl was low between 5 and 9 weeks, relatively high between 10 and 13 weeks, and then temporarily decreasing before increasing progressively during sexual maturation. Concentrations of T3 and T4 were higher in juvenile than in adult birds.

  4. Activation of GABA B receptors in the anterior pituitary inhibits prolactin and luteinizing hormone secretion.

    PubMed

    Lux-Lantos, V; Rey, E; Libertun, C

    1992-11-01

    Previous work from our laboratory showed that baclofen could lower serum prolactin (PRL) levels acting at the central nervous system. The present experiments were designed to evaluate whether the gamma-aminobutyric acid B agonist was also effective in inhibiting hormone release at the pituitary level. In monolayer cultures of adenohypophyseal dispersed cells, baclofen inhibited basal PRL secretion after 1 or 2 h of incubation. This inhibition was significantly abolished by three antagonists: phaclofen, 3-aminopropyl-phosphonic acid and 4-aminobutylphosphonic acid. Furthermore, baclofen inhibited the thyrotropin-releasing hormone-induced PRL release in a concentration-dependent manner. With regard to gonadotropin secretion, baclofen was unable to modify basal luteinizing hormone (LH) secretion, but significantly inhibited the LH-releasing hormone-induced LH release. These results show that baclofen, in addition to its central neuroendocrine effects, inhibits pituitary hormone secretion, under basal and/or stimulated conditions, by direct action at the pituitary level.

  5. Prolactin levels and autoantibodies in female patients with systemic lupus erythematosus.

    PubMed

    Kozáková, D; Rovenský, J; Cebecauer, L; Bosák, V; Jahnová, E; Vigas, M

    2000-01-01

    We investigated the relationships between prolactin (PRL) levels and antibody occurrence in systemic lupus erythematosus (SLE). No significant association between PRL levels and the majority of the autoantibodies studied (anti-U1 RNP, anti-rRNP, anti-Sm, anti-dsDNA, anti-DNP, auto-LCA, anti-EACA) could be confirmed (P > 0.05), anti-Ro/SSA antibodies being an exception. Our results showed significantly increased frequencies of these antibodies in the group of female SLE patients with normal PRL levels (< 20 micrograms/L): anti Ro/SSA in 53% (P < 0.025, chi 2 = 5.80, RR = 4.0) and anti-Ro/SSA + anti-Ro/La in 60% (P < 0.05, chi 2 = 4.05) compared with female SLE patients with hyperprolactinemia.

  6. Reorganization of visual processing in macular degeneration is not specific to the “preferred retinal locus”

    PubMed Central

    Dilks, Daniel D.; Baker, Chris I.; Peli, Eli; Kanwisher, Nancy

    2009-01-01

    Recent work has shown that foveal cortex, deprived of its normal bottom-up input as a result of macular degeneration (MD), begins responding to stimuli presented to a peripheral retinal location. However, these studies have only presented stimuli to the “preferred retinal location”, or PRL, a spared part of the peripheral retina used by individuals with MD for fixating, face recognition, reading, and other visual tasks. Thus, previous research has not yet answered a question critical for understanding the mechanisms underlying this reorganization: Does formerly foveal cortex respond only to stimuli presented at the PRL, or does it also respond to other peripheral locations of similar eccentricity? If foveal cortex responds to stimuli at PRL because it is the long-term habitual use of this region as a functional fovea that drives the formerly foveal cortex to respond to stimuli presented at the PRL (the “Use-Dependent Reorganization” hypothesis), then foveal cortex will not respond to stimuli presented at other locations. Alternatively, it may be that foveal cortex responds to any peripheral retinal input, independent of whether input at that retinal location has been chronically attended for months or years (the “Use-Independent Reorganization” hypothesis). Using fMRI, we found clear activation of foveal cortex to stimuli presented at either the PRL or an iso-eccentric non-PRL location in two individuals with MD, supporting the Use-Independent Reorganization hypothesis. This finding suggests that reorganization is driven by passive, not use-dependent mechanisms. PMID:19261872

  7. Effect of constant-release melatonin implants and prolonged exposure to a long day photoperiod on prolactin secretion and hair growth in mouflon (Ovis gmelini musimon).

    PubMed

    Santiago-Moreno, J; López-Sebastián, A; del Campo, A; González-Bulnes, A; Picazo, R; Gómez-Brunet, A

    2004-05-01

    The aims of this study were to examine whether mouflons exposed to constant long and short day photoperiods are able to exhibit an annual cycle of hair growth and moult, and prolactin (PRL) secretion. Mouflon ewes were assigned to three groups of treatment. Ewes were maintained, either under natural photoperiod (control, n = 9), or received a series of subcutaneous melatonin implants from December to April (n = 8), or were exposed to a constant long day photoperiod (16-h light:8-h dark; 16L:8D) during 18 months (n = 7). Blood was collected weekly to determine PRL concentrations, and hair samples were clipped weekly from the base of the neck to measure the length of predominant hair. Under constant long days and with melatonin implants, mouflons expressed an annual rhythm of PRL secretion, even though these treatments modified the times of rise or falling of PRL concentrations throughout the year. Hair growth initiation was almost coincident with the summer solstice in both control and melatonin-implanted mouflons but occurred two months earlier in long day hold mouflons (P < 0.001). Long day hold mouflons had a lower hair growth rate than control and melatonin-implanted mouflons (P < 0.001), and at the end of the experiment, a shorter hair length (3.4 +/- 0.24 cm; P < 0.01) than control (4.3 +/- 0.17 cm), and melatonin-implanted mouflons (4.2 +/- 0.12 cm). Our data support the conclusion that in mouflon, an endogenous circannual rhythm of PRL secretion exists, and that the seasonal cycle of hair growth and moult appears to depend, at least in part, on circulating levels of PRL.

  8. Pituitary regulation of corpus luteum progesterone secretion in cyclic rats.

    PubMed

    Sánchez-Criado, J E; López, F; Aguilar, E

    1986-09-01

    Pituitary LH and PRL secretion during the early postovulatory period of the rat estrous cycle seem to affect the corpus luteum (CL) autonomy to secrete progesterone. Thus, while PRL would act luteotropically, LH would be luteolytic. To further investigate these facts, 4-day cyclic rats, treated with either 1 mg bromocriptine (CB) or 0.25 ml 70% ethanol (ETOH) at 1600 h on estrus, were injected with 0.5 ml of either an anti-LH serum (LHAS) or normal horse serum (NHS) at 0800 h on metestrus. Rats treated at 0800 h on metestrus with both, CB and LHAS, were also used. To verify through a different procedure the effect of LH and/or PRL deprivation in estrous cycle CL progesterone secretion, hypophysectomy (HYPOX) and sham HYPOX (SHAM) were done at 0800 h on metestrus in either CB- or ETOH-injected rats at 1600 h on estrus. Hypophysectomized rats at 1600 h on estrus were also used. Progesterone secretion was prolonged up to 0800 h on diestrus in those rats deprived of LH from 0800 h on metestrus (ETOH/LHAS, -/CB + LHAS, ETOH/HYPOX) compared with controls (ETOH/NHS, ETOH/SHAM). This luteotropic effect was absent in those rats lacking estrous afternoon PRL (CB/LHAS, CB/HYPOX, HYPOX/-). No effect on CL progesterone secretion was detected in those rats exclusively deprived of PRL on the afternoon of estrus (CB/NHS, CB/SHAM). These results suggest that in the absence of the protective effects of PRL secretion on the afternoon of estrus, rat CL become extremely sensitive to the luteolytic effects of early diestrous LH levels, and this results in 4-day estrous cycles.

  9. Role of Estradiol in the Regulation of Prolactin Secretion During Late Pregnancy.

    PubMed

    Villegas-Gabutti, Carlos; Pennacchio, Gisela E; Jahn, Graciela A; Soaje, Marta

    2016-12-01

    Estrogen action is necessary for evidencing the stimulatory action of mifepristone and naloxone on prolactin (PRL) secretion during late pregnancy. Our aim is to determine the mechanism mediating this facilitator action of estrogens. To investigate the hypothalamic mechanisms involved in estrogen actions in PRL secretion at the end of pregnancy, we measured the effect of pretreatment with the estrogen antagonist tamoxifen on the expression of tyrosine hydroxylase (TH), hormone receptors (ERα and β, PRs, PRLR(long)), and μ- and κ- opioid receptors (ORs) at mRNA (by semiquantitative RT-PCR) and protein (by western blot for TH, PRLR(long), ERα, PRs, μ- and ORs) levels in extracts of medial basal hypothalamus (MBH) and serum PRL, E2 and P4 levels (by RIA) in mifepristone- and naloxone-treated rats. Tamoxifen administration partially prevented PRL release induced by the combined treatment. TH expression diminished and ERα expression increased in mifepristone-treated rats at mRNA and protein levels and tamoxifen partially prevented these changes with no effect on PRs expression. Mifepristone increased PRLR(long) mRNA levels; this increase was blocked by tamoxifen. Combined tamoxifen and mifepristone treatment decreased μ- and k-ORs mRNA but not protein levels. In conclusion, E2 induces neuroadaptive mechanisms necessary to facilitate PRL release preceding delivery. Acting through ERα, E2 modulates hypothalamic dopaminergic neurons activity, regulating TH, μ- and κ-ORs and PRLR(long) expression, and is necessary for evidencing the effects of P4 withdrawal. Its presence on days 14 and 15 of pregnancy is crucial to facilitate the opioid system modulation of PRL secretion at the end of pregnancy in the rat.

  10. Is a stable or decreasing prolactin level in a patient with prolactinoma a surrogate marker for lack of tumor growth?

    PubMed

    Alkabbani, Abdulrahman G; Mon, Sann Y; Hatipoglu, Betul; Kennedy, Laurence; Faiman, Charles; Weil, Robert J; Hamrahian, Amir H

    2014-04-01

    The optimal interval for follow-up imaging of patients with prolactinomas is unclear. We wish to determine the likelihood of tumor enlargement in patients with prolactinomas who have a stable or reduced prolactin (PRL) level over time, whether or not they are treated with a dopamine agonist (DA). We identified 80 patients with prolactinomas (34 men, 46 women) who had at least two paired sets of serum PRL levels and pituitary MRIs, 3 or more months apart. Patients with hyperprolactinemia due to drug or stalk effects were excluded. The median (range) age was 45 (25-77) years. Sixty-three patients (78.8%) were treated with DA. PRL levels (ng/mL) at the initial and latest sets were 114 (0.3-15,732) and 16 (0.3-1,204), respectively. In patients with identifiable tumors, the maximum tumor diameters (mm) at the initial and latest MRI studies were 12.5 (2-60) and 12.5 (2-39) respectively, with an interval of 2.9 (0.3-9.7) years. Sixty percent of patients (n = 48) had a macroadenoma. Forty-two (52.5%) patients had either disappearance of the tumor (n = 22) or reduction (n = 20) in tumor size. In the remainder, tumor size was stable in 35 but increased in 3 patients. One of these patients, observed off therapy had a concomitant rise in PRL level. The other 2 had evidence of pituitary hemorrhage with no PRL increase. Tumor growth in prolactinoma patients with a stable or decreasing PRL level, regardless of size, is a rare event. Repetitive pituitary imaging in these patients may not be warranted.

  11. Prolactin, TNF alpha and nitric oxide expression in nitroso-N-methylurea-induced-mammary tumours

    PubMed Central

    Vegh, Irene; de Salamanca, Rafael Enríquez

    2007-01-01

    Background The N-Nitrosomethylurea breast cancer model induced in rats is used for the study of carcinogenesis in mammary cancer, prostate, pancreas, etc. This model is very similar to human neoplastic disease. Methods The present experimental study was designed to assess whether metoclopramide administration has any effect on development of MNU-induced tumours, and evaluate the treatment of goserelin acetate on PRL, TNF alpha and NO expression. NMU was administered to female Wistar rats on 2 occasions (5 mg/100 g body w/rat). PRL and TNF alpha were performed by immune-assay. Nitric Oxide by semi automated-assay and ploidy analyses by flow cytometry. Results The administration of metoclopramide made the induction time shorter and increased the incidence and average of tumours per rat. Tumours development was inhibited by a goserelin chronic administration. The ploidy of adenocarcinoma was polyploid-aneuploid type (average S = 60%). It was higher basal PRL plasma levels in rats with NMU induced tumours than in basal controls without tumour (p < 0.001). The goserelin "in bolus" administration showed maximal inhibition of plasma PRL at 90 min. Plasmatic TNF alpha expression was inhibited at 60 min and also remained inhibited in tissue homogenate post chronic treatment (P < 0.0125). Plasmatic NO expression is higher in rats with induced tumours than healthy controls (P < 0.001). In tissue homogenate NO values were inhibited at 90 min (P < 0.01), as well during chronically goserelin treatment (P < 0.005). Conclusion The increase of blood PRL levels in NMU-induced rats may be an indicator of a poor prognosis of mammary cancer evolution. The metoclopramide administration accelerates tumour growth. However goserelin administration achieves regression in tumour development associated to inhibition PRL, TNF alpha and NO expression. PMID:18045456

  12. Varenicline, the clinically effective smoking cessation agent, restores probabilistic response reversal performance during withdrawal from nicotine.

    PubMed

    Jackson, Anne; Silk, Sarah; Buhidma, Yazead; Shoaib, Mohammed

    2016-07-20

    There is recognition that cognitive problems can contribute to renewed drug taking in former addicts. Our previous work has indicated that current smokers show reduced performance on a probabilistic reversal learning (PRL) task, relative to former smokers. To further explore PRL performance and its relevance to smoking, in addition to the role of nicotine, we developed a model of nicotine withdrawal-induced deficits in rodents. A second goal was to test varenicline, an α4β2 partial agonist, for its ability to restore any cognitive impairment. Acute effects of nicotine and varenicline on PRL performance in non-dependent animals were minimal and confined to speed of responding. When rats were made dependent on nicotine via osmotic minipumps implanted for 7 days (3.16 mg/kg/day), repeated tests at specified withdrawal time points revealed PRL disruption peaking at 12 and 24 hours following surgical removal of minipumps. Withdrawal was characterized by significant deficits in the number of reversals (P < 0.05), speed of responding (P < 0.01) and increases in omissions (P < 0.05). Nicotine (0.2 mg/kg SC) or varenicline (0.3 and 1.0 mg/kg SC) administered 10-minute prior to PRL test sessions during withdrawal, relieved the performance deficits. At 24-hour withdrawal, nicotine and varenicline (1 mg/kg) prevented decrements in reversals, in addition to ameliorating slower speed of responding. The high dose of varenicline only reduced omissions. These results confirm the role of nicotine in withdrawal-induced disruption of PRL performance and suggest that the model may be useful for investigating efficacy of potential new treatments for smoking cessation.

  13. The LIM homeobox protein mLIM3/Lhx3 induces expression of the prolactin gene by a Pit-1/GHF-1-independent pathway in corticotroph AtT20 cells.

    PubMed

    Girardin, S E; Benjannet, S; Barale, J C; Chrétien, M; Seidah, N G

    1998-07-24

    mLIM3, a member of the LIM homeobox family, was recently demonstrated to be critical for proliferation and differentiation of the pituitary cell lineage. Using a pool of degenerate oligonucleotides we determined the DNA sequence ANNAGGAAA(T/C)GA(CIG)AA as the set preferentially recognized by mLIM3. A nearly identical sequence is found in the prolactin (PRL) promoter, within a 15-mer stretch from nucleotides (nts) -218 to -204 which is highly conserved between human, rat, and bovine. In order to test the hypothesis of a transcriptional effect of mLIM3 on the prolactin promoter, stable transfectants of mLIM3 cDNA in AtT20 tumor cells revealed that PRL mRNA expression was induced in 3 separate stable clones. Gel retardation experiments performed using nuclear extracts isolated from one of the AtT20/mLIM3 stable transfectants revealed affinity towards the 15-mer element of the PRL promoter. From these results, we propose that the PRL promoter element (nts -218 to -204) could be functional in vivo. Finally, we demonstrate that in AtT20 cells prolactin mRNA expression is not induced by the Pit-1/GHF-1 pathway and that growth hormone mRNA is not detected concomitantly with prolactin. We conclude that mLIM3 may play a key role in inducing PRL gene expression in lactotrophs by binding to a conserved motif close to a Pit-1/GHF-1 site within the proximal PRL promoter.

  14. Effects of cabergoline on hyperprolactinemia, psychopathology, and sexual functioning in schizophrenic patients.

    PubMed

    Kalkavoura, Christina S; Michopoulos, Ioannis; Arvanitakis, Periklis; Theodoropoulou, Pitsa; Dimopoulou, Konstantina; Tzebelikos, Errikos; Lykouras, Lefteris

    2013-08-01

    Antipsychotic medications are associated to different degrees with sexual dysfunction mainly through their potential to induce hyperprolactinemia. Prolactin (PRL) secretion is mainly regulated by the hypothalamic dopaminergic systems. We conducted this 6-month, parallel-group study to prospectively investigate the effects of the dopamine agonist cabergoline on sexual dysfunction in clinically stable patients with schizophrenia (DSM-IV, AP 194) and hyperprolactinemia (PRL > 20 ng/ml for men and PRL > 25 ng/ml for women). In total 80 patients were enrolled; 33 were receiving risperidone, 17 haloperidol, 11 amisulpride, and 8 risperidone microspheres long acting. Based on PRL levels (< 50, 50-99, or > 100 ng/ml), patients were assigned in 3 cabergoline doses (0.25, 0.5, and 1 mg/day in 38, 23, and 19 patients, respectively). The psychopathology was evaluated using the Positive and Negative Syndrom Scale (PANSS), and sexual dysfunction was evaluated using the Arizona Sexual Experiences Scale (ASEX). PRL levels were reduced in all patients, from 73.3 (± 46.8) to 42.0 (± 27.8) at Month 3 and 27.1 (± 20.4) at Month 6 (p < .001). ASEX scores declined from 19.1 (± 5.1) to 17.6 (± 5.5) at Month 3 and 15.0 (± 6.5) at Month 6 (p < .001). PANSS scores were reduced in the third and in the sixth month (p = .001 at 6 month vs. baseline). The decrease in PRL was not statistically different between groups. Our data suggest that cabergoline administration to clinically stable patients with schizophrenia may improve sexual functioning without adversely affecting their psychopathologic status, provided that the dose has been suited to the severity of the hyperprolactinemia.

  15. Subregional differences in the generation of fast network oscillations in the rat medial prefrontal cortex (mPFC) in vitro

    PubMed Central

    Glykos, Vasileios; Whittington, Miles A; LeBeau, Fiona E N

    2015-01-01

    Fast network oscillations in the beta (20–30 Hz) and low gamma (30–80 Hz) range underlie higher cognitive functions associated with the medial prefrontal cortex (mPFC) including attention and working memory. Using a combination of kainate (KA, 200 nm) and the cholinergic agonist carbachol (Cb, 10 μm) fast network oscillations, in the beta frequency range, were evoked in the rat mPFC in vitro. Oscillations were elicited in the prelimbic (PrL), infralimbic (IL) and the dorsopeduncular (DP) cortex, with the largest oscillations observed in DP cortex. Oscillations in both the PrL and DP were dependent, with slightly different sensitivities, on γ-aminobutyric acid (GABA)A, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, but only oscillations in the DP were significantly reduced by N-methyl-d-aspartate (NMDA) receptor blockade. Intracellular recordings showed that 9/20 regular spiking (RS) cells in the PrL exhibited a notable cAMP-dependent hyperpolarisation activated current (Ih) in contrast to 16/17 in the DP cortex. Extracellular single unit recordings showed that the majority of cells in the PrL, and DP regions had interspike firing frequencies (IFFs) at beta (20–30 Hz) frequencies and fired at the peak negativity of the field oscillation. Recordings in DP revealed presumed inhibitory postsynaptic potentials (IPSPs) that were larger in amplitude and more rhythmic than those in the PrL region. Our data suggest that each PFC subregion may be capable of generating distinct patterns of network activity with different cell types involved. Variation in the properties of oscillations evoked in the PrL and DP probably reflects the distinct functional roles of these different PFC regions. PMID:26041504

  16. Identification and partial characterization of a prolactin-like hormone produced by rat decidual tissue.

    PubMed Central

    Jayatilak, P G; Glaser, L A; Basuray, R; Kelly, P A; Gibori, G

    1985-01-01

    Previous studies have strongly, but indirectly, suggested that rat decidual tissue produces a prolactin-like hormone, decidual luteotropin, which markedly affects luteal cell function. However, it was also found that extracts of decidual tissue do not cross-react with antisera to either rat or ovine prolactin (PRL). The purpose of this study was to determine whether the decidual tissue contains a substance that binds to PRL receptors in rat luteal membranes and, if so, to identify, quantitate, and characterize this molecule with the use of an ovarian radioreceptor assay. Decidual tissue was induced in day 5 pseudopregnant rats by scratching the antimesometrial wall of the uterus; it was collected on day 9 and homogenized and extracted. Decidual tissue extracts bound specifically to ovarian PRL receptors. Graded dilutions of the extracts yielded curves that were parallel to the ovine PRL standard, indicating that decidual luteotropin competes for the same receptor sites on rat luteal membranes. To determine the levels of decidual luteotropin throughout pseudopregnancy, decidual tissue was obtained on each day between days 6-12. The PRL-like activity was detectable in decidual tissue as early as day 6, reached a maximum on day 9, and declined thereafter. The elution profile obtained from gel filtration of a day 9 decidual tissue extract displayed a major component of decidual luteotropin eluting at a Ve/Vo ratio of approximately equal to 2.0. Column chromatography indicated that decidual luteotropin corresponds to a protein with a molecular weight of 23,500. The hormone was heat labile, digestible by trypsin, and appears to contain disulfide linkages. In summary, this study reports the identification, quantitation, and partial characterization of a PRL-like hormone produced by the decidual tissue of the rat. Images PMID:2982145

  17. Somatotropic, lactotropic and adrenocortical responses to insulin-induced hypoglycemia in patients with rheumatoid arthritis.

    PubMed

    Rovensky, Jozef; Bakosová, Jana; Koska, Juraj; Ksinantová, Lucia; Jezová, Daniela; Vigas, Milan

    2002-06-01

    Neuroendocrine mechanisms have been suggested to play an important role in the onset and progression of rheumatoid arthritis (RA). The aim of this study was to evaluate hypothalamic-pituitary functions in RA patients by measurement of hormone responses to insulin-induced hypoglycemia. Insulin-hypoglycemia (Actrapid HM 0.1 IU/kg, i.v. as a bolus) was induced in 17 male patients and in 11 age-, gender-, and weight-matched healthy subjects. Concentrations of growth hormone (GH), prolactin (PRL) and cortisol were analyzed in plasma. PRL release after thyreoliberin stimulation (TRH, 200 g, i.v.) was determined in 21 patients with active forms of RA and in 12 control subjects to evaluate pituitary lactotropic response. In RA patients, basal concentrations of glucose, GH, PRL, and cortisol were in the normal range and they were comparable to those in the control group. Stress of hypoglycemia induced significant elevation of GH, PRL, and cortisol concentrations in all groups. Cortisol responses to hypoglycemia were comparable in patients and in control subjects. GH release during hypoglycemia was increased (p < 0.05) and PRL response was attenuated (p < 0.05) in RA patients versus control subjects. After TRH administration, PRL response was the same in patients as in healthy subjects. In conclusion, the present study revealed an altered hypothalamic-pituitary function in patients with RA, namely, an enhanced somatotropic and reduced lactotropic activation in response to insulin-induced hypoglycemia. Basal hormone levels and cortisol release during hypoglycemia were similar to those in healthy subjects.

  18. The osmoregulatory effects of rearing Mozambique tilapia in a tidally changing salinity.

    PubMed

    Moorman, Benjamin P; Inokuchi, Mayu; Yamaguchi, Yoko; Lerner, Darren T; Grau, E Gordon; Seale, Andre P

    2014-10-01

    The native distribution of Mozambique tilapia, Oreochromis mossambicus, is characterized by estuarine areas subject to salinity variations between fresh water (FW) and seawater (SW) with tidal frequency. Osmoregulation in the face of changing environmental salinity is largely mediated through the neuroendocrine system and involves the activation of ion uptake and extrusion mechanisms in osmoregulatory tissues. We compared plasma osmolality, plasma prolactin (PRL), pituitary PRL mRNA, and mRNA of branchial ion pumps, transporters, channels, and PRL receptors in tilapia reared in FW, SW, brackish water (BW) and in tidally-changing salinity, which varied between FW (TF) and SW (TS) every 6h. Plasma PRL was higher in FW tilapia than in SW, BW, TF, and TS tilapia. Unlike tilapia reared in FW or SW, fish in salinities that varied tidally showed no correlation between plasma osmolality and PRL. In FW fish, gene expression of PRL receptor 1 (PRLR1), Na(+)/Cl(-) cotransporter (NCC), aquaporin 3 (AQP3) and two isoforms of Na(+)/K(+)-ATPase (NKA α1a and NKA α1b) was higher than that of SW, BW or tidally-changing salinity fish. Gene expression of the Na(+)/K(+)/2Cl(-) cotransporter (NKCC1a), and the cystic fibrosis transmembrane conductance regulator (CFTR) were higher in fish in SW, BW or a tidally-changing salinity than in FW fish. Immunocytochemistry revealed that ionocytes of fish in tidally-changing salinities resemble ionocytes of SW fish. This study indicated that tilapia reared in a tidally-changing salinity can compensate for large changes in external osmolality while maintaining osmoregulatory parameters within a narrow range closer to that observed in SW-acclimated fish.

  19. Epithelial defect in prostates of Stat5a-null mice.

    PubMed

    Nevalainen, M T; Ahonen, T J; Yamashita, H; Chandrashekar, V; Bartke, A; Grimley, P M; Robinson, G W; Hennighausen, L; Rui, H

    2000-07-01

    The transcription factor Stat5a critically mediates prolactin (PRL)-induced mammary gland development and lactogenesis. PRL also stimulates growth and differentiation of prostate tissue. Specifically, hyperprolactinemia gives rise to prostate hyperplasia, and prostate size is reduced in PRL-deficient mice. We therefore investigated the importance of Stat5a for prostate development and function by examining Stat5a-null mice. The absence of Stat5a in mice was associated with a distinct prostate morphology characterized by an increased prevalence of local disorganization within acinar epithelium of ventral prostates. Affected acini were typically filled with desquamated, granular epithelial cells that had become embedded in dense, coagulated secretory material. These features were reminiscent of acinar cyst formation and degeneration frequently observed in human benign prostate hyperplasia, however, cystic changes in prostate acini of Stat5a-deficient mice were not associated with increased prostate size or morphologic hallmarks of epithelial hyperplasia. Instead, immunohistochemistry of the prostate-specific secretory marker, probasin, suggested that hypersecretory function of the epithelium could underlie local congestion and cyst formation in prostates of Stat5a-null mice. Serum testosterone and PRL levels were normal in Stat5a knockout mice, but prostate PRL receptor expression was reduced as determined by immunohistochemistry. Expression levels or activation states of other PRL signal transduction proteins, including Stat5b, Stat3, Stat1, ERK1, and ERK2 were not altered. The present study offers the first evidence for a direct role of Stat5a in the maintenance of normal tissue architecture and function of the mouse prostate.

  20. Early postnatal administration of growth hormone increases tuberoinfundibular dopaminergic neuron numbers in Ames dwarf mice.

    PubMed

    Khodr, Christina E; Clark, Sara; Bokov, Alex F; Richardson, Arlan; Strong, Randy; Hurley, David L; Phelps, Carol J

    2010-07-01

    Hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons secrete dopamine, which inhibits pituitary prolactin (PRL) secretion. PRL has demonstrated neurotrophic effects on TIDA neuron development in PRL-, GH-, and TSH-deficient Ames (df/df) and Snell (dw/dw) dwarf mice. However, both PRL and PRL receptor knockout mice exhibit normal-sized TIDA neuron numbers, implying GH and/or TSH influence TIDA neuron development. The current study investigated the effect of porcine (p) GH on TIDA neuron development in Ames dwarf hypothalamus. Normal (DF/df) and dwarf mice were treated daily with pGH or saline beginning at 3 d of age for a period of 42 d. After treatment, brains were analyzed using catecholamine histofluorescence, tyrosine hydroxylase immunocytochemistry, and bromodeoxyuridine (BrdU) immunocytochemistry to detect BrdU incorporation. DF/df males and df/df treated with pGH experienced increased (P PRL, and likely GH-induced preservation of TIDA neurons rather than generation of new TIDA neurons via neurogenesis.

  1. Electrophoretic separation of kidney and pituitary cells on STS-8

    NASA Technical Reports Server (NTRS)

    Morrison, D. R.; Nachtwey, D. S.; Barlow, G. H.; Cleveland, C.; Lanham, J. W.; Farrington, M. A.; Hatfield, J. M.; Hymer, W. C.; Grindeland, R.; Lewis, M. L.

    1984-01-01

    Specific secretory cells were separated from suspensions of cultured primary human embryonic cells and rat pituitary cells in microgravity conditions, with an objective of isolating the subfractions of kidney cells that produce the largest amount of urakinase, and the subfractions of rat pituitary cells that secrete growth hormones (GH), prolactin (PRL), and other hormones. It is inferred from the experimental observations that the surface charge distributions of the GH-containing cells differ from those of the PRL-containing cells, which is explained by the presence of secretory products on the surface of pituitary cells. For kidney cells, the electrophoretic mobility distributions in flight experiments were spread more than the ground controls.

  2. Comparing Extremal and Hysteretic Optimization on the Satisfiability Problem

    NASA Astrophysics Data System (ADS)

    Gonçalves, Bruno; Boettcher, Stefan

    2006-03-01

    We apply physically inspired optimization methods to the classical combinatorial Satisfiablity problem. Treating the usual boolean variables as Ising spins and each clause as a p-spin interaction we can use the pre-existing physical intuition about spin glasses and magnetic systems to find the optimal solution for this problem (the ground state energy). We compare the performance of Extremal OptimizationootnotetextPRL 23:5211, 2001 (τEO) and Hysteretic OptimizationootnotetextPRL 89:150201, 2002 (HO) and determine the parameter values that provide the best results. Comparisons with previously published results on well known benchmarksootnotetextDIMACS 35:393, 1997 are also made.

  3. The response of serum growth hormone and prolactin to training in weight-maintaining healthy males.

    PubMed

    Hurley, R S; Bossetti, B M; O'Dorisio, T M; Welch, M A; Rice, R R; Tenison, E B; Wasson, C J; Malarkey, W B

    1990-03-01

    Resting levels of serum growth hormone (GH) and prolactin (PRL) were measured pretraining, 3 weeks and 10 weeks posttraining in seven college age males. The exercise consisted of thrice weekly sessions at 70% VO2max for 20 minutes plus warmup and cool down. Body weight remained constant during the ten week training period. However, body fat decreased significantly. Resting daytime levels of GH decreased significantly with training while resting PRL levels were unchanged. The hormone responses suggest attenuation of resting GH levels with training and may relate to changes in body fat.

  4. Convergent evolution of endometrial prolactin expression in primates, mice, and elephants through the independent recruitment of transposable elements.

    PubMed

    Emera, Deena; Casola, Claudio; Lynch, Vincent J; Wildman, Derek E; Agnew, Dalen; Wagner, Günter P

    2012-01-01

    Prolactin (PRL) is a multifunctional signaling molecule best known for its role in regulating lactation in mammals. Systemic PRL is produced by the anterior pituitary, but extrapituitary PRL has also been detected in many tissues including the human endometrium. Prolactin is essential for pregnancy in rodents and one of the most dramatically induced genes in the endometrium during human pregnancy. The promoter for human endometrial Prl is located about 5.8 kb upstream of the pituitary promoter and is derived from a transposable element called MER39. Although it has been shown that prolactin is expressed in the pregnant endometrium of a few mammals other than humans, MER39 has been described as primate specific. Thus, in an effort to understand mechanisms of prolactin regulatory evolution, we sought to determine how uterine prolactin is transcribed in species that lack MER39. Using a variety of complementary strategies, including reverse transcriptase-polymerase chain reaction, 5' rapid amplification of cDNA ends, and whole-transcriptome sequencing, we show that endometrial Prl expression is not a shared character of all placental mammals, as it is not expressed in rabbits, pigs, dogs, or armadillos. We show that in primates, mice, and elephants, prolactin mRNA is transcribed in the pregnant endometrium from alternative promoters, different from the pituitary promoter and different from each other. Moreover, we demonstrate that the spider monkey promoter derives from the long terminal repeat (LTR) element MER39 as in humans, the mouse promoter derives from the LTR element MER77, and the elephant promoter derives from the lineage-specific LINE retrotransposon L1-2_LA. We also find surprising variation of transcriptional start sites within these transposable elements and of Prl splice variants, suggesting a high degree of flexibility in the promoter architecture even among closely related species. Finally, the three groups shown here to express endometrial prolactin

  5. The neural underpinnings of cognitive flexibility and their disruption in psychotic illness.

    PubMed

    Waltz, James A

    2017-03-14

    Schizophrenia (SZ) has long been associated with a variety of cognitive deficits, including reduced cognitive flexibility. More recent findings, however, point to tremendous inter-individual variability among patients on measures of cognitive flexibility/set-shifting. With an eye toward shedding light on potential sources of variability in set-shifting abilities among SZ patients, I examine the neural substrates of underlying probabilistic reversal learning (PRL) - a paradigmatic measure of cognitive flexibility - as well as neuromodulatory influences upon these systems. Finally, I report on behavioral and neuroimaging studies of PRL in SZ patients, discussing the potentially influences of illness profile and antipsychotic medications on cognitive flexibility in SZ.

  6. Presence and possible site of action of secretin in the rat pituitary and hypothalamus

    SciTech Connect

    Samson, W.K.; Lumpkin, M.D.; McCann, S.M.

    1984-01-09

    Secretin-like immunoreactivity was detected in extracts of several rat brain structures by radioimmunoassay, most notably in the pituitary, hypothalamus, pineal and septum. Its localization to these structures suggested that it might play a role in neuroendocrine events similar to its structural homolog vasoactive intestinal peptide. Dose-related stimulations (MED, 10/sup -7/ M) of prolactin (PRL) release were observed after incubation of synthetic secretin with dispersed, cultured pituitary cells from male and ovariectomized (OVX) female rats. Secretin can now be added to the growing list of putative PRL-releasing agents.

  7. A STUDY OF SERUM PROLACTIN AND PLASMA HUMAN GROWTH HORMONE IN MALE ALCOHOLICS

    PubMed Central

    Sengupta, Somnath; Ray, Rajat; Desai, Nimesh; Shetty, K. Taranath

    1997-01-01

    Serum levels of prolactin (PRL) and Human Growth Hormone (HGH) were assayed in 38 male alcoholics and 24 male control subjects using radioimmunoassay (RIA) technique. Biochemical parameters of hepatic function and severity of withdrawal state were also assessed. Significantly elevated values of plasma HGH were found in alcoholics as a group. Nineteen percent and eight percent of the patient had elevated serum PRL and HGH levels respectively. Evidence of advanced liver disease was scant and withdrawal symptoms were by and large mild. The findings indicate a dysfunction in hypothalamic adenohypophyseal axis in a subgroup of alcoholics. PMID:21584040

  8. Technology for return of planetary samples

    NASA Technical Reports Server (NTRS)

    1975-01-01

    Technological requirements of a planetary return sample mission were studied. The state-of-the-art for problems unique to this class of missions was assessed and technological gaps were identified. The problem areas where significant advancement of the state-of-the-art is required are: life support for the exobiota during the return trip and within the Planetary Receiving Laboratory (PRL); biohazard assessment and control technology; and quarantine qualified handling and experimentation methods and equipment for studying the returned sample in the PRL. Concepts for solving these problems are discussed.

  9. Advanced Solid-State Lasers, Twelfth Topical Meeting (1997) Held in Orlando, Florida on January 27-29, 1997

    DTIC Science & Technology

    1997-01-01

    sers, (p. 74) VI MONDAY JANUARY 27, 1997 2:15pm MD4 • 7-12 pm generation using a Cr,Er:YSGG pump laser and CdSe and ZnGeP2 OPOs, Toomas H...Rich- ard Utano, US Army CECOM. 2.79 pm Cr,Er:YSGG pumping of a CdSe OPO yielded a 59% slope efficiency (r|) and 1.2-2.4 mj idler output between 8.5...3 4 5 6 7 Average diode power (W) MD4-1/77 7 -12 ^irn generation using a Cr,Er:YSGG pump laser and CdSe and ZnGeP2 OPOs Toomas H. Allik

  10. In vitro modulation of prolactin mRNA by toxaphene and 3,3',4,4'-tetrachlorobiphenyl.

    PubMed

    Graham, Meghan; Cossette, Louis; Gélinas, Sylvie; Martinoli, Maria Grazia

    2003-07-01

    It is now well recognized that many environmental contaminants are capable of disrupting endocrine processes in a variety of species, including birds, mammals, reptiles, and fish. Among these contaminants are toxaphene and polychlorinated biphenyls (PCBs), two of the most prevalent contaminants present in aquatic food chains of the Great Lakes and the Canadian Arctic region. We set out to investigate the possible endocrine-modulating activities of toxaphene, the PCB congener 3,3',4,4'-tetrachlorobiphenyl (TeCB), an equimolar mixture of both compounds (toxaphene/TeCB), and estradiol (E(2)) (E(2)/toxaphene, E(2)/TeCB) on prolactin (PRL) mRNA expression. Concentrations ranging from 10(-7) to 10(-11)M for both toxaphene and TeCB were assayed but only toxaphene modulated PRL mRNA levels, as determined by relative quantitative reverse transcriptase-polymerase chain reaction. Maximal induction by toxaphene was seen at 10(-7)M, resulting in a fourfold increase in PRL mRNA levels. No interactions were observed for combinations of the test substances. Our study demonstrates that toxaphene may exhibit estrogen-like activity by modulating PRL mRNA levels in GH(3) cells.

  11. Seasonal Expression of Prolactin Receptor in the Scented Gland of Male Muskrat (Ondatra zibethicus).

    PubMed

    Cao, Han; Wang, Liang; Zhang, Shuo; Lu, Lu; Sheng, Xia; Han, Yingying; Yuan, Zhengrong; Weng, Qiang

    2015-10-19

    Prolactin (PRL) has numerous actions in mammalian biological systems including mammary development and biological processes. The aim of this study was to investigate the seasonal changes of prolactin receptor (PRLR) expression in the scented gland of muskrat during the breeding and nonbreeding seasons. Histologically, glandular cells, interstitial cells and excretory tubules were identified in the scented glands in both seasons, whereas epithelial cells were sparse in the nonbreeding season. PRLR was observed in glandular cells of scented glands during the breeding and nonbreeding seasons with stronger immunostaining during the breeding season. Consistent with the immunohistochemical results, both the mean of protein and mRNA levels of PRLR were higher in the scented glands of the breeding season, and relatively lower level in the nonbreeding season. In addition, differential seasonal changes were also detected in the expression profile of microRNAs (miRNAs) in the scented gland of muskrat. Besides, plasma PRL concentration was remarkably higher in the breeding season than that in the nonbreeding season. These results suggested that muskrat scented gland was the direct target organ of PRL, and stronger expression of PRLR in scented glands during the breeding season indicated that PRL may directly regulate scented glandular function of the muskrats.

  12. Increased milk production by Holstein cows consuming endophyte-infected fescue seed during the dry period.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ergot alkaloids in endophyte-infected grasses inhibit prolactin (PRL) secretion and may reduce milk production of cows consuming endophyte-infected grasses. We hypothesized that consumption of endophyte-infected fescue during the dry period inhibits mammary differentiation and subsequent milk produ...

  13. Prolactin and breast cancer: The need to avoid undertreatment of serious psychiatric illnesses in breast cancer patients: A review.

    PubMed

    Froes Brandao, Denise; Strasser-Weippl, Kathrin; Goss, Paul E

    2016-01-15

    Hyperprolactinemia, defined as a sustained elevation of prolactin (PRL) levels greater than 530 mIU/L in women and greater than 424 mIU/L in men, has been implicated for a long time in breast cancer etiology and prognosis. Elevated PRL values (approximately 2-3 times higher than the reference values) are a common adverse effect of antipsychotic medications, especially with first-generation drugs, and most antipsychotics carry a standard warning regarding PRL elevations on their US product labels. These associations foster undertreatment of serious psychiatric illnesses in both otherwise healthy patients and cancer patients. This review assesses both the preclinical and clinical evidence that has led to the hypothesis of PRL's role in breast cancer risk or breast cancer progression. It is concluded that taken together, the published data are unconvincing and insufficient to deprive cancer patients in general and breast cancer patients specifically of potentially effective antipsychotic or antidepressant medications for serious psychiatric indications. We thus call on revised medication guidelines to avoid the existing undertreatment of serious psychiatric illnesses among cancer patients based on an unproven contraindication to psychiatric medications. Cancer 2016;122:184-188. © 2015 American Cancer Society.

  14. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy.

    PubMed

    Halkein, Julie; Tabruyn, Sebastien P; Ricke-Hoch, Melanie; Haghikia, Arash; Nguyen, Ngoc-Quynh-Nhu; Scherr, Michaela; Castermans, Karolien; Malvaux, Ludovic; Lambert, Vincent; Thiry, Marc; Sliwa, Karen; Noel, Agnes; Martial, Joseph A; Hilfiker-Kleiner, Denise; Struman, Ingrid

    2013-05-01

    Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found that 16K PRL induced microRNA-146a (miR-146a) expression in ECs, which attenuated angiogenesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a-loaded exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a levels, which resulted in a subsequent decrease in metabolic activity and decreased expression of Erbb4, Notch1, and Irak1. Mice with cardiomyocyte-restricted Stat3 knockout (CKO mice) exhibited a PPCM-like phenotype and displayed increased cardiac miR-146a expression with coincident downregulation of Erbb4, Nras, Notch1, and Irak1. Blocking miR-146a with locked nucleic acids or antago-miRs attenuated PPCM in CKO mice without interrupting full-length prolactin signaling, as indicated by normal nursing activities. Finally, miR-146a was elevated in the plasma and hearts of PPCM patients, but not in patients with dilated cardiomyopathy. These results demonstrate that miR-146a is a downstream-mediator of 16K PRL that could potentially serve as a biomarker and therapeutic target for PPCM.

  15. Late presentation of acromegaly in medically controlled prolactinoma patients

    PubMed Central

    Manuylova, Ekaterina; Calvi, Laura M; Hastings, Catherine; Vates, G Edward; Johnson, Mahlon D; Cave, William T

    2016-01-01

    Summary Co-secretion of growth hormone (GH) and prolactin (PRL) from a single pituitary adenoma is common. In fact, up to 25% of patients with acromegaly may have PRL co-secretion. The prevalence of acromegaly among patients with a newly diagnosed prolactinoma is unknown. Given the possibility of mixed GH and PRL co-secretion, the current recommendation is to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the initial diagnosis. Long-term follow-up of IGF-1 is not routinely done. Here, we report two cases of well-controlled prolactinoma on dopamine agonists with the development of acromegaly 10–20 years after the initial diagnoses. In both patients, a mixed PRL/GH-cosecreting adenoma was confirmed on the pathology examination after transsphenoidal surgery (TSS). Therefore, periodic routine measurements of IGF-1 should be considered regardless of the duration and biochemical control of prolactinoma. Learning points: Acromegaly can develop in patients with well-controlled prolactinoma on dopamine agonists. The interval between prolactinoma and acromegaly diagnoses can be several decades. Periodic screening of patients with prolactinoma for growth hormone excess should be considered and can 
lead to an early diagnosis of acromegaly before the development of complications. PMID:27855229

  16. ZBTB20 is required for anterior pituitary development and lactotrope specification.

    PubMed

    Cao, Dongmei; Ma, Xianhua; Cai, Jiao; Luan, Jing; Liu, An-Jun; Yang, Rui; Cao, Yi; Zhu, Xiaotong; Zhang, Hai; Chen, Yu-Xia; Shi, Yuguang; Shi, Guang-Xia; Zou, Dajin; Cao, Xuetao; Grusby, Michael J; Xie, Zhifang; Zhang, Weiping J

    2016-04-15

    The anterior pituitary harbours five distinct hormone-producing cell types, and their cellular differentiation is a highly regulated and coordinated process. Here we show that ZBTB20 is essential for anterior pituitary development and lactotrope specification in mice. In anterior pituitary, ZBTB20 is highly expressed by all the mature endocrine cell types, and to some less extent by somatolactotropes, the precursors of prolactin (PRL)-producing lactotropes. Disruption of Zbtb20 leads to anterior pituitary hypoplasia, hypopituitary dwarfism and a complete loss of mature lactotropes. In ZBTB20-null mice, although lactotrope lineage commitment is normally initiated, somatolactotropes exhibit profound defects in lineage specification and expansion. Furthermore, endogenous ZBTB20 protein binds to Prl promoter, and its knockdown decreases PRL expression and secretion in a lactotrope cell line MMQ. In addition, ZBTB20 overexpression enhances the transcriptional activity of Prl promoter in vitro. In conclusion, our findings point to ZBTB20 as a critical regulator of anterior pituitary development and lactotrope specification.

  17. MATERNAL ATRAZINE (ATR) ALTERS HYPOTHALAMIC DOPAMINE (HYP-DA) AND SERUM PROLACTIN (SPRL) IN MALE PUPS

    EPA Science Inventory

    Maternal Atrazine (ATR) alters hypothalamic dopamine (HYP-DA) and serum prolactin (sPRL) in male pups. 1Christopher Langdale, 2Tammy Stoker and 2Ralph Cooper. 1 Dept. of Cell Biology, North Carolina State University College of Veterinary Medicine, Raleigh, NC. 2 Endocrinology ...

  18. Seasonal Expression of Prolactin Receptor in the Scented Gland of Male Muskrat (Ondatra zibethicus)

    PubMed Central

    Cao, Han; Wang, Liang; Zhang, Shuo; Lu, Lu; Sheng, Xia; Han, Yingying; Yuan, Zhengrong; Weng, Qiang

    2015-01-01

    Prolactin (PRL) has numerous actions in mammalian biological systems including mammary development and biological processes. The aim of this study was to investigate the seasonal changes of prolactin receptor (PRLR) expression in the scented gland of muskrat during the breeding and nonbreeding seasons. Histologically, glandular cells, interstitial cells and excretory tubules were identified in the scented glands in both seasons, whereas epithelial cells were sparse in the nonbreeding season. PRLR was observed in glandular cells of scented glands during the breeding and nonbreeding seasons with stronger immunostaining during the breeding season. Consistent with the immunohistochemical results, both the mean of protein and mRNA levels of PRLR were higher in the scented glands of the breeding season, and relatively lower level in the nonbreeding season. In addition, differential seasonal changes were also detected in the expression profile of microRNAs (miRNAs) in the scented gland of muskrat. Besides, plasma PRL concentration was remarkably higher in the breeding season than that in the nonbreeding season. These results suggested that muskrat scented gland was the direct target organ of PRL, and stronger expression of PRLR in scented glands during the breeding season indicated that PRL may directly regulate scented glandular function of the muskrats. PMID:26477851

  19. Reversed-phase liquid chromatography of radiolabeled peptides using a C18 guard-PAK precolumn system

    SciTech Connect

    Carriere, P.D.; Bennett, H.P. )

    1989-03-01

    In order to avoid radioactive contamination of high-performance liquid chromatography columns and injectors, we have investigated the use of a Guard-PAK precolumn system for the chromatography of ({sup 125}I) labeled peptides. Two gonadotropin-releasing hormone analogs: (1) (D-Ala6-des-Gly10)-GnRH (GnRH-(Ala6)) and (2) (D-Ser(TBu)6-des-Gly10)-GnRH (GnRH-(Ser6)) and rat prolactin (r-PRL) were radiolabeled with {sup 125}I and subjected to reversed-phase liquid chromatography using a C18 Guard-PAK precolumn system. Major peak fractions of purified ({sup 125}I)GnRH-(Ala6), ({sup 125}I)GnRH-(Ser6), and ({sup 125}I)r-PRL eluted at 24%, 28%, and 55% acetonitrile, respectively. Purified ({sup 125}I)GnRH analogs showed specific high affinity binding to rat anterior pituitary gland membranes (specific activity: 1500-1700 Ci/mmol). Purified ({sup 125}I)r-PRL showed high affinity binding to r-PRL antibody by RIA (specific activity: 70-75 microCi/micrograms). This rapid and efficient chromatographic method should be useful in the separation of a wide range of radiolabeled protein and peptide molecules.

  20. AFHRL Conference on Human Appraisal: Proceedings Held at San Antonio, Texas, 19-21 March 1979

    DTIC Science & Technology

    1981-06-01

    technique (JAN; Christal , 1963) to cluster together raters with similar policies (i.e., similar patterns of weights), and then correlated several...Journal of Applied Psychology, 1977, 62, 278-282. Christal , R.E. JAN: A technique for analyzing group judgment. PRL-TDR-63-3, A 403 813, Lackland

  1. 76 FR 21906 - Proposed Data Collections Submitted for Public Comment and Recommendations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-19

    ... the NIOSH-Pittsburgh Research Laboratory (PRL) have found that one of the key human behavior processes... improve the ability of miners to escape (or be rescued). The research proposed here will help address this... practical aspects of training miners. The research will result in the improved science of decision...

  2. 76 FR 51982 - Agency Forms Undergoing Paperwork Reduction Act Review

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-19

    ... in mines, researchers at the NIOSH-Pittsburgh Research Laboratory (PRL) have found that one of the... during emergency situations to improve the ability of miners to escape (or be rescued). The research... in dynamic situations with the practical aspects of training miners. The research will result in...

  3. Comparative genomics reveals tissue-specific regulation of prolactin receptor gene expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prolactin (PRL), acting via the prolactin receptor, fulfills a diversity of biological functions including the maintenance of solute balance and mineral homeostasis via tissues such as the heart, kidneys and intestine. Expression and activity of the prolactin receptor (PRLR) is regulated by various ...

  4. Consumption of endophyte-infected fescue seed during the dry period and lactation affects mammary gland gene expression in dairy cows

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ergot alkaloids in endophyte-infected grasses inhibit prolactin (PRL) secretion and reduce milk production when fed to lactating cows. However, we have shown this affect is temporal in that pre-partum consumption of inflected seed throughout the dry period does not inhibit subsequent milk productio...

  5. A novel first exon directs hormone-sensitive transcription of the pig prolactin receptor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Endocrine, paracrine, and autocrine prolactin (PRL) acts through its receptor (PRLR) to confer a wide range of biological functions, including its established role during lactation.We have identified a novel first exon of the porcine PRLR that gives rise to three different mRNA transcripts. Transcri...

  6. Enhancement of maternal lactation performance during prolonged lactation in the mouse by mouse GH and long-R3-IGF-I is linked to changes in mammary signaling and gene expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    GH, prolactin (PRL), and IGF-I stimulate lactation-related metabolic processes in mammary epithelial cells. However, the ability of these factors to stimulate milk production in animals varies depending on species and experimental variables. Previous work in our laboratory demonstrated that transgen...

  7. Complex topological structures of frustrated liquid crystals with potential for optics and photonics (Presentation Recording)

    NASA Astrophysics Data System (ADS)

    Žumer, Slobodan; Čančula, Miha; Čopar, Simon; Ravnik, Miha

    2015-10-01

    Geometrical constrains and intrinsic chirality in nematic mesophases enable formation of stable and metastable complex defect structures. Recently selected knotted and linked disclinations have been formed using laser manipulation of nematic braids entangling colloidal particles in nematic colloids [Tkalec et al., Science 2011; Copar et al., PNAS 2015]. In unwinded chiral nematic phases stable and metastable toron and hopfion defects have been implemented by laser tweezers [Smalyukh et al., Nature Materials 2010; Chen et al., PRL2013] and in chiral nematic colloids particles dressed by solitonic deformations [Porenta et al., Sci. Rep. 2014]. Modelling studies based on the numerical minimisation of the phenomenological free energy, supported with the adapted topological theory [Copar and Zumer, PRL 2011; Copar, Phys. Rep. 2014] allow describing the observed nematic defect structures and also predicting numerous structures in confined blue phases [Fukuda and Zumer, Nature Comms 2011 and PRL 2011] and stable knotted disclinations in cholesteric droplets with homeotropic boundary [Sec et al., Nature Comms 2014]. Coupling the modeling with finite difference time domain light field computation enables understanding of light propagation and light induced restructuring in these mesophases. The method was recently demonstrated for the description of low intensity light beam changes during the propagation along disclination lines [Brasselet et al., PRL 2009; Cancula et al., PRE 2014]. Allowing also high intensity light an order restructuring is induced [Porenta et al., Soft Matter 2012; Cancula et al., 2015]. These approaches help to uncover the potential of topological structures for beyond-display optical and photonic applications.

  8. General Estimators for the Reliability of Qualitative Data.

    ERIC Educational Resources Information Center

    Cooil, Bruce; Rust, Roland T.

    1995-01-01

    A proportional reduction in loss (PRL) measure for reliability of categorical data is explored for the situation in which each of "N" judges assigns a subject to one of "K" categories. Calculating a lower bound for reliability under more general conditions than had been proposed is demonstrated. (SLD)

  9. Developmental expression and estrogen responses of endocrine genes in juvenile yellow perch (Perca flavescens)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study examines the expression of growth-regulating genes (gh, prl, smtl and igf1b), the estrogen receptors (esr1 and esr2a) and aromatase (cyp19a1a) in developing yellow perch. To gain an initial understanding into the endocrine control of growth preceding and involved with sexual size d...

  10. "Physical Review Letters" in the Classroom

    ERIC Educational Resources Information Center

    Angiolillo, Paul J.; Lynch, Jonathan

    2010-01-01

    Ask any physicist what the preeminent journal in the field is, and I think the almost unanimous answer will be "Physical Review Letters" ("PRL"). This weekly journal of the American Physical Society publishes high-impact research from all the major subdisciplines of physics. This journal is not the one you would think is the first place a high…

  11. Cellular and Molecular Basis for Stress-Induced Depression

    PubMed Central

    Seo, Ji-Seon; Wei, Jing; Qin, Luye; Kim, Yong; Yan, Zhen

    2016-01-01

    Chronic stress plays a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2+) glutamatergic neurons. Viral expression of p11 in D2+ PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2+ neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2+ PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses. PMID:27457815

  12. 75 FR 35856 - Self-Regulatory Organizations; Notice of Filing of Proposed Rule Change by New York Stock...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-23

    ... (``parity'') with other interest available at that price. In addition, where there is more than one bidder... of quoting as explained in more detail below. \\11\\ See Proposed NYSE Rule 55 and 56. In addition... authorizing automatic execution for the round lot portion of a PRL order. In addition, the Exchange...

  13. 75 FR 35865 - Self-Regulatory Organizations; Notice of Filing of Proposed Rule Change by NYSE Amex LLC Amending...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-23

    ... available at that price. In addition, where there is more than one bidder (offerer) participating in an... addition, proposed NYSE Amex Equities Rule 55 retains the ability of the Exchange to designate securities... portion of a PRL order. In addition, the Exchange proposes to delete the provisions of...

  14. Near-infrared observations of the black hole transient GRS 1716-249.

    NASA Astrophysics Data System (ADS)

    Joshi, Vishal; Vadwale, Santosh; Ganesh, Shashikiran

    2017-03-01

    We report near-infrared photometric observations of GRS 1716-249 during the on-going outburst (ATel #9876, #9895, #10036, #10069). Observations were carried out on UT 20.99 March 2017 with the Mount Abu 1.2 meter telescope (+ PRL Near-Infrared Imager/Spectrograph).

  15. US EPA, Pesticide Product Label, , 11/18/1982

    EPA Pesticide Factsheets

    2011-04-14

    ... _lth a: ,:;:cod machine adJII",t<>d tf} rj,'I1\\'(r 3. fin'" ah;t or 'og.'1 tor rapl~ c()ntf"ol tit l"\\ouot;{> flies. ("I..IJt. fUI'",:. ljn:lt~. ... ur tIt I \\"'rt f '""~I ~pr;l\\" I .. ' .. k ...

  16. Association between endometriosis and hyperprolactinemia in infertile women

    PubMed Central

    Esmaeilzadeh, Seddigheh; Mirabi, Parvaneh; Basirat, Zahra; Zeinalzadeh, Mahtab; Khafri, Soraya

    2015-01-01

    Background: The association of endometriosis with hyperprolactinemia is controversial. Objective: The present study aimed to determine the frequency of endometriosis and association of prolactin with endometriosis in infertile women. Materials and Methods: 256 infertile women who underwent diagnostic laparoscopy for the evaluation of infertility, referred to Fatemezahra Infertility and Reproductive Health Research Center were included in a cross-sectional study. The presence of endometriosis was evaluated. To investigate the association of endometriosis with hyperprolactinemia, the patients whose infertility was not caused by endometriosis were included as control group. Serum prolactin (PRL) level was measured in both groups. The comparison of basal serum PRL levels between the two groups was performed, using independent t-test. One way ANOVA was used to determine PRL association with endometriosis stages. Results: The frequency of endometriosis was found to be 29%. PRL levels were significantly higher in endometriosis group compared to control group (23.02±1.25 vs. 17.22±1.22 respectively, p=0.004). Statistically significant associations were found between staging of endometriosis and prolactin levels (p=0.01). Conclusion: Hyperprolactinemia may be associated with endometriosis and its progression. PMID:26000006

  17. 8 CFR 324.5 - Former citizen of the United States whose naturalization by taking the oath is authorized by a...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...: WOMEN WHO HAVE LOST UNITED STATES CITIZENSHIP BY MARRIAGE AND FORMER CITIZENS WHOSE NATURALIZATION IS AUTHORIZED BY PRlVATE LAW § 324.5 Former citizen of the United States whose naturalization by taking the oath... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Former citizen of the United States...

  18. Dynamics of prolactin, gonadotropin, and of sex steroids in the blood serum of parturients during laser therapy

    NASA Astrophysics Data System (ADS)

    Kovalyov, M. I.

    2001-04-01

    An investigation was made of the effect (lambda) equals 0.63 micrometers diode laser radiation with the energy density of 0.6 to 0.8 J cm-2 on parturients affected by nipples' rhagades. In our experiments, we determined the content of prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and of progesterone (P) in the parturients' blood serum. It was found that laser radiation produced an insignificant effect on the prolactic (PRL) content in parturients with the normal lactation level. On the contrary, it produced a stimulating effect on the PRL level in parturients with hypogalactia. Possibly, laser radiation promoted the decrease in the FSH level in the parturients' blood serum. It was also found that this laser radiation produced an insignificant effect on the levels of LH, estradiol (E2), and of progesterone. Women subsequently affected by mastitis exhibited a significantly higher PRL level in their blood serum, as compared with women of the control group.

  19. Cabergoline Effectively Induced Remission of Prolactinoma in a 9-year-old Japanese Boy

    PubMed Central

    Sano, Hitomi; Takigami, Masayoshi; Ogino, Tetsuo; Morioka, Keita; Ito, Tomoshiro; Sudo, Akira; Fukushima, Naoki

    2009-01-01

    Prolactinomas are rarely diagnosed in children under the age of 10. A 9-yr-old Japanese boy complained of severe headache and progressive visual disturbance. His growth had been retarded for approximately 3 yr, and his serum PRL level was 811.6 ng/ml. Brain magnetic resonance imaging (MRI) revealed an enlarged pituitary (2.8 × 2.6 × 2.1 cm) with heterogeneous enhancement. He was diagnosed as having a macroprolactinoma accompanied by pituitary apoplexy and growth hormone deficiency. A surgical approach was initially undertaken due to the progressive visual deficits, but a residual tumor was observed, and the level of serum PRL was still high after the surgery. Cabergoline was then started, and the dose was gradually increased to 1.5 mg/wk. The serum PRL level decreased from 138.8 ng/ml to 32.5 ng/ml and 17.7 ng/ml after 5 wk and 19 wk, respectively. At 33 wk of cabergoline treatment, brain MRI demonstrated no evidence of the residual tumor. Thereafter, the serum level of PRL decreased to less than 10 ng/ml, and remission was consistently confirmed on repeated MRI. No adverse events have been observed. The present case suggests that cabergoline can be an effective treatment for prolactinomas in prepubertal children as well as in adults. PMID:24790382

  20. Effects of pterostilbene on treating hyperprolactinemia and related mechanisms

    PubMed Central

    Zhang, Haoru; Wang, Changhua; Li, Xiaokun; Zhang, Yong

    2016-01-01

    Hyperprolactinemia (HPRL) frequently causes primary menopause and reproductive disorders. Pterostilbene is known to have anti-inflammation and modulation on cell apoptosis. However, its role in treating HPRL and potential mechanisms remain unclear yet. Healthy female virgin SD rats were randomly assigned into control, HPRL model group, bromocriptine treatment group, and low (20 mg/kg) and high (40 mg/kg) pterostilbene treatment groups. All groups except control ones received metoclopramide hydrochloride injection for generating HPRL model. Uterus and ovarian index in all animals were monitored. Prolactin (PRL), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were quantified by ELISA. Caspase 3 activity was assayed, with real time PCR measuring Bcl-2 and Bax mRNA levels. HPRL rats had lower uterus and ovarian index, accompanied with elevated PRL, caspase 3 activity, Bax expression, and decreased FSH, LH, E2 and Bcl-2 expression as compared to control group (p<0.05). Pterostilbene treatment significantly increased uterus and ovarian index, FSH, LH, E2 and Bcl-2 expression, and decreased PRL, caspase 3 activity and Bax expression as compared to control group (p<0.05). 40 mg/kg pterostilbene had similar efficacy as those of bromocriptine. Pterostilbene exerts its function in the treatment of HPRL via modulating apop