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1

Marked stimulation of growth and motility of human keratinocytes by hepatocyte growth factor  

Microsoft Academic Search

Effect of hepatocyte growth factor (HGF) on normal human epidermal keratinocytes cultured under conditions of low Ca2+ (0.1 mM, growth-promoting condition) and physiological Ca2+ (1.8 mM, differentiation-promoting condition) was investigated. In low Ca2+, HGF markedly enhanced the migration of keratinocytes while it suppressed cell growth and DNA synthesis in a dose-dependent manner. In contrast, HGF enhanced the migration, cell growth,

K. Matsumoto; K. Hashimoto; K. Yoshikawa; T. Nakamura

1991-01-01

2

Interleukin1? Stimulates Keratinocyte Migration Through an Epidermal Growth Factor\\/Transforming Growth Factor-?-Independent Pathway  

Microsoft Academic Search

Epidermal growth factor (EGF) and transforming growth factor-? (TGF-?) stimulate keratinocyte migration on collagen by up-regulating the ?2 subunit of the collagen integrin, ?2?1. Interleukin-1 (IL-1) is an autocrine factor, produced by keratinocytes them- selves, that is modulated by ultraviolet light and increases the proliferative potential of keratinocytes in culture. The autocrine nature of keradnocyte- derived IL-1? is emphasized by

John D. Chen; Jean-Christophe Lapiere; Daniel N. Sauder; Christina Peavey; David T. Woodley

1995-01-01

3

Cortactin involvement in the keratinocyte growth factor and fibroblast growth factor 10 promotion of migration and cortical actin assembly in human keratinocytes  

SciTech Connect

Keratinocyte growth factor (KGF/FGF7) and fibroblast growth factor 10 (FGF10/KGF2) regulate keratinocyte proliferation and differentiation by binding to the tyrosine kinase KGF receptor (KGFR). KGF induces keratinocyte motility and cytoskeletal rearrangement, whereas a direct role of FGF10 on keratinocyte migration is not clearly established. Here we analyzed the motogenic activity of FGF10 and KGF on human keratinocytes. Migration assays and immunofluorescence of actin cytoskeleton revealed that FGF10 is less efficient than KGF in promoting migration and exerts a delayed effect in inducing lamellipodia and ruffles formation. Both growth factors promoted phosphorylation and subsequent membrane translocation of cortactin, an F-actin binding protein involved in cell migration; however, FGF10-induced cortactin phosphorylation was reduced, more transient and delayed with respect to that promoted by KGF. Cortactin phosphorylation induced by both growth factors was Src-dependent, while its membrane translocation and cell migration were blocked by either Src and PI3K inhibitors, suggesting that both pathways are involved in KGF- and FGF10-dependent motility. Furthermore, siRNA-mediated downregulation of cortactin inhibited KGF- and FGF10-induced migration. These results indicate that cortactin is involved in keratinocyte migration promoted by both KGF and FGF10.

Ceccarelli, Simona [Dipartimento di Medicina Sperimentale, Universita di Roma 'La Sapienza', Viale Regina Elena 324, 00161, Rome (Italy); Cardinali, Giorgia [Istituto Dermatologico San Gallicano, IRCCS, Rome (Italy); Aspite, Nicaela [Istituto Dermatologico San Gallicano, IRCCS, Rome (Italy); Picardo, Mauro [Istituto Dermatologico San Gallicano, IRCCS, Rome (Italy); Marchese, Cinzia [Dipartimento di Medicina Sperimentale, Universita di Roma 'La Sapienza', Viale Regina Elena 324, 00161, Rome (Italy); Torrisi, Maria Rosaria [Dipartimento di Medicina Sperimentale, Universita di Roma 'La Sapienza', Viale Regina Elena 324, 00161, Rome (Italy); Azienda Ospedaliera Sant'Andrea, Rome (Italy); Mancini, Patrizia [Dipartimento di Medicina Sperimentale, Universita di Roma 'La Sapienza', Viale Regina Elena 324, 00161, Rome (Italy)]. E-mail: patrizia.mancini@uniroma1.it

2007-05-15

4

L-Serine Potentiates the Mitogenic Effects of Growth Factors on Cultured Human Keratinocytes  

Microsoft Academic Search

L-Serine increased the growth of passaged human foreskin keratinocytes in terms of DNA and protein per dish of cells, and potentiated the mitogenic effects of serum and epidermal growth factor and also insulin, keratinocyte growth factor, and a bovine pituitary extract. The effects of serine were apparent with as little as 0.05 mM. The stimulatory effects of these various growth

David I. Wilkinson

1987-01-01

5

Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212).  

PubMed Central

Nerve growth factor (NGF) is a polypeptide that is required for normal development and maintenance of the sympathetic and sensory nervous systems. Skin has been shown to contain relatively high amounts of NGF, which is in keeping with the finding that the quantity of NGF in a tissue is proportional to the extent of sympathetic innervation of that organ. Since the keratinocyte, a major cellular constituent of the skin, is known to produce other growth factors and cytokines, our experiments were designed to determine whether keratinocytes are a source of NGF. Keratinocyte-conditioned media from the keratinocyte cell line PAM 212 contained NGF-like activity, approximately 2-3 ng/ml, as detected by the neurite outgrowth assay. Freshly isolated BALB/c keratinocytes contained approximately 0.1 ng/ml. Using a cDNA probe directed against NGF, we demonstrated the presence of a 1.3-kb NGF mRNA in both PAM 212 and BALB/c keratinocytes. Since ultraviolet radiation (UV) is a potentially important modulating factor for cytokines in skin, we examined the effect of UV on NGF mRNA expression. Although UV initially inhibited the expression of keratinocyte NGF mRNA (4 h), by 24 h an induction of NGF mRNA was seen. The NGF signal could also be induced by phorbol esters. Thus, keratinocytes synthesize and express NGF, and its expression is modulated by UVB and phorbol esters. Images PMID:2318966

Tron, V A; Coughlin, M D; Jang, D E; Stanisz, J; Sauder, D N

1990-01-01

6

Keratinocyte Derived T-Cell Growth Factor (KTGF) Is Identical to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)  

Microsoft Academic Search

Keratinocyte derived T-cell growth factor was initially described as a product of cultured neonatal keratinocytes and keratinocyte cell lines that induced the proliferation of HT-2 cells, a murine T-cell line that responds to IL-2 and IL-4 by incorporating 3H-Thymidine. Subsequently, KTGF has been purified to high specific activity and found to be distinct from IL-2 and IL-4 by a variety

Thomas S. Kupper; Frank Lee; David Coleman; Jeffrey Chodakewitz; Patrick Flood; Mark Horowitz

1988-01-01

7

Effects of growth factors on the proliferation of human keratinocytes and fibroblasts in vitro.  

PubMed

Growth/differentiation factor-5 (GDF-5) is a new member of the transforming growth factor-beta (TGF-beta) superfamily of multifunctional peptide growth factors that appear to mediate many key events in cell growth and development. The effects of GDF-5 and other growth factors (epidermal growth factor, EGF; TGF-beta 1) on the proliferation of human keratinocytes and fibroblasts compared with desoximetasone and calcipotriol have been investigated. The proliferation rate was determined by a hemocytometer, MTT assay and the incorporation of [3H]-thymidine. Moreover, cell cycle analyses were performed and the influence on interleukin-1 alpha (IL-1 alpha) production in keratinocytes was measured by enzyme-linked immunosorbent assay (ELISA) because of its pronounced proinflammatory effect. In keratinocytes, GDF-5 stimulated cell proliferation to a minor extent. The drug already proved to be effective at very low concentrations (0.1 ng/ml). Growth stimulatory effects with EGF have been observed only in keratinocyte basal medium (KBM), but not in keratinocyte growth medium (KGM). TGF-beta 1 markedly inhibited the proliferation of keratinocytes at concentrations > 1 ng/ml. Calcipotriol and desoximetasone also showed a dose-dependent cell growth inhibition in epidermal cell cultures. IL-1 alpha synthesis was greatly suppressed by calcipotriol 10(-8)-10(-6) M. EGF at 10 ng/ml, in contrast, strongly stimulated IL-1 alpha production. Neither GDF-5 nor TGF-beta 1 had a significant effect on IL-1 alpha production in keratinocyte monolayer cultures. In fibroblasts, GDF-5 induced very weak antiproliferative effects. Calcipotriol and desoximetasone also inhibited cell growth in fibroblast cultures whereas proliferation and DNA synthesis were strongly stimulated by 1 ng/ml EGF. There was, however, a contradiction between TGF-beta 1 results on fibroblasts. Whereas TGF-beta 1 increased proliferation in cell number determination and in the thymidine incorporation assay, MTT assays showed slight antiproliferative effects. Due to these controversial results, in addition cell cycle analysis was employed. TGF-beta 1 led to an increased S phase, which indicates a stimulation of cell division. The different results obtained with the MTT test suggest that TGF-beta 1 may stimulate cell division of fibroblasts not only by increasing the S phase, but also by shortening the G1 phase of the cell cycle. PMID:9476258

Kim, D S; Korting, H C; Schäfer-Korting, M

1998-01-01

8

Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice.  

PubMed Central

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. Synthesized by cells of the dermal component of skin, KGF's potent mitogenic activity is on the epidermal component, which harbors the receptors for this factor. To explore the possible role of KGF in mesenchymal-epithelial interactions in skin, we used a human keratin 14 promoter to target expression of human KGF cDNA to the stratified squamous epithelia of transgenic mice. Mice expressing KGF in their epidermis typically appeared frail and weak, and often had grossly wrinkled skin. These mice exhibited a gross increase in epidermal thickness accompanied by alterations in epidermal growth and differentiation. Most remarkably, animals displayed several striking and unexpected changes, including a marked suppression of hair follicle morphogenesis and suppression of adipogenesis. With age, some animals developed gross transformations in the tongue epithelium and in epidermis. In addition, they exhibited elevated salivation and their salivary glands showed signs of altered differentiation. Collectively, our findings provide new and important insights into the roles of KGF, implicating this potent growth factor in eliciting global effects not only on growth, but also on development and differentiation, of skin and other tissues. In particular, KGF seems to interfere with signalling of some mesenchymal-epithelial interactions. Images PMID:7681397

Guo, L; Yu, Q C; Fuchs, E

1993-01-01

9

Retinoic acid induces transforming growth factor-beta 2 in cultured keratinocytes and mouse epidermis.  

PubMed Central

We have studied the functional interaction between retinoic acid and transforming growth factor-beta (TGF-beta), using the mouse epidermis as a model system. Treatment with retinoic acid increases expression of TGF-beta 2 in cultured keratinocytes in vitro, as well as in the epidermis in vivo. This TGF-beta 2 is secreted in a biologically active form that can bind to surface receptors, in contrast to most other conditions in which TGF-beta is secreted in a latent form. Specific antibodies to TGF-beta 2 partially reverse the ability of retinoic acid to inhibit DNA synthesis in cultured keratinocytes. The regulation of TGF-beta 2 expression by retinoic acid may have important physiological and pharmacological roles in the maintenance of epidermal homeostasis. Images PMID:2519621

Glick, A B; Flanders, K C; Danielpour, D; Yuspa, S H; Sporn, M B

1989-01-01

10

Effects of transforming growth factor beta-1 on growth-regulatory genes in tumour-derived human oral keratinocytes  

Microsoft Academic Search

This study examined the effect of transforming growth factor beta-1 (TGF-beta 1) on c-myc, RB1, junB and p53 expression together with pRb phosphorylation, in carcinoma-derived and normal human oral keratinocytes with a range of inhibitory responses to this ligand. Amplification of c-myc was observed in eight of eight tumour-derived cell lines and resulted in corresponding mRNA expression. The down-regulation of

IC Paterson; V Patel; JR Sandy; SS Prime; WA Yeudall

1995-01-01

11

Cyclophosphamide Prevents Systemic Keratinocyte Growth Factor-induced Up-Regulation of Surfactant Protein A after Allogeneic Transplant in Mice  

Microsoft Academic Search

We reported that systemic keratinocyte growth factor (KGF) given before bone marrow transplantation (BMT) prevents allogeneic T cell-dependent lung inflammation assessed on Day 7 post-BMT, but the antiinflammatory effects of KGF were impaired in mice in- jected with both T cells and conditioning regimen of cyclophos- phamide (Cy). Intratracheal KGF is known to stimulate the expres- sion of surfactant protein

SHUXIA YANG; ANGELA PANOSKALTSIS-MORTARI; DAVID H. INGBAR; SADIS MATALON; SHA ZHU; ERNESTO R. RESNIK; CATHERINE L. FARRELL; DAVID L. LACEY; BRUCE R. BLAZAR; IMAD Y. HADDAD

2000-01-01

12

Vitamin A prevents the irreversible proliferation of vaginal epithelium induced by neonatal injection of keratinocyte growth factor in mice  

Microsoft Academic Search

Exposure of female mice to estrogen during the perinatal period results in estrogen-independent persistent proliferation and cornification of the vaginal epithelium when the animals become adults. However, the occurrence of such irreversible vaginal changes is blocked by concurrent vitamin A treatment. Neonatal exposure to keratinocyte growth factor (KGF), which is a paracrine mediator of epithelial-mesenchymal interactions, also induces the persistent

Fujiko Masui; Manabu Matsuda; Takao Mori

2003-01-01

13

Keratinocytes can differentiate into eccrine sweat ducts in vitro: involvement of epidermal growth factor and fetal bovine serum  

Microsoft Academic Search

Background: in addition to formation of an epidermal sheet and dermal substitution, reconstruction of skin that possesses functionality is an important goal for dermatologists. Objective: we attempted to regenerate eccrine sweat glands in vitro. Methods: we constructed skin equivalent models with various combination of normal human keratinocytes and fibroblasts and also examined the effect of various growth factors. Results: we

Takanori Shikiji; Mitsuyoshi Minami; Toshiyuki Inoue; Kenji Hirose; Hajimu Oura; Seiji Arase

2003-01-01

14

Expression of keratinocyte growth factor and its receptor in human breast cancer.  

PubMed Central

The level of expression of keratinocyte growth factor (KGF) mRNA has been measured in human breast cell lines, purified populations of epithelial cells, myoepithelial cells and fibroblasts from reduction mammoplasty tissue and a panel of 42 breast cancers and 30 non-malignant human breast tissues using a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) procedure. We found similar levels of KGF mRNA in malignant and non-malignant breast tissues. The study of the amount of KGF mRNA in breast cell lines and purified populations of cells revealed that fibroblasts are the predominant source of KGF with malignant and non-malignant epithelial cells containing very low levels of KGF mRNA. We have examined the distribution of fibroblast growth factor receptor (FGFR)-2-IIIb, which is a high-affinity receptor for KGF and find that it is present on malignant and non-malignant epithelial cells. The level of FGFR-2-IIIb present on breast cancer cell lines was sufficient for KGF stimulation of breast cancer cell proliferation. Other members of the fibroblast growth factor family have been either not expressed in the human breast (FGF3, FGF4) or have been found at much reduced levels in breast cancer (FGF1, FGF2) and this is the first member of the family to potentially influence the progression of breast cancer through stimulation of cell division. Images Figure 1 Figure 3 Figure 4 PMID:9184170

Bansal, G. S.; Cox, H. C.; Marsh, S.; Gomm, J. J.; Yiangou, C.; Luqmani, Y.; Coombes, R. C.; Johnston, C. L.

1997-01-01

15

Enhanced Expression of Keratinocyte Growth Factor and Its Receptor Correlates with Venous Invasion in Pancreatic Cancer  

PubMed Central

Keratinocyte growth factor (KGF) and KGF receptor (KGFR) have been implicated in cancer growth as well as tissue development and repair. In this study, we examined whether KGF and KGFR have a role in human pancreatic ductal adenocarcinoma (PDAC). KGFR mRNA was expressed in eight pancreatic cancer cell lines, whereas the KGF mRNA was detected in seven of the cell lines and was absent in MIA PaCa-2 cells. KGFR and KGF immunoreactivity were localized in the cancer cells in 41.5 and 34.0% of patients, respectively. There was a significant correlation between KGFR or KGF immunoreactivity and venous invasion and a significant correlation between the presence of both markers and venous invasion, vascular endothelial growth factor (VEGF)-A expression, and poor prognosis. Exogenous KGF increased VEGF-A expression and release in MIA PaCa-2 cells, and PANC-1 cells stably transfected to overexpress KGF-exhibited increased VEGF-A expression. Moreover, short hairpin-KGFR transfection in MIA PaCa-2 cells reduced the stimulatory effect of exogenous KGF on VEGF-A expression. Short hairpin-KGF transfection in KLM-1 cells reduced VEGF-A expression in the cells. KGFR and KGF may act to promote venous invasion and tumor angiogenesis in PDAC, raising the possibility that they may serve as novel therapeutic targets in anti-angiogenic strategies in PDAC. PMID:17525264

Cho, Kazumitsu; Ishiwata, Toshiyuki; Uchida, Eiji; Nakazawa, Nando; Korc, Murray; Naito, Zenya; Tajiri, Takashi

2007-01-01

16

Immunolocalization and expression of vascular endothelial growth factor receptors (VEGFRs) and neuropilins (NRPs) on keratinocytes in human epidermis.  

PubMed

Vascular endothelial growth factor (VEGF) plays an important role in normal and pathological angiogenesis. VEGF receptors (VEGFRs, including VEGFR-1, VEGFR-2, and VEGFR-3) and neuropilins (NRPs, including NRP-1 and NRP-2) are high-affinity receptors for VEGF and are typically considered to be specific for endothelial cells. Here we showed expression of VEGFRs and NRPs on cultured epidermal keratinocytes at both mRNA and protein levels. We further localized these receptors by immunofluorescence (IF) staining in the epidermis of surgical skin specimens. We found positive staining for VEGFRs and NRPs in all layers of the epidermis except for the stratum corneum. VEGFR-1 and VEGFR-2 are primarily expressed on the cytoplasmic membrane of basal cells and the adjacent spinosum keratinocytes. All layers of the epidermis except for the horny cell layer demonstrated a uniform pattern of VEGFR-3, NRP-1, and NRP-2. Sections staining for NRP-1 and NRP-2 also showed diffuse intense fluorescence and were localized to the cell membrane and cytoplasm of keratinocytes. In another panel of experiments, keratinocytes were treated with different concentrations of VEGF, with or without VEGFR-2 neutralizing antibody in culture. VEGF enhanced the proliferation and migration of keratinocytes, and these effects were partially inhibited by pretreatment with VEGFR-2 neutralizing antibody. Adhesion of keratinocytes to type IV collagen-coated culture plates was decreased by VEGF treatment, but this reduction could be completely reversed by pretreatment with VEGFR-2 neutralizing antibody. Taken together, our results suggest that the expression of VEGFRs and NRPs on keratinocytes may constitute important regulators for its activity and may possibly be responsible for the autocrine signaling in the epidermis. PMID:17088944

Man, Xiao-Yong; Yang, Xiao-Hong; Cai, Sui-Qing; Yao, Yong-Gang; Zheng, Min

2006-01-01

17

Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation  

PubMed Central

Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8+ T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8+ cells, as well as increased numbers of CD8+ cells producing interferon-? (IFN-?) and tumor necrosis factor-? (TNF-?). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell–receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution. PMID:19011222

Jenq, Robert R.; King, Christopher G.; Volk, Christine; Suh, David; Smith, Odette M.; Rao, Uttam K.; Yim, Nury L.; Holland, Amanda M.; Lu, Sydney X.; Zakrzewski, Johannes L.; Goldberg, Gabrielle L.; Diab, Adi; Alpdogan, Onder; Penack, Olaf; Na, Il-Kang; Kappel, Lucy W.; Wolchok, Jedd D.; Houghton, Alan N.; Perales, Miguel-Angel

2009-01-01

18

Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor.  

PubMed

Intratracheal instillation of bleomycin produces pulmonary fibrosis in rats. Alveolar type II cell proliferation is thought to minimize the fibrotic response after lung injury. Because keratinocyte growth factor (KGF) stimulates type II cell proliferation in the rat, we designed experiments to evaluate whether intratracheal KGF before or after intratracheal bleomycin would prevent pulmonary fibrosis. Intratracheal bleomycin without KGF resulted in moderate to severe lung injury and subsequent fibrosis. Conversely, intratracheal KGF pretreatment at 48 or 72 hr before bleomycin resulted in minimal to no visible lung injury. Rats pretreated with phosphate buffered saline before bleomycin had significantly more neutrophils and protein in bronchoalveolar lavage fluid at 4 and 6 days and higher hydroxyproline levels after bleomycin as compared to KGF-pretreated rats. Pretreatment with KGF at 48 hr protected against bleomycin-induced alterations in pulmonary physiology and increased surfactant protein C-positive (SP-C)-positive cells and SP-A, SP-B, SP-C, and SP-D mRNA levels after bleomycin instillation when compared to saline pretreated rats on day 1 or day 7. KGF posttreatment protocols did not prevent bleomycin lung injury and fibrosis. We conclude that KGF pretreatment attenuates bleomycin lung injury and increases type II cell proliferation and surfactant protein gene expression after bleomycin instillation in the rat. PMID:9154642

Deterding, R R; Havill, A M; Yano, T; Middleton, S C; Jacoby, C R; Shannon, J M; Simonet, W S; Mason, R J

1997-05-01

19

Keratinocyte Growth Factor Protects Alveolar Epithelium and Endothelium from Oxygen-Induced Injury in Mice  

PubMed Central

Keratinocyte growth factor (KGF) has been used successfully to prevent alveolar damage induced by oxygen exposure in rodents. However, this treatment was used intratracheally and before oxygen exposure, which limited its clinical application. In the present study, mice were treated with the recombinant human KGF intravenously before (days ?2 and ?1) or during (days 0 and +1) oxygen exposure. In both cases, lung damage was attenuated. KGF increased the number of cells incorporating bromodeoxyuridine (BrdU) in the septa and in bronchial epithelium of air-breathing mice but not of oxygen-exposed mice, indicating that the protective effect of KGF is not necessarily associated with proliferation. Oxygen-induced damage of alveolar epithelium and, unexpectedly, of endothelium was prevented by KGF treatment as seen by electron microscopy. We investigated the effect of KGF on different mechanisms known to be involved in oxygen toxicity. The induction of p53, Bax, and Bcl-x mRNAs during hyperoxia was to a large extent prevented by KGF. Surfactant proteins A and B mRNAs were not markedly modified by KGF. The anti-fibrinolytic activity observed in the alveoli during hyperoxia was to a large extent prevented by KGF, most probably by suppressing the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA and protein. As PAI-1 ?/? mice are more resistant to hyperoxia, KGF might act, at least in part, by decreasing the expression of this protease inhibitor and by restoring the fibrinolytic activity into the lungs. PMID:10329601

Barazzone, Constance; Donati, Yves R.; Rochat, Anne F.; Vesin, Christian; Kan, Chen-Da; Pache, Jean C.; Piguet, Pierre F.

1999-01-01

20

Keratinocyte growth factor protects murine hepatocytes from tumor necrosis factor-induced apoptosis in vivo and in vitro.  

PubMed

Keratinocyte growth factor (KGF) promotes epithelial growth and differentiation and has potent effects on the liver. The coinjection of lipopolysaccharide (LPS) and D-galactosamine (GalN) results in hepatic failure in mice. Mechanistically, LPS-induced tumor necrosis factor (TNF) triggers hepatocyte apoptosis, which is enhanced by GalN-arrested transcription. Similarly, the combination of TNF and actinomycin D (ActD) causes hepatocyte apoptosis in vitro. We studied the effect of KGF on LPS and GalN-induced hepatic failure in vivo and on TNF- and ActD-induced hepatocyte apoptosis in vitro, where it was compared with those of hepatic growth factor (HGF) and epidermal growth factor (EGF). Mice treated with human recombinant KGF (1 mg/kg subcutaneously) 24 hours before intraperitoneal coinjection of LPS and GalN sustained prolonged survival compared with control mice, although overall mortality was not changed. The counts of apoptotic hepatocytes, serum alanine and aspartate transaminases, and DNA fragments in the cytosolic fraction of liver homogenates were higher in control mice than in treated mice 6 hours after LPS and GalN coinjection, before any mortality occurred. In vitro, hepatocytes pretreated with KGF exhibited reduced TNF- and ActD-induced cell damage and DNA fragmentation, similar to hepatocytes pretreated with HGF and EGF. In conclusion, KGF prolongs survival during LPS- and GalN-induced hepatic failure by temporarily protecting hepatocytes against apoptosis. It also protects hepatocytes in vitro against TNF- and ActD-induced apoptosis. PMID:9620331

Senaldi, G; Shaklee, C L; Simon, B; Rowan, C G; Lacey, D L; Hartung, T

1998-06-01

21

Inhibition of sup 125 I-epidermal growth factor binding to cultured keratinocytes by antiproliferative molecules gamma interferon, cyclosporin A, and transforming growth factor-beta  

SciTech Connect

The growth of cultured human keratinocytes (KC) is inhibited by gamma interferon (IFN-gamma), cyclosporin A and transforming growth factor-beta, but not by tumor necrosis factor. When these antiproliferative molecules were added to KC they induced a concentration and time-dependent inhibition of {sup 125}I-epidermal growth factor (I-EGF) binding. These anti-proliferative molecules primarily reduced the number of binding sites by approximately 25%-50% without affecting the binding affinity. Tumor necrosis factor did not influence the ligand binding by I-EGF. In parallel with the ability of the antiproliferative molecules to inhibit I-EGF binding, there was an increase in transforming growth factor-alpha production. These results suggest that several different antiproliferative molecules may share a common mechanism to inhibit cell growth by reducing I-EGF binding to KC.

Nickoloff, B.J.; Mitra, R.S. (Univ. of Michigan Medical Center, Ann Arbor (USA))

1989-12-01

22

Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns  

PubMed Central

Current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory. Thus, the aim of the present study was to investigate the efficacy of keratinocyte growth factor, in the form of palifermin, for the prevention of stricture development following esophageal caustic injuries in a rat model. A total of 32 female Wistar albino rats were divided into four groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups. An experimental corrosive esophageal burn model was established in the B, S and S/P groups. Weight gain was recorded and histopathological evaluation was performed for each group. Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed. In addition, statistically significant differences in weight gain were observed between the S/P group and the B group. Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group. In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group. Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group. The stenosis indexes in the C and S groups were significantly lower compared with the B group. In addition, the stenosis index in the S/P group was significantly lower compared with the S group. To the best of our knowledge, the present study is the first to investigate the effect of palifermin on corrosive esophageal burns. The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats. PMID:25187801

NUMANOGLU, KEMAL VARIM; TATLI, DUYGU; BEKTAS, SIBEL; ER, EBUBEKIR

2014-01-01

23

Keratinocyte Growth Factor Induces Gene Expression Signature Associated with Suppression of Malignant Phenotype of Cutaneous Squamous Carcinoma Cells  

PubMed Central

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n?=?6) than in normal skin samples (n?=?6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes. PMID:22427941

Toriseva, Mervi; Ala-aho, Risto; Peltonen, Sirkku; Peltonen, Juha; Grénman, Reidar; Kähäri, Veli-Matti

2012-01-01

24

Intratracheal Administration of Recombinant Human Keratinocyte Growth Factor Promotes Alveolar Epithelial Cell Proliferation during Compensatory Lung Growth in Rat  

PubMed Central

Keratinocyte growth factor (KGF) is considered to be one of the most important mitogens for lung epithelial cells. The objectives of this study were to confirm the effectiveness of intratracheal injection of recombinant human KGF (rhKGF) during compensatory lung growth and to optimize the instillation protocol. Here, trilobectomy in adult rat was performed, followed by intratracheal rhKGF instillation with low (0.4 mg/kg) and high (4 mg/kg) doses at various time-points. The proliferation of alveolar cells was assessed by the immunostaining for proliferating cell nuclear antigen (PCNA) in the residual lung. We also investigated other immunohistochemical parameters such as KGF, KGF receptor and surfactant protein A as well as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Consequently, intratracheal single injection of rhKGF in high dose group significantly increased PCNA labeling index (LI) of alveolar cells in the remaining lung. Surprisingly, there was no difference in PCNA LI between low and high doses of rhKGF with daily injection, and PCNA LI reached a plateau level with 2 days-consecutive administration (about 60%). Our results indicate that even at low dose, daily intratracheal injection is effective to maintain high proliferative states during the early phase of compensatory lung growth. PMID:24610965

Furukawa, Katsuro; Matsumoto, Keitaro; Nagayasu, Takeshi; Yamamoto-Fukuda, Tomomi; Tobinaga, Shuichi; Abo, Takafumi; Yamasaki, Naoya; Tsuchiya, Tomoshi; Miyazaki, Takuro; Kamohara, Ryotaro; Nanashima, Atsushi; Obatake, Masayuki; Koji, Takehiko

2013-01-01

25

Intratracheal Administration of Recombinant Human Keratinocyte Growth Factor Promotes Alveolar Epithelial Cell Proliferation during Compensatory Lung Growth in Rat.  

PubMed

Keratinocyte growth factor (KGF) is considered to be one of the most important mitogens for lung epithelial cells. The objectives of this study were to confirm the effectiveness of intratracheal injection of recombinant human KGF (rhKGF) during compensatory lung growth and to optimize the instillation protocol. Here, trilobectomy in adult rat was performed, followed by intratracheal rhKGF instillation with low (0.4 mg/kg) and high (4 mg/kg) doses at various time-points. The proliferation of alveolar cells was assessed by the immunostaining for proliferating cell nuclear antigen (PCNA) in the residual lung. We also investigated other immunohistochemical parameters such as KGF, KGF receptor and surfactant protein A as well as terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Consequently, intratracheal single injection of rhKGF in high dose group significantly increased PCNA labeling index (LI) of alveolar cells in the remaining lung. Surprisingly, there was no difference in PCNA LI between low and high doses of rhKGF with daily injection, and PCNA LI reached a plateau level with 2 days-consecutive administration (about 60%). Our results indicate that even at low dose, daily intratracheal injection is effective to maintain high proliferative states during the early phase of compensatory lung growth. PMID:24610965

Furukawa, Katsuro; Matsumoto, Keitaro; Nagayasu, Takeshi; Yamamoto-Fukuda, Tomomi; Tobinaga, Shuichi; Abo, Takafumi; Yamasaki, Naoya; Tsuchiya, Tomoshi; Miyazaki, Takuro; Kamohara, Ryotaro; Nanashima, Atsushi; Obatake, Masayuki; Koji, Takehiko

2013-12-28

26

Profiling and metaanalysis of epidermal keratinocytes responses to epidermal growth factor  

PubMed Central

Background One challenge of systems biology is the integration of new data into the preexisting, and then re-interpretation of the integrated data. Here we use readily available metaanalysis computational methods to integrate new data on the transcriptomic effects of EGF in primary human epidermal keratinocytes with preexisting transcriptomics data in keratinocytes and in EGF-treated non-epidermal cell types. Results We find that EGF promotes keratinocyte proliferation, attachment and motility and, surprisingly, induces DUSPs that attenuate the EGF signal. Our metaanalysis identified overlapping effects of EGF with those of IL-1 and IFN?, activators of keratinocyte in inflammation and wound healing. We also identified the genes and pathways suppressed by EGF but induced by agents promoting epidermal differentiation. Metaanalysis comparison with the EGF effects in other cell types identified extensive similarities between responses in keratinocytes and in other epithelial cell types, but specific differences with the EGF effects in endothelial cells, and in transformed, oncogenic epithelial cell lines. Conclusions This work defines the specific transcriptional effects of EGF on human epidermal keratinocytes. Our approach can serve as a suitable paradigm for integration of new omics data into preexisting databases and re-analysis of the integrated data sets. PMID:23391100

2013-01-01

27

The role of keratinocyte growth factor in melanogenesis: a possible mechanism for the initiation of solar lentigines.  

PubMed

Solar lentigines (SLs) are hyperpigmentary lesions presented on sun-exposed areas of the skin and associated with ageing. The molecular mechanism of SL initiation is not completely understood. Ultraviolet B (UVB) stimulates keratinocytes to produce interlukin-1 alpha (IL-1?), which then induces keratinocyte growth factor (KGF) secretion; therefore, we examined their possible roles in the induction of SLs. We found that KGF increases pigment production in both pigmented epidermal equivalents and human skin explants. In addition, UVB exposure increases KGF expression, and KGF treatment induces tyrosinase (TYR) expression in primary melanocytes. The KGF-induced pigmentary changes were confirmed using pigmented Yucatan swine, and human skins grafted onto immuno-deficient mice. In both model systems, the topical treatment with KGF, alone or in combination with IL-1?, resulted in the in vivo formation of hyperpigmentary lesions with increased pigment deposition and elongated rete ridges, which resemble the histological features of human SLs. Preliminary immunohistochemical analysis of human skins showed a moderate increase in KGF, and a strong induction in KGF receptor (KGFR) in SL lesions. In summary, KGF increases pigment production and deposition in vitro and in vivo. Moreover, we show for the first time the in vivo generation of hyperpigmentary lesions with histological resemblance to human SLs and indicate the involvement of KGF/KGFR in the molecular pathology of human SLs. PMID:19780816

Chen, Nannan; Hu, Yaping; Li, Wen-Hwa; Eisinger, Magdalena; Seiberg, Miri; Lin, Connie B

2010-10-01

28

YAC tripeptide of epidermal growth factor promotes the proliferation of HaCaT keratinocytes through activation of EGFR.  

PubMed

Epidermal growth factor (EGF) is known to play key roles in skin regeneration and wound-healing. Here, we demonstrate that Pep2-YAC, a tripeptide covering residues 29-31 in the B loop of EGF, promotes the proliferation of HaCaT keratinocytes with activity comparable to EGF. The treatment of HaCaT cells with Pep2-YAC induced phosphorylation, internalization, and degradation of EGFR and organization of signaling complexes, which consist of Grb2, Gab1, SHP2, and PI3K. In addition, it stimulated the phosphorylation of ERK1/2 at Thr 202/Tyr 204 and of Akt1 at Ser 473 and the nuclear translocation of EGFR, STAT3, c-Jun, and c-Fos. These results suggest that Pep2-YAC may be useful as a therapeutic agent for skin regeneration and wound-healing as an EGFR agonist. [BMB Reports 2014; 47(10): 581-586]. PMID:25179402

Yoo, Yeon Ho; Kim, Yu Ri; Kim, Min Seo; Lee, Kyoung-Jin; Park, Kyeong Han; Hahn, Jang-Hee

2014-10-01

29

Regulation of HMG-CoA Synthase and HMG-CoA Reductase by Insulin and Epidermal Growth Factor in HaCaT Keratinocytes  

Microsoft Academic Search

Synthesis of cholesterol, via the isoprenoid\\/mevalonate pathway, is required for keratinocyte growth and differentiation, and maintenance of the stratum corneum lipid lamellae. 3-hydroxy-3-methylglutaryl coenzyme A synthase catalyzes the first step in isoprenoid\\/mevalonate synthesis and under some conditions controls the flux into the pathway. We have investigated whether selected growth factors and hormones could increase 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA in

Ian R. Harris; Hendrik Höppner; Wilfried Siefken; Angela M. Farrell; Klaus-Peter Wittern

2000-01-01

30

Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model.  

PubMed

Allogeneic stem cell transplantations (SCT) are currently being used as a therapy for hematological malignancies, some solid tumors and nonmalignant bone marrow deficiencies. Nevertheless, clinical applicability is limited due to toxicity of conditioning regimens, graft-versus-host disease (GVHD) and the scarcity of HLA-identical family donors. New concepts are based on nonmyeloablative conditioning to reduce toxicity, prevention or amelioration of GVHD and the use of haploidentical donors to increase donor availability. To combine these requirements, we have developed a nonmyeloablative conditioning regimen, consisting of low-dose total body irradiation and cyclophosphamide-based chemotherapy. In a haploidentical F1 --> F1 mouse model, this nonmyeloablative transplantation protocol resulted in stable full donor chimerism, but also in the development of severe GVHD. Administration of keratinocyte growth factor (KGF) reduced GVHD, evident as reduced weight loss and a lesser degree of dermatitis, compared to saline-treated controls. KGF preserved plasma citrulline and tumor necrosis factor-alpha levels, both indicative for reduced injury to the gastrointestinal tract. This was confirmed by histological findings. At 6 months after transplantation, survival rates were significantly higher in KGF-treated animals as compared to phosphate buffered saline-treated controls. These results indicate that KGF preserves gut integrity and might therefore contribute substantially to reduction of lethal GVHD in (nonmyeloablative) haploidentical transplantation. PMID:16151417

Vanclée, A; Lutgens, L C H W; Oving, E B H; Deutz, N E P; Gijbels, M J J; Schouten, H C; Bos, G M J

2005-11-01

31

Keratinocyte Growth Factor Gene Delivery via Mesenchymal Stem Cells Protects against Lipopolysaccharide-Induced Acute Lung Injury in Mice  

PubMed Central

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality, and have no specific therapy. Keratinocyte growth factor (KGF) is a critical factor for pulmonary epithelial repair and acts via the stimulation of epithelial cell proliferation. Mesenchymal stem cells (MSCs) have been proved as good therapeutic vectors. Thus, we hypothesized that MSC-based KGF gene therapy would have beneficial effects on lipopolysaccharide(LPS)-induced lung injury. After two hours of intratracheal LPS administration to induce lung injury, mice received saline, MSCs alone, empty vector-engineered MSCs (MSCs-vec) or KGF-engineered MSCs (MSCs-kgf) via the tail vein. The MSCs-kgf could be detected in the recipient lungs and the level of KGF expression significantly increased in the MSCs-kgf mice. The MSC-mediated administration of KGF not only improved pulmonary microvascular permeability but also mediated a down-regulation of proinflammatory responses (reducing IL-1? and TNF-?) and an up-regulation of anti-inflammatory responses (increasing cytokine IL-10). Furthermore, the total severity scores of lung injury were significantly reduced in the MSCs-kgf group compared with the other three groups. The underlying mechanism of the protective effect of KGF on ALI may be attributed to the promotion of type II lung epithelial cell proliferation and the enhancement of surfactant synthesis. These findings suggest that MSCs-based KGF gene therapy may be a promising strategy for ALI treatment. PMID:24367590

Chen, Jie; Li, Chunsun; Gao, Xiaofang; Li, Chonghui; Liang, Zhixin; Yu, Ling; Li, Yanqin; Xiao, Xiaoyi; Chen, Liangan

2013-01-01

32

Myofibroblast Differentiation Is Induced in Keratinocyte-Fibroblast Co-Cultures and Is Antagonistically Regulated by Endogenous Transforming Growth Factor-? and Interleukin-1  

PubMed Central

In wound healing epidermal-dermal interactions are known to regulate keratinocyte proliferation and differentiation. To find out how fibroblasts respond to epithelial stimuli, we characterized fibroblasts in monolayer co-culture with keratinocytes. On co-culture numerous extracellular matrix- and smooth muscle cell-associated gene transcripts were up-regulated in fibroblasts, suggesting a differentiation into myofibroblasts. Increased ?-smooth muscle actin (?-SMA) protein expression in co-cultured fibroblasts started at approximately day 4, was serum-independent, but required endogenous transforming growth factor (TGF)-?. In co-cultures, TGF-? neutralizing monoclonal antibody strongly reduced ?-SMA induction. Endogenous TGF-? production and activation were increased at 24 and 48 hours, requiring, like ?-SMA induction, close keratinocyte-fibroblast proximity. As myofibroblast differentiation only started after 4 days, we analyzed the presence of endogenous inhibitors at early time points. Blocking keratinocyte-derived interleukin (IL)-1 using IL-1 receptor antagonist, ?-SMA expression in co-cultures was potentiated. Conversely, adding exogenous IL-1? completely suppressed endogenous ?-SMA induction. In co-cultured fibroblasts strong nuclear factor-?B binding activity was observed from 2 hours, decreasing at 2 and 4 days, suggesting an early, IL-1-mediated inhibition of TGF-? signaling in co-cultured fibroblasts. This biphasic differentiation event is regulated by the balance of endogenous TGF-? and IL-1 activity and is reminiscent of myofibroblast differentiation at early and later stages of wound healing. PMID:15161640

Shephard, Pierre; Martin, Gail; Smola-Hess, Sigrun; Brunner, Georg; Krieg, Thomas; Smola, Hans

2004-01-01

33

A protective role for keratinocyte growth factor in a murine model of chemotherapy and radiotherapy-induced mucositis  

SciTech Connect

Purpose: To evaluate the activity of palifermin (rHuKGF) in a murine model of mucosal damage induced by a radiotherapy/chemotherapy (RT/CT) regimen mimicking treatment protocols used in head-and-neck cancer patients. Methods and Materials: A model of mucosal damage induced by RT/CT was established by injecting female BDF1 mice with cisplatin (10 mg/kg) on Day 1; 5-fluorouracil (40 mg/kg/day) on Days 1-4, and irradiation (5 Gy/day) to the head and neck on Days 1-5. Palifermin was administered subcutaneously on Days -2 to 0 (5 mg/kg/day) and on Day 5 (5 mg/kg). Evaluations included body weight, organ weight, keratinocyte growth factor receptor expression, epithelial thickness, and cellular proliferation. Results: Initiation of the radiochemotherapeutic regimen resulted in a reduction in body weight in control animals. Palifermin administration suppressed weight loss and resulted in increased organ weight (salivary glands and small intestine), epithelial thickness (esophagus and tongue), and cellular proliferation (tongue and salivary glands). Conclusions: Administration of palifermin before RT/CT promotes cell proliferation and increases in epithelial thickness in the oral mucosa, salivary glands, and digestive tract. Palifermin administration before and after RT/CT mitigates weight loss and a trophic effect on the intestinal mucosa and salivary glands, suggesting that palifermin use should be investigated further in the RT/CT settings, in which intestinal mucositis and salivary gland dysfunction are predominant side effects of cytotoxic therapy.

Borges, Luis [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States)]. E-mail: borgesl@amgen.com; Rex, Karen L. [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States); Chen, Jennifer N. [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States); Wei, Ping [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States); Kaufman, Stephen [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States); Scully, Sheila [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States); Pretorius, James K. [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States); Farrell, Catherine L. [Departments of Hematology, Cancer Biology, and Pathology, Amgen Inc., Thousand Oaks, CA (United States)

2006-09-01

34

Infection of Keratinocytes with Trichophytum rubrum Induces Epidermal Growth Factor-Dependent RNase 7 and Human Beta-Defensin-3 Expression  

PubMed Central

Human keratinocytes are able to express various antimicrobial peptides (AMP) to protect the skin from exaggerated microbial colonization and infection. Recently, in vitro growth-inhibiting activity of the skin-derived AMP psoriasin, RNase 7 and human beta-defensin (hBD)-2 against dermatophytes such as Trichophyton (T.) rubrum have been reported. To evaluate whether keratinocytes are able to respond to T. rubrum infection by an induced expression of AMP we exposed primary keratinocytes to living conidia of T. rubrum. This led to conidia germination and mycelial growth which was paralleled by a strong gene induction of the skin-derived AMP RNase 7 and hBD-3. Gene expression of the AMP psoriasin (S100A7) and hBD-2 were only slightly induced. The T. rubrum-mediated RNase 7 gene induction was accompanied by increased secretion of RNase 7. Parallel treatment of the keratinocytes with T. rubrum and the cytokine combination IL-17A/IFN-? resulted in synergistic induction of RNase 7 and hBD-3 expression. Since patients receiving therapy by inhibition of the epidermal growth factor receptor (EGFR) more often suffer from dermatophytoses we investigated whether EGFR may be involved in the T. rubrum-mediated RNase 7 and hBD-3 induction. Primary keratinocytes incubated with an EGFR blocking antibody as well as with the EGFR antagonist AG1478 showed a significantly diminished RNase 7 and hBD-3 induction upon exposure of the keratinocytes to T. rubrum indicating that EGFR is involved in the T. rubrum-mediated induction of RNase 7 and hBD-3. The growth of T. rubrum in vitro was inhibited by hBD-3 in a dose-dependent manner suggesting that hBD-3 may contribute to cutaneous innate defense against T. rubrum. Taken together our data indicate that keratinocytes are able to initiate a fast defense response towards T. rubrum by the increased expression of AMP active against T. rubrum. A dysregulation of AMP may contribute to chronic and recurring dermatophytoses. PMID:24747887

Rademacher, Franziska; Schroder, Lena; Brasch, Jochen; Harder, Jurgen

2014-01-01

35

Long-Term Maintenance of Limbal Epithelial Progenitor Cells Using Rho Kinase Inhibitor and Keratinocyte Growth Factor  

PubMed Central

Corneal epithelial stem cells are located in the limbus, the junction between the cornea and the conjunctiva. A limbal epithelium model in vitro would be useful for the study of epithelial stem cells, as well as improving the quality of cultivated epithelial sheets for the treatment of limbal stem cell deficiency. In this study, we succeeded in constructing a limbal epithelium-like structure that could be maintained for at least 5 months in vitro. We modified conventional medium by replacing epidermal growth factor with keratinocyte growth factor (KGF) and adding Y-27632, a rho kinase inhibitor. Using this medium, epithelial cells freshly isolated from human limbus were cocultured with human mesenchymal stem cell-derived feeder cells. Cells formed a stratified layer without air exposure, and both basal and suprabasal layers maintained their unique morphologies for up to 5 months. Basal layers expressed the progenitor marker p63 uniformly and K15 heterogeneously. Expressions of PAX6, K3, and K12 indicated that cell sheets underwent normal differentiation in the corneal epithelium lineage. Although medium was changed daily after day 7, cell debris was observed every day, suggesting that cell sheets underwent turnover. Furthermore, secondary colonies were observed from cells dissociated from 1-month and 3-month cultured sheets. In conclusion, human limbal epithelial cell sheet cultures with KGF and Y-27632 maintained stratification, high expression of both stem/progenitor markers and differentiation markers, and colony-forming cells long-term. This protocol may be useful as an in vitro limbal epithelial model for basic studies. PMID:23981725

Miyashita, Hideyuki; Yokoo, Seiichi; Yoshida, Satoru; Kawakita, Tetsuya; Yamagami, Satoru; Tsubota, Kazuo

2013-01-01

36

Urokinase expression and binding activity associated with the transforming growth factor beta1-induced migratory and invasive phenotype of mouse epidermal keratinocytes.  

PubMed

Transforming growth factor beta1(TGF-beta1) is a stimulator of malignant progression in mouse skin carcinogenesis. TGF-beta1 exerts a differential effect on cultured nontumorigenic (MCA3D cell line) and transformed (PDV cell line) keratinocytes. Whereas MCA3D cells are growth arrested and committed to die in the presence of the factor, it induces a reversible epithelial-fibroblastic conversion in PDV cells. This conversion is associated in vivo with a squamous-spindle cell carcinoma transition. Here we have investigated the role of urokinase (uPA) during malignant progression of transformed epidermal keratinocytes. We show that the levels of uPA expression/secretion, and the uPA binding activity to the cell surface, correlate with the invasive and malignant potentials of mouse epidermal cell lines. TGF-beta1 enhanced uPA production, the number of uPA cell surface binding sites, and the expression of the plasminogen activator inhibitor PAI-1, in transformed PDV cells, but had no major effect on nontumorigenic MCA3D keratinocytes. Increased uPA production depended on the presence of the factor in the culture medium and occurred concomitantly to the stimulation of the migratory and invasive abilities of PDV cells. Synthetic peptides containing the amino terminal sequence of the mature mouse uPA inhibited the binding of uPA to the cell surface and decreased TGF-beta1-induced cell motility and invasiveness. These results demonstrate that the uPA system mediates at least part of the migratory and invasive phenotype induced by TGF-beta1 in transformed keratinocytes, and suggest a role for uPA on the changes that lead to the appearance of spindle carcinomas. PMID:10381262

Santibáńez, J F; Frontelo, P; Iglesias, M; Martínez, J; Quintanilla, M

1999-07-01

37

Reduction of radiochemotherapy-induced early oral mucositis by recombinant human keratinocyte growth factor (palifermin): Experimental studies in mice  

SciTech Connect

Purpose: To study the effect of recombinant human keratinocyte growth factor (rHuKGF or palifermin) on oral mucositis induced by radiochemotherapy in a mouse model. Methods and Materials: Cis-diamminedichloroplatinum (cisplatin) and/or 5-fluorouracil were given before single dose irradiation, combined with palifermin before or after the treatment, or both. Daily fractionated irradiation for 2 weeks was followed by graded test doses. With additional chemotherapy in Week 1, palifermin was given before radiotherapy and at the end of the first week, or additionally at the end of Week 2. Radiochemotherapy in Week 2 was combined with palifermin at the end of Weeks 1 and 2, Weeks 1, 2, and 3, or additionally before radiotherapy. Ulceration of mouse tongue mucosa was analyzed as the endpoint. Results: The dose associated with ulcer induction in 50% of the mice (ED{sub 50}) for single-dose irradiation was 11.5 {+-} 0.7 Gy. Palifermin increased the ED{sub 50} to about 19 Gy in all protocols tested. Similar values were observed when chemotherapy was added before irradiation. With fractionated irradiation, palifermin increased the ED{sub 50} for test irradiation from 5.7 {+-} 1.5 Gy to 12-15 Gy, depending on the administration protocol. With chemotherapy in Week 1, two palifermin injections had no significant effect, but a third injection increased the ED{sub 50} to 13 Gy. With chemotherapy in Week 2, all palifermin protocols resulted in ED{sub 50} values of 13-14 Gy. Conclusion: A marked increase in oral mucosal radiation tolerance by palifermin was found, which was preserved in combinations with chemotherapy using cisplatin and/or 5-fluorouracil.

Doerr, Wolfgang [Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany) and Experimentelles Zentrum, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany)]. E-mail: doerr@rcs.urz.tu-dresden.de; Baessler, Stefan; Reichel, Sandra [Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany); Spekl, Kathrin [Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany); Experimentelles Zentrum, Medical Faculty Carl Gustav Carus, University of Technology, Dresden (Germany)

2005-07-01

38

Interferon regulatory factor 6 regulates keratinocyte migration.  

PubMed

Interferon regulatory factor 6 (Irf6) regulates keratinocyte proliferation and differentiation. In this study, we tested the hypothesis that Irf6 regulates cellular migration and adhesion. Irf6-deficient embryos at 10.5?days post-conception failed to close their wound compared with wild-type embryos. In vitro, Irf6-deficient murine embryonic keratinocytes were delayed in closing a scratch wound. Live imaging of the scratch showed deficient directional migration and reduced speed in cells lacking Irf6. To understand the underlying molecular mechanisms, cell-cell and cell-matrix adhesions were investigated. We show that wild-type and Irf6-deficient keratinocytes adhere similarly to all matrices after 60?min. However, Irf6-deficient keratinocytes were consistently larger and more spread, a phenotype that persisted during the scratch-healing process. Interestingly, Irf6-deficient keratinocytes exhibited an increased network of stress fibers and active RhoA compared with that observed in wild-type keratinocytes. Blocking ROCK, a downstream effector of RhoA, rescued the delay in closing scratch wounds. The expression of Arhgap29, a Rho GTPase-activating protein, was reduced in Irf6-deficient keratinocytes. Taken together, these data suggest that Irf6 functions through the RhoA pathway to regulate cellular migration. PMID:24777480

Biggs, Leah C; Naridze, Rachelle L; DeMali, Kris A; Lusche, Daniel F; Kuhl, Spencer; Soll, David R; Schutte, Brian C; Dunnwald, Martine

2014-07-01

39

Localization of nerve growth factor (NGF) and low-affinity NGF receptors in touch domes and quantification of NGF mRNA in keratinocytes of adult rats.  

PubMed

Touch domes are clearly delineated mechanoreceptors that are visible on the depilated skin of mammals. These structures consist of a sharply circumscribed disk of thickened epithelium surmounting a group of Merkel cells that are innervated by type I sensory neurons. These characteristic cutaneous structures provide an ideal opportunity for investigating whether the localization of nerve growth factor (NGF) in the skin is related to sites of sensory axon termination. For these reasons, we have used immunocytochemistry to study the distribution of NGF and the low-affinity NGF receptor (p75NGFR) in the touch domes of adult rat skin. Intense NGF-like immunoreactivity was sharply restricted to keratinocytes (excluding the stratum corneum) of the thickened epidermis of touch domes. The epidermis immediately surrounding touch domes and the epidermis of the tylotrich hair follicle associated with touch domes were not stained by anti-NGF antiserum. Merkel cells of the basal epidermis of touch domes were immunonegative for NGF but were immunopositive for p75NGFR as were the type I nerve endings innervating these cells. Quantitative Northern blotting revealed that the level of NGF mRNA was substantially higher in keratinocytes isolated from the stratum granulosum and stratum spinosum than in keratinocytes isolated from the stratum germinativum. These findings indicate that NGF synthesis in mature skin has a highly restricted regional distribution that is primarily associated with the innervation of a specialized touch receptor. PMID:8063962

English, K B; Harper, S; Stayner, N; Wang, Z M; Davies, A M

1994-06-15

40

Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras/MAPK signaling pathway in transformed keratinocytes.  

PubMed

Mouse transformed keratinocytes cultured in the presence of transforming growth factor-beta1 (TGF-beta1) acquire a set of morphological and functional properties giving rise to a more motile phenotype that expresses mesenchymal markers. In this work, we present evidence showing that TGF-beta1 stimulates cellular production of MMP-9 (Gelatinase B), a metalloproteinase that plays an important role in tumoral invasion. Our results demonstrate that TGF-beta1stimulates MMP-9 production and MMP-9 promoter activity in a process that depends of the activation of the Ras-ERK1,2 MAP kinase pathway. The latter was demonstrated by cellular transfection of TGF-beta1-sensitive cells with a RasN17 mutant gene, using PD 098059, a MEK 1,2 inhibitor, and treating cells with anti-sense oligodeoxinucleotides. The enhanced MMP-9 production proved to be an important factor in the acquisition of migratory and invasive properties as shown by the use of a specific inhibitor of MMP-9 (GM6001) that inhibits the TGF-beta1-stimulated invasive and migratory properties of these transformed keratinocytes. PMID:12163012

Santibáńez, Juan Francisco; Guerrero, Javier; Quintanilla, Miguel; Fabra, Angels; Martínez, Jorge

2002-08-16

41

Insulin-like growth factor-binding protein-7 (IGFBP7) transcript: A-to-I editing events in normal and cancerous human keratinocytes.  

PubMed

Non-melanoma skin cancers (NMSC) are the most common malignancies in caucasians worldwide. Insulin-like growth factor-binding protein-7 (IGFBP7) was suggested to function as a tumor suppressor gene in several cancers, and to play a role in the proliferation of keratinocytes. A-to-I RNA editing is a post-transcriptional mechanism frequently used to expand and diversify transcriptome and proteome repertoire in eukaryotic cells. A-to-I RNA editing can alter codons, substitute amino acids and affect protein sequence, structure, and function. Two editing sites were identified within the IGFBP7 transcript. To evaluate the expression and editing of IGFBP7 mRNA in NMSC compared to normal epidermis. We examined the expression and mRNA editing level of IGFBP7 in 22 basal cell carcinoma (BCC), 15 squamous cell carcinoma (SCC), and 18 normal epidermis samples that were surgically removed from patients by the Mohs Micrographic Surgery procedure. We studied the effect of IGFBP7 editing on an immortalized HaCaT keratinocyte cell model. IGFBP7 mRNA is over expressed in BCC and SCC compared to normal epidermis. Moreover, the IGFBP7 transcript is highly edited in normal epidermis, but its editing is significantly reduced in BCC and SCC. The edited form of IGFBP7 can inhibit proliferation and induce senescence in cultured keratinocytes. This study describes for the first time A-to-I editing in the coding sequence of a tumor suppressor gene in humans, and suggests that IGFBP7 editing serves as a fine-tuning mechanism to maintain the equilibrium between proliferation and senescence in normal skin. PMID:23543219

Hochberg, Malka; Gilead, Leon; Markel, Gal; Nemlich, Yael; Feiler, Yulia; Enk, Claes David; Denichenko, Polina; Karni, Rotem; Ingber, Arieh

2013-08-01

42

A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: Activation of proteinase-activated receptor 1 and epidermal growth factor receptor  

SciTech Connect

Biological functions of tissue kallikrein (TK, KLK1) are mainly mediated by kinin generation and subsequent kinin B2 receptor activation. In this study, we investigated the potential role of TK and its signaling pathways in cultured human keratinocyte migration and in a rat skin wound healing model. Herein, we show that TK promoted cell migration and proliferation in a concentration- and time-dependent manner. Inactive TK or kinin had no significant effect on cell migration. Interestingly, cell migration induced by active TK was not blocked by icatibant or L-NAME, indicating an event independent of kinin B2 receptor and nitric oxide formation. TK's stimulatory effect on cell migration was inhibited by small interfering RNA for proteinase-activated receptor 1 (PAR{sub 1}), and by PAR{sub 1} inhibitor. TK-induced migration was associated with increased phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), which was blocked by inhibition of protein kinase C (PKC), Src, EGFR and ERK. TK-induced cell migration and EGFR phosphorylation were blocked by metalloproteinase (MMP) inhibitor, heparin, and antibodies against EGFR external domain, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR). Local application of TK promoted skin wound healing in rats, whereas icatibant and EGFR inhibitor blocked TK's effect. Skin wound healing was further delayed by aprotinin and neutralizing TK antibody. This study demonstrates a novel role of TK in skin wound healing and uncovers new signaling pathways mediated by TK in promoting keratinocyte migration through activation of the PAR{sub 1}-PKC-Src-MMP pathway and HB-EGF/AR shedding-dependent EGFR transactivation.

Gao, Lin; Chao, Lee [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)] [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States); Chao, Julie, E-mail: chaoj@musc.edu [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)] [Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425-2211 (United States)

2010-02-01

43

Platelet Derived Growth Factor (PDGF) Responsive Epidermis Formed from Human Keratinocytes Transduced with the PDGF? Receptor Gene  

Microsoft Academic Search

Platelet-derived growth factor is a major proliferative and migratory stimulus for connective tissue cells during the initiation of skin repair processes. In response to injury, locally produced platelet-derived growth factor is secreted by a diversity of cutaneous cell types whereas target activity is confined to cells of mesenchymal origin, e.g. dermal fibroblasts and smooth muscle cells. Although epidermal cells contribute

Ola Rollman; Uffe B Jensen; Arne Östman; Lars Bolund; Sigrún M Gústafsdóttir; Thomas G Jensen

2003-01-01

44

Transcriptional Control of the Mouse Col7a1 Gene in Keratinocytes: Basal and Transforming Growth Factor-? Regulated Expression  

Microsoft Academic Search

Anchoring fibrils at the cutaneous basement membrane zone of the stratified squamous epithelia are essential to maintaining skin integrity, as absence of these structures leads to the chronic blistering disease, dystrophic epidermolysis bullosa. Type VII collagen, the major component of anchoring fibrils, is synthesized primarily by basal keratinocytes and to a lesser degree by dermal fibroblasts. To elucidate the transcriptional

Michael Naso; Jouni Uitto; John F. Klement

2003-01-01

45

The basic helix-loop-helix/leucine zipper transcription factor USF2 integrates serum-induced PAI-1 expression and keratinocyte growth.  

PubMed

Plasminogen activator inhibitor type-1 (PAI-1), a major regulator of the plasmin-dependent pericellular proteolytic cascade, is prominently expressed during the tissue response to injury although the factors that impact PAI-1 induction and their role in the repair process are unclear. Kinetic modeling using established biomarkers of cell cycle transit (c-MYC; cyclin D1; cyclin A) in synchronized human (HaCaT) keratinocytes, and previous cytometric assessments, indicated that PAI-1 transcription occurred early after serum-stimulation of quiescent (G0) cells and prior to G1 entry. It was established previously that differential residence of USF family members (USF1?USF2 switch) at the PE2 region E box (CACGTG) characterized the G0 ???G1 transition period and the transcriptional status of the PAI-1 gene. A consensus PE2 E box motif (5'-CACGTG-3') at nucleotides -566 to -561 was required for USF/E box interactions and serum-dependent PAI-1 transcription. Site-directed CG???AT substitution at the two central nucleotides inhibited formation of USF/probe complexes and PAI-1 promoter-driven reporter expression. A dominant-negative USF (A-USF) construct or double-stranded PE2 "decoy" attenuated serum- and TGF-?1-stimulated PAI-1 synthesis. Tet-Off induction of an A-USF insert reduced both PAI-1 and PAI-2 transcripts while increasing the fraction of Ki-67(+) cells. Conversely, overexpression of USF2 or adenoviral-delivery of a PAI-1 vector inhibited HaCaT colony expansion indicating that the USF1???USF2 transition and subsequent PAI-1 transcription are critical events in the epithelial go-or-grow response. Collectively, these data suggest that USF2, and its target gene PAI-1, regulate serum-stimulated keratinocyte growth, and likely the cadence of cell cycle progression in replicatively competent cells as part of the injury repair program. PMID:24905330

Qi, Li; Higgins, Craig E; Higgins, Stephen P; Law, Brian K; Simone, Tessa M; Higgins, Paul J

2014-10-01

46

GM-CSF Activates Regenerative Epidermal Growth and Stimulates Keratinocyte Proliferation in Human Skin In Vivo  

Microsoft Academic Search

Granulocyte\\/macrophage – colony-stimulating factor (GM-CSF), an immunomodulator of hematopoietic cells, has also been shown to stimulate human keratinocyte proliferation in vitro and speed healing of wounds in the skin of lepromatous leprosy patients. In this study we have examined the in vivo effects of recombinant human GM-CSF on epidermal keratinocyte proliferation and on expression of proteins marking regenerative epidermal growth.

Scott Braunstein; Gilla Kaplan; Alice B. Gottlieb; Melanie Schwartz; Gerald Walsh; Rodolfo M. Abalos; Tranquilino T. Fajardo; Laarni S. Guido; James G. Krueger

1994-01-01

47

Prevention of Radiation-Induced Oral Mucositis after Adenoviral Vector - Mediated Transfer of the Keratinocyte Growth Factor cDNA to Mouse Submandibular Glands  

PubMed Central

Purpose The study aims to evaluate if human keratinocyte growth factor (hKGF), secreted after transduction of murine salivary glands with adenoviral vectors, can prevent oral mucositis resulting from radiation. Experimental Design Two serotype 5 adenoviral vectors encoding hKGF were constructed: AdEF1?-hKGF and AdLTR2EF1?-hKGF. Female C3H mice, 8 weeks old, were irradiated by single (22.5 Gy) or fractionated (5 × 8 Gy for 5 days) doses to induce oral mucositis (ulcers on tongue). One day before irradiation, the above viral vectors or an empty vector, Adcontrol, was given (1010 particles per gland) to both submandibular glands by retrograde ductal instillation. Each experiment included five groups: no irradiation and irradiation (± Adcontrol, AdEF1?-hKGF, or AdLTR2EF1?-hKGF). Blood, saliva, submandibular glands, and tongue were collected on day 7 for single-dose studies orday10 for fractionated dosing. HKGF levels were measured by ELISA. Results In three separate single-dose irradiation experiments, lingual ulcers were dramatically reduced after either KGF-expressing vector. Similarly, in two separate fractionated irradiation experiments, the hKGF-expressing vectors completely prevented ulcer formation. QPCR data indicated that ~ 107 to 108 particles of each vector remained in the targeted submandibular glands at the terminal time. Transgenic hKGF protein was found at high levels in saliva, serum, and submandibular gland extracts. Conclusions hKGF gene transfer to salivary glands prevented radiation-induced oral mucositis in mice. This proof of concept study suggests that transgenic hKGF secreted from transduced salivary glands may be useful clinically to prevent oral mucositis caused by radiation. PMID:19584147

Zheng, Changyu; Cotrim, Ana P.; Sunshine, Abraham N.; Sugito, Takayuki; Liu, Lina; Sowers, Anastasia; Mitchell, James B.; Baum, Bruce J.

2009-01-01

48

Immunomodulatory effects of palifermin (recombinant human keratinocyte growth factor) in an SLE-like model of chronic graft-versus-host disease.  

PubMed

Keratinocyte growth factor (KGF) promotes epithelial cell proliferation and survival. Recombinant human KGF, also known as palifermin, protects epithelial cells from injury induced by chemicals, irradiation and acute murine graft-versus-host disease (GVHD). Findings from our studies and others have shown that palifermin also has immunomodulatory properties. In a model of acute GVHD, we showed that it shifts the immune response from one in which Th1 cytokines dominate to mixed Th1 and Th2 cytokine profile. Using the DBA/2?(C57BL/6 × DBA/2)F(1)-hybrid model of chronic, systemic lupus erythematosus-like GVHD, we showed that palifermin treatment is associated with higher levels of Th2 cytokines, the production of anti-nuclear antibodies, cryoglobulinemia and the development of more severe pathological changes in the kidney. The aim of our current study was to gain a better understanding of the immunobiology of KGF by further characterizing the palifermin-mediated effects in this model of chronic GVHD. Because the pathological changes we observed resemble those seen in thymic stromal lymphopoietin (TSLP) transgenic mice, we had originally hypothesized that palifermin might augment TSLP levels. Surprisingly, we did not observe an increase in thymic TSLP mRNA expression in palifermin-treated recipients. We did, however, observe some differences in the percentages of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the spleen at some time points in palifermin-treated recipients. Most importantly, we found that TGF? levels were higher in palifermin-treated recipients early in the GVH reaction, raising the possibility that KGF might indirectly induce the development of fibrosis and glomerulonephritis through a pathway involving TGF?. PMID:21916922

Ellison, C A; Lissitsyn, Y V; Gheorghiu, I; Gartner, J G

2012-01-01

49

The autonomous growth of human papillomavirus type 16-immortalized keratinocytes is related to the endothelin-1 autocrine loop.  

PubMed Central

Some human papillomaviruses (HPVs) such as HPV type 16 (HPV16) and HPV18 are involved in cervical carcinoma, and they can immortalize and transform keratinocytes. Endothelin-1 (ET-1) is produced in keratinocytes and has been shown to act through ETA receptors as an autocrine growth factor for keratinocytes. This study examines whether HPV16 alters the ET-1-mediated autocrine loop in human keratinocytes, providing a selective growth advantage for transformed cells. ET-1 is released in similar amounts from normal and HPV-transfected keratinocytes. All HPV-transfected cell lines express high-affinity ETA receptors. A two-fold increase in ET-1 binding sites is present in HPV16-immortalized keratinocytes, and this effect seems to be linked to the overexpression of mRNA for this receptor rather than to differences in the surface/internalized ratio of the receptors. ET-1 induces significant increases in [3H]thymidine incorporation and cell proliferation. Furthermore, HPV-transfected keratinocytes can proliferate in the absence of any growth factor added to the growth medium, and the ETA receptor antagonist BQ123 prevents this proliferation. These data suggest a new mechanism in the growth control of HPV-transformed cells mediated by the upregulation of ET-1 autocrine loop. PMID:9261416

Venuti, A; Marcante, M L; Flamini, S; Di Castro, V; Bagnato, A

1997-01-01

50

Coculture system of keratinocytes and dorsal-root-ganglion-derived cells for screening neurotrophic factors involved in guidance of neuronal axon growth in the skin.  

PubMed

The density of peripheral nerve fibres is increased in atopic dermatitis. Moreover, reduction in the fibres in a mouse model of atopic dermatitis reduces scratching behaviour. Thus, regulation of nerve fibre extension could be an effective strategy to reduce itching in pruritus dermatosis. In this study, we established a new coculture system of keratinocytes and dorsal-root-ganglion-derived cells using an apparatus, AXIS(™) , which consists of two different channels connected via a set of microgrooves, through which signalling molecules and axons, but not living cells, can pass. When we seeded keratinocytes in one chamber, extension of nerve fibres was observed from dorsal root ganglion cells seeded in the other chamber. Addition of anti-BDNF antibody in the keratinocyte-seeded chamber significantly reduced the extension. Application of Semaphorin 3A also reduced the extension by approximately 50%. We suggest that this coculture system may be useful for screening of anti-itching drugs. PMID:24267269

Kumamoto, Jun-Ichi; Nakatani, Masashi; Tsutsumi, Moe; Goto, Makiko; Denda, Sumiko; Takei, Kentaro; Denda, Mitsuhiro

2014-01-01

51

Platelet-activating factor induces proliferation in differentiated keratinocytes.  

PubMed

Increased levels of platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) are found in several inflammatory dermatoses, but PAF's exact role in epidermis is uncertain. In order to better understand the physiological consequences of excess PAF production in epidermis, we examined the gene regulatory effects of PAF short-term stimulation in differentiated HaCaT keratinocytes by transcriptional profiling. Even though PAF induces COX2 expression, we found that PAF regulates only few genes associated with inflammation in differentiated keratinocytes. Rather, we show that natural PAF rapidly regulates genes involved in proliferation, (anti)-apoptosis and migration, all sub-processes of re-epithelialization and wound healing. Moreover, profiling of phosphorylated kinases, cellular wound-scratch experiments, resazurin assay and flow cytometry cell cycle phase analysis all support a role for PAF in keratinocyte proliferation and epidermal re-epithelialization. In conclusion, these results suggest that PAF acts as an activator of proliferation and may, therefore, function as a connector between inflammation and proliferation in differentiated keratinocytes. PMID:23975504

Feuerherm, Astrid J; Jřrgensen, Katarina M; Sommerfelt, Randi M; Eidem, Live E; Lćgreid, Astrid; Johansen, Berit

2013-12-01

52

Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing  

PubMed Central

The molecular mechanism underlying the promotion of wound healing by TGF-beta 1 is incompletely understood. We report that TGF-beta 1 regulates the regenerative/migratory phenotype of normal human keratinocytes by modulating their integrin receptor repertoire. In growing keratinocyte colonies but not in fully stratified cultured epidermis, TGF-beta 1: (a) strongly upregulates the expression of the fibronectin receptor alpha 5 beta 1, the vitronectin receptor alpha v beta 5, and the collagen receptor alpha 2 beta 1 by differentially modulating the synthesis of their alpha and beta subunits; (b) downregulates the multifunctional alpha 3 beta 1 heterodimer; (c) induces the de novo expression and surface exposure of the alpha v beta 6 fibronectin receptor; (d) stimulates keratinocyte migration toward fibronectin and vitronectin; (e) induces a marked perturbation of the general mechanism of polarized domain sorting of both beta 1 and beta 4 dimers; and (f) causes a pericellular redistribution of alpha v beta 5. These data suggest that alpha 5 beta 1, alpha v beta 6, and alpha v beta 5, not routinely used by keratinocytes resting on an intact basement membrane, act as "emergency" receptors, and uncover at least one of the molecular mechanisms responsible for the peculiar integrin expression in healing human wounds. Indeed, TGF-beta 1 reproduces the integrin expression pattern of keratinocytes located at the injury site, particularly of cells in the migrating epithelial tongue at the leading edge of the wound. Since these keratinocytes are inhibited in their proliferative capacity, these data might account for the apparent paradox of a TGF-beta 1-dependent stimulation of epidermal wound healing associated with a growth inhibitory effect on epithelial cells. PMID:7537276

1995-01-01

53

Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta(1) in transformed keratinocytes.  

PubMed

Transformed PDV keratinocytes respond to TGF-beta(1) by stimulating cell motility and invasiveness concomitantly to enhancement of the urokinase-type plasminogen activator (uPA) expression/secretion. Depletion of extracellular signal-regulated kinase (ERK1, 2) proteins by treatment of PDV cells with antisense oligonucleotides reduced basal uPA production and abolished stimulation of uPA secreted levels and cell motility by TGF-beta(1). PD098059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase (MEK), decreased TGF-beta(1)-induced uPA mRNA expression, secreted activity in a dose-dependent manner, and abrogated TGF-beta(1)-stimulated cell motility and invasiveness. PDV-derived dominant-negative RasN17 cell transfectants secreted similar amounts of uPA and exhibited similar invasive abilities as the parental cells or control clones, but were unable to respond to TGF-beta(1) for stimulation of uPA-secreted levels and invasiveness. These results suggest that a Ras/MAPK transduction pathway is involved in the invasive response of transformed keratinocytes to TGF-beta(1). PMID:10873638

Santibáńez, J F; Iglesias, M; Frontelo, P; Martínez, J; Quintanilla, M

2000-07-01

54

Retinoic acid resistance at late stages of human papillomavirus type 16-mediated transformation of human keratinocytes arises despite intact retinoid signaling and is due to a loss of sensitivity to transforming growth factor-beta.  

PubMed

In our in vitro model of human cell carcinogenesis, normal human foreskin keratinocytes (HKc) transfected with human papillomavirus type 16 DNA (HKc/HPV16) progress toward malignancy through several phenotypically defined and reproducible "steps" that include immortalization, growth factor independence (HKc/GFI), differentiation resistance (HKc/DR), and ultimately malignant conversion. While HKc/HPV16 are very sensitive to growth inhibition by all-trans-retinoic acid (RA) at early passages, they lose their sensitivity to RA during progression in culture. However, gel mobility shift assays using the retinoid response elements DR1 and DR5 showed no changes in binding activity of nuclear extracts obtained from HKc/HPV16 at different stages of in vitro progression. Similarly, Western blot analyses for retinoic acid receptor gamma-1 and the retinoid X receptors failed to reveal any decreases in the levels of these retinoid receptors throughout progression. In addition, luciferase activity driven by the SV40 promoter with a DR5 enhancer element was activated following RA treatment of HKc/DR that were resistant to growth inhibition by RA. Since RA induces transforming growth factor-beta2 (TGF-beta2) in normal HKc and HKc/HPV16, we investigated whether this response changed during progression. Again, RA induced TGF-beta2 mRNA in early and late passage HKc/HPV16, HKc/GFI, and HKc/DR approximately to the same extent, confirming that the RA signaling pathways remained intact during in vitro progression despite the fact that the cells become resistant to growth inhibition by RA. We then investigated the sensitivity of HKc/HPV16 to growth inhibition by TGF-beta. While early passage HKc/HPV16 were as sensitive as normal HKc to growth inhibition by TGF-beta1 and TGF-beta2, the cells became increasingly resistant to both TGF-beta isotypes during in vitro progression. In addition, while both RA and TGF-beta produced a decrease in the levels of mRNA for the HPV16 oncogenes E6 and E7 in early passage HKc/HPV16, this effect was also lost at later stages of progression. Finally, blocking anti-TGF-beta antibodies partially prevented RA inhibition of growth and E6/E7 expression in early passage HKc/HPV16. Taken together, these data strongly suggest that inhibition of growth and HPV16 early gene expression in HKc/HPV16 by RA is mediated by TGF-beta and that a loss of RA sensitivity is linked to TGF-beta resistance rather than alterations in RA signaling. PMID:10792999

Borger, D R; Mi, Y; Geslani, G; Zyzak, L L; Batova, A; Engin, T S; Pirisi, L; Creek, K E

2000-05-10

55

P. gingivalis Modulates Keratinocytes through FOXO Transcription Factors  

PubMed Central

P. gingivalis is a prominent periodontal pathogen that has potent effects on host cells. In this study we challenged gingival epithelial cells with P. gingivalis with the aim of assessing how mRNA levels of key target genes were modulated by P. gingivalis via the transcription factors FOXO1 and FOXO3. Primary mono- and multi-layer cultures of gingival epithelial cells were challenged and barrier function was examined by fluorescent dextran and apoptosis was measured by cytoplasmic histone associated DNA. Gene expression levels were measured by real-time PCR with and without FOXO1 and FOXO3 siRNA compared to scrambled siRNA. P. gingivalis induced a loss of barrier function and stimulated gingival epithelial cell apoptosis in multilayer cultures that was in part gingipain dependent. P. gingivalis stimulated an increase in FOXO1 and FOXO3 mRNA, enhanced mRNA levels of genes associated with differentiated keratinocyte function (keratin-1, -10, -14, and involucrin), increased mRNA levels of apoptotic genes (BID and TRADD), reduced mRNA levels of genes that regulate inflammation (TLR-2 and -4) and reduced those associated with barrier function (integrin beta-1, -3 and -6). The ability of P. gingivalis to modulate these genes was predominantly FOXO1 and FOXO3 dependent. The results indicate that P. gingivalis has pronounced effects on gingival keratinocytes and modulates mRNA levels of genes that affect host response, differentiation, apoptosis and barrier function. Moreover, this modulation is dependent upon the transcription factors FOXO1 or FOXO3. In addition, a new function for FOXO1 was identified, that of suppressing TLR-2 and TLR-4 and maintaining integrin beta -1, beta -3 and beta -6 basal mRNA levels in keratinocytes. PMID:24265696

Li, Shuai; Dong, Guangyu; Moschidis, Anastasios; Ortiz, Javier; Benakanakere, Manjunatha R.; Kinane, Denis F.; Graves, Dana T.

2013-01-01

56

Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study.  

PubMed

Oral and/or intestinal mucositis is a severe complication of hematopoietic SCT. Keratinocyte growth factor (KGF) has proven activity in the prevention of oral mucositis. We examined the efficacy of KGF in the prevention of intestinal mucositis. From January 2006 until December 2007, 35 consecutive patients underwent autologous SCT (auto-SCT) in our institution. A total of 15 consecutive patients who underwent auto-SCT from March 2007 to December 2007 received KGF for the prevention of mucositis and were included in the study group A, whereas 20 consecutive patients treated from January 2006 to March 2007, were included in the historical control group B. Oral and intestinal mucositis were significantly less severe in group A (P=0.002 and P<0.001, respectively). These results were confirmed with the use of video-capsule endoscopy. Patients in group A had a significantly lower incidence of neutropenic fever (P=0.026). Severe intestinal mucositis was significantly associated with a higher incidence of documented infections too (P=0.019). KGF is effective in the prevention of intestinal mucositis in patients undergoing auto-SCT. Patients with severe intestinal mucositis run a higher risk to develop infections. PMID:18560408

Tsirigotis, P; Triantafyllou, K; Girkas, K; Giannopoulou, V; Ioannidou, E; Chondropoulos, S; Kalli, T; Papaxoinis, G; Pappa, V; Papageorgiou, E; Economopoulos, T; Ladas, S D; Dervenoulas, J

2008-09-01

57

N-cadherin and keratinocyte growth factor receptor mediate the functional interplay between Ki-RASG12V and p53V143A in promoting pancreatic cell migration, invasion, and tissue architecture disruption.  

PubMed

The genetic basis of pancreatic ductal adenocarcinoma, which constitutes the most common type of pancreatic malignancy, involves the sequential activation of oncogenes and inactivation of tumor suppressor genes. Among the pivotal genetic alterations are Ki-RAS oncogene activation and p53 tumor suppressor gene inactivation. We explain that the combination of these genetic events facilitates pancreatic carcinogenesis as revealed in novel three-dimensional cell (spheroid cyst) culture and in vivo subcutaneous and orthotopic xenotransplantation models. N-cadherin, a member of the classic cadherins important in the regulation of cell-cell adhesion, is induced in the presence of Ki-RAS mutation but subsequently downregulated with the acquisition of p53 mutation as revealed by gene microarrays and corroborated by reverse transcription-PCR and Western blotting. N-cadherin modulates the capacity of pancreatic ductal cells to migrate and invade, in part via complex formation with keratinocyte growth factor receptor and neural cell adhesion molecule and in part via interaction with p120-catenin. However, modulation of these complexes by Ki-RAS and p53 leads to enhanced cell migration and invasion. This preferentially induces the downstream effector AKT over mitogen-activated protein kinase to execute changes in cellular behavior. Thus, we are able to define molecules that in part are directly affected by Ki-RAS and p53 during pancreatic ductal carcinogenesis, and this provides a platform for potential new molecularly based therapeutic interventions. PMID:16705170

Deramaudt, Therese B; Takaoka, Munenori; Upadhyay, Rabi; Bowser, Mark J; Porter, Jess; Lee, Amy; Rhoades, Ben; Johnstone, Cameron N; Weissleder, Ralph; Hingorani, Sunil R; Mahmood, Umar; Rustgi, Anil K

2006-06-01

58

Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF?B and AhR and EGFR–ERK pathway  

Microsoft Academic Search

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor

Alla I. Potapovich; Daniela Lulli; Paolo Fidanza; Vladimir A. Kostyuk; Chiara De Luca; Saveria Pastore; Liudmila G. Korkina

2011-01-01

59

Essential role of an activator protein-2 (AP-2)/specificity protein 1 (Sp1) cluster in the UVB-mediated induction of the human vascular endothelial growth factor in HaCaT keratinocytes.  

PubMed Central

Chronic sun exposure of the skin has long been postulated to enhance cutaneous angiogenesis, resulting in highly vascularized skin cancers. As the UVB component of sunlight is a major contributor to photocarcinogenesis, we aimed to explore the effects of UVB radiation on vascular endothelial growth factor (VEGF) gene expression, using the immortalized keratinocyte cell line HaCaT as a model for transformed premalignant epithelial cells. In the present paper, we studied the molecular mechanism of UVB-induced VEGF providing a major angiogenic activity in tumour progression and invasion. After 12-24 h of UVB irradiation, a 2.4- to 2.7-fold increase in endogenous VEGF protein level was measured, correlating with an up to 2.5-fold induction of promoter-based reporter gene constructs of VEGF. Furthermore, we identified a GC-rich UVB-responsive region between -87 and -65 bp of the VEGF promoter. In electrophoretic mobility-shift assays, this region binds Sp1-dependent protein complexes constitutively and an additional UVB-inducible protein complex distinct from Sp1 protein. The transcription factor AP-2 (activator protein-2) was detected as a component of the UVB-inducible protein complex. The critical role of the AP-2/Sp1 (specificity protein 1) cluster was supported by demonstration of a significant reduction of UVB-mediated promoter activity upon deletion of this recognition site. The specificity of this region for UVB irradiation was demonstrated using PMA, which increased VEGF activity in HaCaT cells after transient transfection of the deleted promoter construct. In conclusion, our data clarified regulatory mechanisms of UVB-dependent VEGF stimulation which may be critical for angiogenic processes in the skin. PMID:12358602

Brenneisen, Peter; Blaudschun, Ralf; Gille, Jens; Schneider, Lars; Hinrichs, Ralf; Wlaschek, Meinhard; Eming, Sabine; Scharffetter-Kochanek, Karin

2003-01-01

60

Interferon regulatory factor 6 is necessary, but not sufficient, for keratinocyte differentiation.  

PubMed

Regulation of epidermal proliferation and differentiation is critical for maintenance of cutaneous homeostasis. Interferon Regulatory Factor 6 (Irf6)-deficient mice die perinatally and exhibit ectopic proliferation and defective epidermal differentiation. We sought to determine whether these disruptions of epidermal function were cell autonomous, and used embryonic Irf6(-/-) keratinocytes to understand the specific role of Irf6 in keratinocyte proliferation and differentiation. In the absence of Irf6, keratinocytes exhibited a heterogeneous phenotype with the presence of large cells. Irf6(-/-) keratinocytes displayed increased colony-forming efficiency compared with wild-type cells, suggesting that Irf6 represses long-term proliferation. Irf6 was present at low levels in wild-type keratinocytes in culture, and upregulated after induction of differentiation in vitro, along with upregulation of markers of early differentiation. However, Irf6(-/-) keratinocytes did not express markers of terminal differentiation. Overexpression of Irf6 in wild-type keratinocytes was insufficient to induce expression of markers of differentiation under growing conditions. Together, these results indicated that Irf6 is necessary, but not sufficient, for keratinocyte differentiation. Finally, using a transgenic mouse expressing Lac-Z under the regulation of an enhancer element 9.7? kb upstream of the Irf6 start site, we demonstrated that this element contributes to the regulation of Irf6 in the epidermis and keratinocytes in culture. PMID:21918538

Biggs, Leah C; Rhea, Lindsey; Schutte, Brian C; Dunnwald, Martine

2012-01-01

61

The Effect of Secretory Factors of Adipose-Derived Stem Cells on Human Keratinocytes  

PubMed Central

The beneficial effects of adipose-derived stem cell conditioned medium (ADSC-CM) on skin regeneration have been reported. Although the mechanism of how ADSC-CM promotes skin regeneration is unclear, ADSC-CM contained various growth factors and it is an excellent raw material for skin treatment. ADSC-CM produced in a hypoxia condition of ADSC—in other words, Advanced Adipose-Derived Stem cell Protein Extract (AAPE)—has great merits for skin regeneration. In this study, human primary keratinocytes (HKs), which play fundamental roles in skin tissue, was used to examine how AAPE affects HK. HK proliferation was significantly higher in the experimental group (1.22 ?g/mL) than in the control group. DNA gene chip demonstrated that AAPE in keratinocytes (p < 0.05) notably affected expression of 290 identified transcripts, which were associated with cell proliferation, cycle and migration. More keratinocyte wound healing and migration was shown in the experimental group (1.22 ?g/mL). AAPE treatment significantly stimulated stress fiber formation, which was linked to the RhoA-ROCK pathway. We identified 48 protein spots in 2-D gel analysis and selected proteins were divided into 64% collagen components and 30% non-collagen components as shown by the MALDI-TOF analysis. Antibody array results contained growth factor/cytokine such as HGF, FGF-1, G-CSF, GM-CSF, IL-6, VEGF, and TGF-?3 differing from that shown by 2-D analysis. Conclusion: AAPE activates HK proliferation and migration. These results highlight the potential of the topical application of AAPE in the treatment of skin regeneration. PMID:22312315

Moon, Kyoung Mi; Park, Ye-Hyoung; Lee, Jae Seol; Chae, Yong-Byung; Kim, Moon-Moo; Kim, Dong-Soo; Kim, Byung-Woo; Nam, Soo-Wan; Lee, Jong-Hwan

2012-01-01

62

Modulation of TGF-?-inducible hypermotility by EGF and other factors in human prostate epithelial cells and keratinocytes.  

PubMed

Keratinocytes migrating from a wound edge or initiating malignant invasion greatly increase their expression of the basement membrane protein Laminin-322 (Lam332). In culture, keratinocytes initiate sustained directional hypermotility when plated onto an incompletely processed form of Lam332 (Lam332') or when treated with transforming growth factor beta (TGF-?), an inducer of Lam332 expression. The development and tissue architecture of stratified squamous and prostate epithelia are very different, yet the basal cells of both express p63, ?6?4 integrin, and Lam332. Keratinocytes and prostate epithelial cells grow well in nutritionally optimized culture media with pituitary extract and certain mitogens. We report that prostate epithelial cells display hypermotility responses indistinguishable from those of keratinocytes. Several culture medium variables attenuated TGF-?-induced hypermotility, including Ca(++), serum, and some pituitary extract preparations, without impairing growth, TGF-? growth inhibition, or hypermotility on Lam322'. Distinct from its role as a mitogen, EGF proved to be a required cofactor for TGF-?-induced hypermotility and could not be replaced by HGF or KGF. Prostate epithelial cells have a short replicative lifespan, restricted both by p16(INK4A) and telomere-related mechanisms. We immortalized the normal prostate epithelial cell line HPrE-1 by transduction to express bmi1 and TERT. Prostate epithelial cells lose expression of p63, ?4 integrin, and Lam332 when they transform to invasive carcinoma. In contrast, HPrE-1/bmi1/TERT cells retained expression of these proteins and normal TGF-? signaling and hypermotility for >100 doublings. Thus, keratinocytes and prostate epithelial cells possess common hypermotility and senescence mechanisms and immortalized prostate cell lines can be engineered using defined methods to yield cells retaining normal properties. PMID:21042878

Wei, Wei; Barron, Patricia D; Rheinwald, James G

2010-12-01

63

The effect of different biologic and biosynthetic wound covers on keratinocyte growth, stratification and differentiation in vitro  

PubMed Central

The purpose of this study was to compare, by means of in vitro cultivation technique, five marketed brands of wound covers used in the treatment of burns and other skin defects (Biobrane®, Suprathel®, Veloderm®, Xe-Derma®, and Xenoderm®) for their ability to stimulate the keratinocyte growth, stratification, and differentiation. In three independent experiments, human keratinocytes were grown on the tested covers in organotypic cultures by the 3T3 feeder layer technique. Vertical paraffin sections of the wound covers with keratinocytes were processed using hematoxylin–eosin staining and immunostaining for involucrin. Keratinocyte populations on the dressings were assessed for (1) number of keratinocyte strata (primary variable), (2) quantitative growth, (3) thickness of the keratinocyte layer, and (4) cell differentiation. The Xe-Derma wound cover provided the best support to keratinocyte proliferation and stratification, with the number of keratinocyte strata significantly (p?keratinocyte proliferation and stratification. The distinctive position of Xe-Derma may be related to its composition, where natural dermal fibers form a smooth surface, similar to the basement membrane. Furthermore, the results indicate that in vitro evaluation of effects on epithelial growth may accelerate the development of new bio-engineering-based wound covers. PMID:25383177

Mestak, Ondrej

2014-01-01

64

Ultraviolet-B-Induced Apoptosis of Keratinocytes: Evidence for Partial Involvement of Tumor Necrosis Factor-? in the Formation of Sunburn Cells  

Microsoft Academic Search

Irradiation with ultraviolet (UV) B radiation results in the formation of apoptotic keratinocytes called sunburn cells. Recently, it was demonstrated that keratinocytes can release tumor necrosis factor-? (TNF-?), which is known to cause apoptosis in particular cells. In addition, it has been shown that UVB light induces the release of TNF-? by keratinocytes and that keratinocytes express the 55-kD receptor

Agatha Schwarz; Ranjit Bhardwaj; Yoshinori Aragane; Karsten Mahnke; Helge Riemann; Dieter Metze; Thomas A. Luger; Thomas Schwarz

1995-01-01

65

Kaposi's Sarcoma-Associated Herpesvirus Can Productively Infect Primary Human Keratinocytes and Alter Their Growth Properties  

PubMed Central

Previous studies have shown the presence of Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) DNA in endothelial cells, in keratinocytes in the basal layer of the epidermis overlying plaque-stage nodular lesions of cutaneous Kaposi's sarcoma (KS), and in the epithelial cells of eccrine glands within KS lesions. We infected primary cell cultures of human keratinocytes with KSHV/HHV8. At 6 days post infection, transcription of viral genes was detected by reverse transcriptase PCR (RT-PCR), and protein expression was documented by an immunofluorescence assay with an anti-LANA monoclonal antibody. To determine whether the viral lytic cycle was inducible by chemical treatment, KSHV/HHV8-infected keratinocytes were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and RT-PCR was performed to confirm the transcription of lytic genes such as open reading frame 26, (which encodes a capsid protein). Finally, to assess infectious viral production, other primary human cells (human umbilical vein endothelial cells), were infected with concentrated supernatant of KSHV-infected, TPA-induced keratinocytes and the presence of viral transcripts was confirmed by RT-PCR. The uninfected keratinocytes senesced 3 to 5 weeks after mock infection, while the KSHV/HHV8-infected keratinocytes continued to proliferate and to date are still in culture. However, 8 weeks after infection, viral genomes were no longer detectable by nested PCR. Although the previously KSHV/HHV8-infected keratinocytes still expressed epithelial markers, they acquired new characteristics such as contact inhibition loss, telomerase activity, anchorage-independent growth, and changes in cytokine production. These results show that KSHV/HHV8, like other herpesviruses, can infect and replicate in epithelial cells in vitro and suggest that in vivo these cells may play a significant role in the establishment of KSHV/HHV8 infection and viral transmission. PMID:11160746

Cerimele, Francesca; Curreli, Francesca; Ely, Scott; Friedman-Kien, Alvin E.; Cesarman, Ethel; Flore, Ornella

2001-01-01

66

C\\/EBPb Modulates the Early Events of Keratinocyte Differentiation Involving Growth Arrest and Keratin 1 and Keratin 10 Expression  

Microsoft Academic Search

The epidermis is a stratified squamous epithelium composed primarily of keratinocytes that become post- mitotic and undergo sequential changes in gene expression during terminal differentiation. The expression of the transcription factor CCAAT\\/enhancer binding protein b (C\\/EBPb) within mouse epidermis and primary keratinocytes has recently been described; however, the function of C\\/EBPb within the epidermal keratinocyte is unknown. We report here

SONGYUN ZHU; HYE-SUN OH; MINSUB SHIM; ESTA STERNECK; PETER F. JOHNSON; ROBERT C. SMART

1999-01-01

67

Ultraviolet B Radiation Upregulates the Production of Macrophage Migration Inhibitory Factor (MIF) in Human Epidermal Keratinocytes  

Microsoft Academic Search

Human epidermal cells are capable of secreting various cytokines with immunologic, inflammatory, and proliferative properties. In a previous study, by reverse transcription–polymerase chain reaction and immunohistochemical analysis, we have shown that human epidermal keratinocytes express macrophage migration inhibitory factor and identified its presence in the cytoplasm. In this study, we detected an increased serum macrophage migration inhibitory factor level by

Tadamichi Shimizu; Riichiro Abe; Akira Ohkawara; Jun Nishihira; J. Nishihira

1999-01-01

68

Vasoactive intestinal peptide and cytokines enhance stem cell factor production from epidermal keratinocytes DJM-1.  

PubMed

Stem cell factor can induce mast cell proliferation and melanocyte activation. Vasoactive intestinal peptide has been suggested to play a part in inflammatory dermatoses, such as atopic dermatitis. The aim of this study was to investigate the possible role of stem cell factor in atopic dermatitis by analyzing epidermal stem cell factor production induced by vasoactive intestinal peptide and cytokines. Full-length type stem cell factor transcript was detected in normal human epidermal keratinocytes, and a human epidermal keratinocyte cell line DJM-1, as well as normal human dermal fibroblasts, using reverse transcription-polymerase chain reaction. Spliced-type stem cell factor transcript was detected in both DJM-1 cells and normal human epidermal keratinocytes. Western blot analysis with stem cell factor antibody revealed a protein of the known molecular size of membrane-bound stem cell factor in the lysates of all three cell types. Stem cell factor immunoreactivity was found in the cytoplasm and the membrane of both DJM-1 cells and normal human epidermal keratinocytes using confocal laser scanning microscope. We examined the effects of vasoactive intestinal peptide and cytokines on stem cell factor production of DJM-1 cells using enzyme-linked immunosorbent assays. Stem cell factor contents significantly increased in culture supernatants of DJM-1 cells treated with 1000 nm vasoactive intestinal peptide and/or cytokines, including interleukins 4 and 13, tumor necrosis factor-alpha, and interferon-gamma. Overall, these results suggest that several inflammatory cytokines (T helper 1 and 2) and vasoactive intestinal peptide from mast cells and nerve endings are capable of inducing stem cell factor production from epidermal keratinocytes in atopic dermatitis. PMID:12445210

Kakurai, Maki; Fujita, Nobuya; Kiyosawa, Tomoharu; Inoue, Tae; Ishibashi, Shun; Furukawa, Yusuke; Demitsu, Toshio; Nakagawa, Hidemi

2002-11-01

69

Motogenic substrata and chemokinetic growth factors for human skin cells  

PubMed Central

Extracellular matrix remodelling and accurate spatio-temporal coordination of growth factor expression are two factors that are believed to regulate mitoses and cell migration in developing and regenerating tissues. The present quantitative videomicroscopical study examined the influence of some of the principal components of extracellular matrix and several growth factors that are known to be expressed in dermal wounds on three important facets of human skin cell behaviour in culture. Keratinocytes, melanocytes and dermal fibroblasts (and myofibroblast controls) exhibited varying degrees of substrate adhesion, division and migration depending on the composition of the culture substrate. Substrates that are recognized components of transitional matrices generally accentuated cell adhesion and proliferation, and were motogenic, when compared with serum-treated control surfaces, whereas components of more stable structures such as basement membrane had less influence. Platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and ? fibroblastic growth factor (?FGF) all promoted cell proliferation and were chemokinetic to dermal fibroblasts, but not keratinocyte growth factor (KGF) or transforming growth factor ? (TGF?). PDGF, EGF and KGF, but not TGF? or ?FGF, all enhanced proliferation of dermal keratinocytes. The same growth factors, and in addition KGF, all stimulated motility in keratinocytes, but TGF? and ?FGF again had no effect. Developing a better understanding of the interdependency of factors that control crucial cell behaviour may assist those who are interested in the regulation of histogenesis and also inform the development of rational therapeutic strategies for the management of chronic and poorly healed wounds. PMID:16011545

Sutherland, Jennifer; Denyer, Morgan; Britland, Stephen

2005-01-01

70

Lithium Regulates Keratinocyte Proliferation Via Glycogen Synthase Kinase 3 and NFAT2 (Nuclear Factor of Activated T Cells 2)  

PubMed Central

Certain environmental factors including drugs exacerbate or precipitate psoriasis. Lithium is the commonest cause of drug-induced psoriasis but underlying mechanisms are currently unknown. Lithium inhibits glycogen synthase kinase 3 (GSK-3). As lithium does not exacerbate other T-cell-mediated chronic inflammatory diseases, we investigated whether lithium may be acting directly on epidermal keratinocytes by inhibiting GSK-3. We report that lithium-induced keratinocyte proliferation at therapeutically relevant doses (1–2 mM) and increased the proportion of cells in S phase of the cell cycle. Inhibition of GSK-3 in keratinocytes by retroviral transduction of GSK-binding protein (an endogenous inhibitory protein) or through a highly selective pharmacological inhibitor also resulted in increased keratinocyte proliferation. Nuclear factor of activated T cells (NFAT) is an important substrate for GSK-3 and for cyclosporin, an effective treatment for psoriasis that inhibits NFAT activation in keratinocytes as well as in lymphocytes. Both lithium and genetic/pharmacological inhibition of GSK-3 resulted in increased nuclear localization of NFAT2 (NFATc1) and increased NFAT transcriptional activation. Finally, retroviral transduction of NFAT2 increased keratinocyte proliferation whereas siRNA-mediated knockdown of NFAT2 reduced keratinocyte proliferation and decreased epidermal thickness in an organotypic skin equivalent model. Taken together, these data identify GSK-3 and NFAT2 as key regulators of keratinocyte proliferation and as potential molecular targets relevant to lithium-provoked psoriasis. J. Cell. Physiol. 227: 1529–1537, 2012. © 2011 Wiley Periodicals, Inc. PMID:21678407

Hampton, Philip J; Jans, Ralph; Flockhart, Ross J; Parker, Graeme; Reynolds, Nick J

2012-01-01

71

The p38MAPK\\/SAPK Pathway is Required for Human Keratinocyte Migration on Dermal Collagen  

Microsoft Academic Search

Human keratinocyte motility plays an important role in the re-epithelialization of human skin wounds. The wound bed over which human keratinocytes migrate is rich in extracellular matrices, such as fibrin, fibronectin, and collagen, and serum factors, such as platelet-derived growth factor and transforming growth factor ?1. Extracellular matrices and the serum factors bind to cell surface receptors and initiate a

Wei Li; Celina Nadelman; Ginard Henry; Jianhua Fan; Matt Muellenhoff; Elenea Medina; Noah S. Gratch; Mei Chen; Jiahuai Han; David Woodley

2001-01-01

72

Expression of the human papillomavirus type 16 E7 oncoprotein induces an autophagy-related process and sensitizes normal human keratinocytes to cell death in response to growth factor deprivation  

SciTech Connect

Expression of oncogenes, such as the human papillomavirus type 16 (HPV16) E7 oncoprotein, promotes aberrant cell proliferation. In the absence of concurrent mitogenic stimuli, this triggers a cell-intrinsic defense mechanism, the 'trophic sentinel response', which eliminates such aberrant cells. The molecular pathways that elicit this response, however, remain obscure. We set up an experimental system to investigate the trophic sentinel pathway triggered by HPV16 E7 expression in normal human keratinocytes, the natural host cells of HPVs. Keratinocytes expressing HPV16 E7 cultured in E-medium undergo cell death and show increased sub-G1 DNA content when grown to confluence or under conditions of serum deprivation. Moreover, HPV16 E7 expressing human keratinocytes express higher levels of the autophagy marker, LC3-II, which can be abrogated by 3-methyladenine, an autophagy inhibitor. These findings indicate that even under normal culture conditions, HPV16 E7 expression triggers metabolic stress that may result in autophagy, a pathway implicated in carcinogenesis.

Zhou Xiaobo [Infectious Diseases Division, Channing Laboratories, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School (United States); Muenger, Karl [Infectious Diseases Division, Channing Laboratories, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School (United States)], E-mail: kmunger@rics.bwh.harvard.edu

2009-03-01

73

Transcription Factors C\\/EBP?, C\\/EBP?, and CHOP (Gadd153) Expressed During the Differentiation Program of Keratinocytes In Vitro and In Vivo  

Microsoft Academic Search

CCAAT-enhancer binding proteins (C\\/EBP) are basic region\\/leucine zipper (bZIP) transcription factors selectively expressed during the differentiation of liver, adipose tissue, blood cells, and the endocrine pancreas. Here we show that C\\/EBP isoforms are differentially expressed in the skin. BALB\\/MK keratinocytes incubated in 0.12 mM calcium medium undergo a differentiation program featuring growth-arrest at 24–48 h, keratin K10 gene expression beginning

Edward V. Maytin; Joel F. Habener

1998-01-01

74

Tumor necrosis factor beta and ultraviolet radiation are potent regulators of human keratinocyte ICAM-1 expression  

SciTech Connect

Intercellular adhesion molecule-1 (ICAM-1) functions as a ligand of leukocyte function-associated antigen-1 (LFA-1), as well as a receptor for human picorna virus, and its regulation thus affects various immunologic and inflammatory reactions. The weak, constitutive ICAM-1 expression on human keratinocytes (KC) can be up-regulated by cytokines such as interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). In order to further examine the regulation of KC ICAM-1 expression, normal human KC or epidermoid carcinoma cells (KB) were incubated with different cytokines and/or exposed to ultraviolet (UV) radiation. Subsequently, ICAM-1 expression was monitored cytofluorometrically using a monoclonal anti-ICAM-1 antibody. Stimulation of cells with recombinant human (rh) interleukin (IL) 1 alpha, rhIL-4, rhIL-5, rhIL-6, rh granulocyte/macrophage colony-stimulating factor (GM-CSF), rh interferon alpha (rhIFN alpha), and rh transforming growth factor beta (TGF beta) did not increase ICAM-1 surface expression. In contrast, rhTNF beta significantly up-regulated ICAM-1 expression in a time- and dose-dependent manner. Moreover, the combination of rhTNF beta with rhIFN gamma increased the percentage of ICAM-1-positive KC synergistically. This stimulatory effect of rhTNF beta was further confirmed by the demonstration that rhTNF beta was capable of markedly enhancing ICAM-1 mRNA expression in KC. Finally, exposure of KC in vitro to sublethal doses of UV radiation (0-100 J/m2) prior to cytokine (rhIFN tau, rhTNF alpha, rhTNF beta) stimulation inhibited ICAM-1 up-regulation in a dose-dependent fashion. These studies identify TNF beta and UV light as potent regulators of KC ICAM-1 expression, which may influence both attachment and detachment of leukocytes and possibly viruses to KC.

Krutmann, J.; Koeck, A.S.; Schauer, E.; Parlow, F.; Moeller, A.K.; Kapp, A.; Foerster, E.S.; Schoepf, E.L.; Luger, T.A. (Univ. of Freiburg (Germany, F.R.))

1990-08-01

75

Keratinocyte growth regulation TRP-ed up over downregulated TRPV4?  

PubMed

This commentary on an exciting new study (Fusi et al., 2014) puts the finding of TRPV4 downregulation in several nonmelanoma skin cancers into context. The original paper point toward possible use of TRPV4 as dermatopathologic marker, also toward the possibility that downregulated TRPV4 can affect biological properties of the cancer, by enhancing, but also regulating tumor growth. As calcium-permeable TRPV4 has recently been identified as UVB-receptor in skin keratinocytes, where it regulates skin tissue injury and pain after UVB overexposure, it is discussed whether TRPV4 downregulation can also be found in other non-UVB-exposed cancers. PMID:25120148

Liedtke, Wolfgang; Zhang, Jennifer Y; Hall, Russell P; Steinhoff, Martin

2014-09-01

76

TWEAK Affects Keratinocyte G2/M Growth Arrest and Induces Apoptosis through the Translocation of the AIF Protein to the Nucleus  

PubMed Central

The soluble TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) binds to the fibroblast growth factor-inducible 14 receptor (FN14, TNFRSF12A) on the cell membrane and induces multiple biological responses, such as proliferation, migration, differentiation, angiogenesis and apoptosis. Previous reports show that TWEAK, which does not contain a death domain in its cytoplasmic tail, induces the apoptosis of tumor cell lines through the induction of TNF? secretion. TWEAK induces apoptosis in human keratinocytes. Our experiments clearly demonstrate that TWEAK does not induce the secretion of TNF? or TRAIL proteins. The use of specific inhibitors and the absence of procaspase-3 cleavage suggest that the apoptosis of keratinocytes follows a caspase- and cathepsin B-independent pathway. Further investigation showed that TWEAK induces a decrease in the mitochondrial membrane potential of keratinocytes. Confocal microscopy showed that TWEAK induces the cleavage and the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, thus initiating caspase-independent apoptosis. Moreover, TWEAK induces FOXO3 and GADD45 expression, cdc2 phosphorylation and cdc2 and cyclinB1 degradation, resulting in the arrest of cell growth at the G2/M phase. Finally, we report that TWEAK and FN14 are normally expressed in the basal layer of the physiological epidermis and are greatly enhanced in benign (psoriasis) and malignant (squamous cell carcinoma) skin pathologies that are characterized by an inflammatory component. TWEAK might play an essential role in skin homeostasis and pathology. PMID:22438963

Pelekanou, Vassiliki; Lkhider, Mustapha; Stathopoulos, Efstathios N.; Castanas, Elias; Bagot, Martine; Bensussan, Armand; Tsapis, Andreas

2012-01-01

77

Knockdown of PKD1 in normal human epidermal keratinocytes increases mRNA expression of keratin 10 and involucrin: early markers of keratinocyte differentiation.  

PubMed

Subconfluent normal human keratinocytes exhibit autonomous (autocrine growth factor driven) proliferation and express the specific markers for keratinocyte proliferation K5 (keratin 5) and K14 (keratin 14). Utilizing this model the effects of PKD1 (Protein kinase D1) knockdown on activation of differentiation was studied. siRNA approach was applied to achieve specific knockdown of PKD1 and the mRNA levels of different keratinocyte markers -- K14 and PCNA (markers of basal proliferating keratinocytes), involucrin and K10 (early differentiation markers) were analyzed. Treatment of cultured keratinocytes with siRNA for PKD1 resulted in reduction of mRNA levels of PKD1, altered cell phenotype and promotion of keratinocyte differentiation, demonstrated by increased expression of involucrin and K10 mRNAs. No significant changes in K14 mRNA expression levels were detected, but the expression of PCNA mRNA was markedly diminished. This study was the first to show that mRNA expression of PKD1 in subconfluent normal human keratinocytes is very low, the PKD1 mRNA levels were more than 8-fold lower than the same ones in hTert keratinocytes. These findings suggest antidifferentiative role of PKD1 in normal human keratinocytes, contrary to the prodiferentiative role of PKD1 in human hTert keratinocytes. We came to the conclusion that there are differences between transduction pathways involving PKD1 in primary human keratinocyte cultures and these in immortalized hTert keratinocytes. PMID:18259765

Ivanova, Petya; Atanasova, Ganka; Poumay, Yves; Mitev, Vanyo

2008-03-01

78

Interleukin1-stimulated Secretion of Interleukin8 and Growth-related Oncogene-? Demonstrates Greatly Enhanced Keratinocyte Growth in Human Raft Cultured Epidermis  

Microsoft Academic Search

The CXC chemokines, interleukin-8 and growth-related oncogene?, are known to play a prominent part in wound healing as well as inflammatory skin disorders, including psoriasis. Both chemokines are potent neutrophil activators and were discussed as potential stimuli in keratinocyte growth. We examined the action of growth-related oncogene ? and interleukin-8 in organotypic raft culture, which resembles in vivo skin in

Judith Steude; Reinhard Kulke; Enno Christophers

2002-01-01

79

Expression and function of neurotrophins and their receptors in cultured human keratinocytes.  

PubMed

Whereas nerve growth factor has been extensively studied in human keratinocytes, little is known on the role of other members of the neurotrophin family. We investigated the expression and function of neurotrophins and neurotrophin receptors in cultured human keratinocytes. We demonstrated by reverse transcription-polymerase chain reaction that keratinocytes synthesize neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5. These cells also express tyrosinase kinase A and C, the nerve growth factor and neuro-trophin-3 high-affinity receptors, respectively. On the other hand, only the truncated extracellular isoform of tyrosinase kinase B, the high-affinity brain-derived neurotrophic factor and neurotrophin-4/5 receptor, is detected in keratinocytes. Moreover, neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5 proteins are secreted by human keratinocytes at low levels. Keratinocyte stem cells synthesize the highest amounts of nerve growth factor, while they secrete higher levels of nerve growth factor as compared with transit amplifying cells. Neurotrophin-3 stimulates keratinocyte proliferation, where brain-derived neurotrophic factor or neurotrophin-4/5 does not exert any effect on keratinocyte proliferation. Addition of neurotrophin-3 slightly upregulates the secretion of nerve growth factor, whereas nerve growth factor strongly augments neurotrophin-3 release. Ultraviolet B irradiation downregulates nerve growth factor, whereas it augments neurotrophin-3 and neurotrophin-4/5 protein levels. Ultraviolet A irradiation increases the level of neurotrophin-3, whereas it does not exert any effect on the other neurotrophins. Finally, neurotrophins other than nerve growth factor fail to protect human keratinocytes from ultraviolet B-induced apoptosis. This work delineates a functional neurotrophin network, which may contribute to epidermal homeostasis. PMID:14675204

Marconi, A; Terracina, M; Fila, C; Franchi, J; Bonté, F; Romagnoli, G; Maurelli, R; Failla, C M; Dumas, M; Pincelli, C

2003-12-01

80

Kr?ppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes  

PubMed Central

Circadian clocks govern a wide range of cellular and physiological functions in various organisms. Recent evidence suggests distinct functions of local clocks in peripheral mammalian tissues such as immune responses and cell cycle control. However, studying circadian action in peripheral tissues has been limited so far to mouse models, leaving the implication for human systems widely elusive. In particular, circadian rhythms in human skin, which is naturally exposed to strong daytime-dependent changes in the environment, have not been investigated to date on a molecular level. Here, we present a comprehensive analysis of circadian gene expression in human epidermis. Whole-genome microarray analysis of suction-blister epidermis obtained throughout the day revealed a functional circadian clock in epidermal keratinocytes with hundreds of transcripts regulated in a daytime-dependent manner. Among those, we identified a circadian transcription factor, Krüppel-like factor 9 (Klf9), that is substantially up-regulated in a cortisol and differentiation-state-dependent manner. Gain- and loss-of-function experiments showed strong antiproliferative effects of Klf9. Putative Klf9 target genes include proliferation/differentiation markers that also show circadian expression in vivo, suggesting that Klf9 affects keratinocyte proliferation/differentiation by controlling the expression of target genes in a daytime-dependent manner. PMID:22711835

Sporl, Florian; Korge, Sandra; Jurchott, Karsten; Wunderskirchner, Minetta; Schellenberg, Katja; Heins, Sven; Specht, Aljona; Stoll, Claudia; Klemz, Roman; Maier, Bert; Wenck, Horst; Schrader, Annika; Kunz, Dieter; Blatt, Thomas; Kramer, Achim

2012-01-01

81

Modulation of TGF?-inducible hypermotility by EGF and other factors in human prostate epithelial cells and keratinocytes  

PubMed Central

Keratinocytes migrating from a wound edge or initiating malignant invasion greatly increase their expression of the basement membrane protein Laminin-322 (Lam332). In culture, keratinocytes initiate sustained directional hypermotility when plated onto an incompletely processed form of Lam332 (Lam332?) or when treated with TGF?, an inducer of Lam332 expression. The development and tissue architecture of stratified squamous and prostate epithelia are very different, yet the basal cells of both express p63, ?6?4 integrin, and Lam332. Keratinocytes and prostate epithelial cells grow well in nutritionally-optimized culture media with pituitary extract and certain mitogens. We report that prostate epithelial cells display hypermotility responses indistinguishable from those of keratinocytes. Several culture medium variables attenuated TGF?-induced hypermotility, including Ca++, serum, and some pituitary extract preparations, without impairing growth, TGF? growth-inhibition, or hypermotility on Lam322?. Distinct from its role as a mitogen, EGF proved to be a required cofactor for TGF?-induced hypermotility and could not be replaced by HGF or KGF. Prostate epithelial cells have a short replicative lifespan, restricted both by p16INK4A and telomere-related mechanisms. We immortalized the normal prostate epithelial cell line HPrE-1 by transduction to express bmi1 and TERT. Prostate epithelial cells lose expression of p63, ?4 integrin, and Lam332 when they transform to invasive carcinoma. In contrast, HPrE-1/bmi1/TERT cells retained expression of these proteins and normal TGF? signaling and hypermotility for >100 doublings. Thus, keratinocytes and prostate epithelial cells possess common hypermotility and senescence mechanisms and immortalized prostate cell lines can be engineered using defined methods to yield cells retaining normal properties. PMID:21042878

Wei, Wei; Barron, Patricia D.; Rheinwald, James G.

2013-01-01

82

Identification of avarol derivatives as potential antipsoriatic drugs using an in vitro model for keratinocyte growth and differentiation.  

PubMed

Avarol, a marine sesquiterpenoid hydroquinone, and 14 avarol derivatives have shown interesting anti-inflammatory properties in previous studies. In this study, avarol and derivatives were evaluated in high-throughput keratinocyte culture models using cytokeratin 10 and SKALP/Elafin expression as markers for respectively normal and psoriatic differentiation. Avarol and five of its derivatives (5, 10, 13, 14 and 15) were selected for further study. Only 10, 13, 14 and 15 were able to inhibit keratinocyte cell growth. Changes in expression levels of 22 genes were assessed by quantitative real time PCR (qPCR). From these genes, TNFalpha mRNA levels showed the strongest changes. For compound 13, 15 and dithranol (used as a model antipsoriatic drug), a dose-dependent downregulation of TNFalpha mRNA was found. The changes in TNFalpha mRNA were confirmed at the protein level for compound 13. Additionally, this compound was able to reduce also IL-8 and COX-2 mRNA levels and this effect was correlated with a reduction in COX-2 protein expression. The mechanism of action of this compound involves at least the inhibition of NF-kappaB-DNA binding activity. In conclusion, our high-throughput screening models in combination with quantitative assessment of changes in gene expression profiles identified the avarol derivative 13, a benzylamine derivative of avarol at the 4' position of benzoquinone ring, as an interesting anti-psoriatic drug candidate that inhibits keratinocyte cell growth and TNFalpha and COX-2 expression. PMID:16973179

Amigó, María; Schalkwijk, Joost; Olthuis, Diana; De Rosa, Salvatore; Payá, Miguel; Terencio, María Carmen; Lamme, Evert

2006-11-17

83

Increased Expression of Vascular Permeability Factor (Vascular Endothelial Growth Factor) in Bullous Pemphigoid, Dermatitis Herpetiformis, and Erythema Multiforme  

Microsoft Academic Search

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), plays an important role in the increased vascular permeability and angiogenesis associated with many malignant tumors. In addition, VPF\\/VEGF is strongly expressed by epidermal keratinocytes in wound healing and psoriasis, disorders that are also characterized by increased microvascular permeability and angiogenesis. In this study, we investigated the expression

Lawrence F. Brown; Terence J. Harrist; Kiang-Teck Yeo; Mona Stĺhle-Bäckdahl; Robert W. Jackman; Brygida Berse; Kathi Tognazzi; Harold F. Dvorak; Michael Detmar

1995-01-01

84

Epidermal growth factor and temperature regulate keratinocyte differentiation  

Microsoft Academic Search

The limited life-span and irregularities in epidermal differentiation and barrier function that have restricted the\\u000a utility of presently available skin culture models for pharmacological and toxicological studies indicate that further modifications\\u000a of culture conditions are required for optimization of these models. In the present study epidermis reconstructed on de-epidermized\\u000a dermis was used to investigate the effects of temperature and epidermal

Maria Ponec; Susan Gibbs; Arij Weerheim; Johanna Kempenaar; Aat Mulder; A. Mieke Mommaas

1997-01-01

85

Tanshinone IIA Inhibits Growth of Keratinocytes through Cell Cycle Arrest and Apoptosis: Underlying Treatment Mechanism of Psoriasis  

PubMed Central

The aim of the present investigation was to elucidate the cellular mechanisms whereby Tanshinone IIA (Tan IIA) leads to cell cycle arrest and apoptosis in vitro in keratinocytes, the target cells in psoriasis. Tan IIA inhibited proliferation of mouse keratinocytes in a dose- and time-dependent manner and induced apoptosis, resulting in S phase arrest accompanied by down-regulation of pCdk2 and cyclin A protein expression. Furthermore, Tan IIA-induced apoptosis and mitochondrial membrane potential changes were also further demonstrated by DNA fragmentation, single-cell gel electrophoresis assay (SCGE), and flow cytometry methods. Apoptosis was partially blocked by the caspase-3 inhibitor Ac-DEVD-CHO. Mitochondrial regulation of apoptosis further downstream was investigated, showing changes in the mitochondrial membrane potential, cytochrome c release into the cytoplasm, and enhanced activation of cleaved caspase-3 and Poly ADP-ribose polymerase (PARP). There was also no translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus in apoptotic keratinocytes, indicating Tan IIA-induced apoptosis occurs mainly through the caspase pathway. Our findings provide the molecular mechanisms by which Tan IIA can be used to treat psoriasis and support the traditional use of Salvia miltiorrhiza Bungee (Labiatae) for psoriasis and related skin diseases. PMID:22203883

Li, Fu-Lun; Xu, Rong; Zeng, Qing-chun; Li, Xin; Chen, Jie; Wang, Yi-Fei; Fan, Bin; Geng, Lin; Li, Bin

2012-01-01

86

RXR? ablation in epidermal keratinocytes enhances UV radiation induced DNA damage, apoptosis, and proliferation of keratinocytes and melanocytes  

PubMed Central

We show here that keratinocytic nuclear receptor Retinoid X Receptor ? (RXR?) regulates mouse keratinocyte and melanocyte homeostasis following acute ultraviolet radiation (UVR). Keratinocytic RXR? has a protective role on UVR-induced keratinocyte and melanocyte proliferation/differentiation, oxidative stress mediated DNA damage and cellular apoptosis. We discovered that keratinocytic RXR? in a cell autonomous manner regulate mitogenic growth responses in skin epidermis via secretion of hbEGF, GMCSF, IL1-? and COX2, and activation of MAPK pathways. We identified altered expression of several keratinocyte-derived mitogenic paracrine growth factors such as ET-1, HGF, ?–MSH, SCF and FGF2 in skin of mice lacking RXR? in epidermal keratinocytes (RXR?ep?/? mice), which in a non-cell autonomous manner modulated melanocyte proliferation and activation after UVR. RXR?ep?/? mouse represents a unique animal model where UVR induces melanocyte proliferation/activation in both epidermis and dermis. Considered together, our results suggest that RXR antagonists, together with inhibitors of cell proliferation can be effective to prevent solar UV radiation induced photo-carcinogenesis. PMID:20944655

Wang, Zhixing; Coleman, Daniel J.; Bajaj, Gaurav; Liang, Xiaobo; Ganguli-Indra, Gitali; Indra, Arup Kumar

2011-01-01

87

FGF growth factor analogs  

DOEpatents

The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

Zamora, Paul O. (Gaithersburg, MD); Pena, Louis A. (Poquott, NY); Lin, Xinhua (Plainview, NY); Takahashi, Kazuyuki (Germantown, MD)

2012-07-24

88

Enhanced Keratinocyte Proliferation and Migration in Co-culture with Fibroblasts  

PubMed Central

Wound healing is primarily controlled by the proliferation and migration of keratinocytes and fibroblasts as well as the complex interactions between these two cell types. To investigate the interactions between keratinocytes and fibroblasts and the effects of direct cell-to-cell contact on the proliferation and migration of keratinocytes, keratinocytes and fibroblasts were stained with different fluorescence dyes and co-cultured with or without transwells. During the early stage (first 5 days) of the culture, the keratinocytes in contact with fibroblasts proliferated significantly faster than those not in contact with fibroblasts, but in the late stage (11th to 15th day), keratinocyte growth slowed down in all cultures unless EGF was added. In addition, keratinocyte migration was enhanced in co-cultures with fibroblasts in direct contact, but not in the transwells. Furthermore, the effects of the fibroblasts on keratinocyte migration and growth at early culture stage correlated with heparin-binding EGF-like growth factor (HB-EGF), IL-1? and TGF-?1 levels in the cultures where the cells were grown in direct contact. These effects were inhibited by anti-HB-EGF, anti-IL-1? and anti-TGF-?1 antibodies and anti-HB-EGF showed the greatest inhibition. Co-culture of keratinocytes and IL-1? and TGF-?1 siRNA-transfected fibroblasts exhibited a significant reduction in HB-EGF production and keratinocyte proliferation. These results suggest that contact with fibroblasts stimulates the migration and proliferation of keratinocytes during wound healing, and that HB-EGF plays a central role in this process and can be up-regulated by IL-1? and TGF-?1, which also regulate keratinocyte proliferation differently during the early and late stage. PMID:22911722

Wang, Zhenxiang; Wang, Ying; Farhangfar, Farhang; Zimmer, Monica; Zhang, Yongxin

2012-01-01

89

Thrombospondin-induced adhesion of human keratinocytes.  

PubMed Central

Human epidermal keratinocytes obtained from normal skin attached and spread on thrombospondin (TSP)-coated plastic dishes but failed to attach and spread on untreated plastic culture dishes or dishes coated with fibronectin or laminin. These cells produced minimal amounts of immunoreactive TSP. Keratinocytes established in culture on MCDB 153 medium and maintained for one to three passages in an undifferentiated state by continued cultivation in this low Ca2+-containing medium attached and spread on plastic dishes as well as on TSP-coated dishes. These cells also secreted significant amounts of TSP into the culture medium. When the keratinocytes were incubated for one day in MCDB 153 medium supplemented with high Ca2+ or in MEM (which also contains high Ca2+), there was decreased secretion of TSP into the culture medium concomitant with a reduction in attachment and spreading on plastic culture dishes. Proteolytic fragments of TSP were examined for stimulation of keratinocyte attachment and spreading. A 140-kd fragment produced by removal of the 25-kd heparin-binding domain had similar activity to the intact molecule while the 25-kd fragment was without effect. Further proteolytic treatment of the 140-kd fragment gave rise to a fragment consisting of 120 kd and 18-D moieties held together in disulphide linkage. This fragment did not support attachment or spreading. This study reveals that normal epidermal keratinocytes grown under conditions that maintain the undifferentiated state are able to produce TSP and utilize it as an attachment factor. When keratinocytes are grown under conditions that promote differentiation, ability to produce and utilize TSP is diminished. Since TSP is present at the dermal-epidermal junction and because TSP promotes keratinocyte attachment and spreading, this molecule may play an important role in maintaining normal growth of the basal cell layer and may also participate in reepithelialization during wound repair. Images PMID:2452837

Varani, J; Nickoloff, B J; Riser, B L; Mitra, R S; O'Rourke, K; Dixit, V M

1988-01-01

90

New microbial growth factor  

NASA Technical Reports Server (NTRS)

A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

Bok, S. H.; Casida, L. E., Jr.

1977-01-01

91

New microbial growth factor.  

PubMed Central

A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a new microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight, and it has high specific activity. When added to the diets for a meadow vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain. PMID:327929

Bok, S H; Casida, L E

1977-01-01

92

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation.  

PubMed

Receptor-interacting protein kinase 4 (RIPK4) and interferon regulatory factor 6 (IRF6) are critical regulators of keratinocyte differentiation, and their mutation causes the related developmental epidermal disorders Bartsocas-Papas syndrome and popliteal pterygium syndrome, respectively. However, the signaling pathways in which RIPK4 and IRF6 operate to regulate keratinocyte differentiation are poorly defined. Here we identify and mechanistically define a direct functional relationship between RIPK4 and IRF6. Gene promoter reporter and in vitro kinase assays, coimmunoprecipitation experiments, and confocal microscopy demonstrated that RIPK4 directly regulates IRF6 trans-activator activity and nuclear translocation. Gene knockdown and overexpression studies indicated that the RIPK4-IRF6 signaling axis controls the expression of key transcriptional regulators of keratinocyte differentiation, including Grainyhead-like 3 and OVO-like 1. Additionally, we demonstrate that the p.Ile121Asn missense mutation in RIPK4, which has been identified recently in Bartsocas-Papas syndrome, inhibits its kinase activity, thereby preventing RIPK4-mediated IRF6 activation and nuclear translocation. We show, through mutagenesis-based experiments, that Ser-413 and Ser-424 in IRF6 are important for its activation by RIPK4. RIPK4 is also important for the regulation of IRF6 expression by the protein kinase C pathway. Therefore, our findings not only provide important mechanistic insights into the regulation of keratinocyte differentiation by RIPK4 and IRF6, but they also suggest one mechanism by which mutations in RIPK4 may cause epidermal disorders (e.g. Bartsocas-Papas syndrome), namely by the impaired activation of IRF6 by RIPK4. PMID:25246526

Kwa, Mei Qi; Huynh, Jennifer; Aw, Jiamin; Zhang, Lianyi; Nguyen, Thao; Reynolds, Eric C; Sweet, Matthew J; Hamilton, John A; Scholz, Glen M

2014-11-01

93

Role of Growth Factors, Cytokines, and Their Receptors in the Pathogenesis of Psoriasis  

Microsoft Academic Search

Psoriasis is characterized by epidermal hyperplasia, altered epidermal maturation, and local accumulation of acute and chronic inflammatory cells. Keratinocyte hyperplasia in psoriasis may be explained in part by overproduction of growth factors or cytokines which stimulate epidermal proliferation and by altered metabolism of growth-factor receptors in affected skin. Psoriatic epidermis displays overproduction of TGF-alpha and interleukin-6 (IL-6), factors produced by

James G. Krueger; Jeffrey F. Krane; D. Martin Carter; Alice B. Gottlieb

1990-01-01

94

Effect of Wnt3a on Keratinocytes Utilizing in Vitro and Bioinformatics Analysis  

PubMed Central

Wingless-type (Wnt) signaling proteins participate in various cell developmental processes. A suppressive role of Wnt5a on keratinocyte growth has already been observed. However, the role of other Wnt proteins in proliferation and differentiation of keratinocytes remains unknown. Here, we investigated the effects of the Wnt ligand, Wnt3a, on proliferation and differentiation of keratinocytes. Keratinocytes from normal human skin were cultured and treated with recombinant Wnt3a alone or in combination with the inflammatory cytokine, tumor necrosis factor ? (TNF?). Furthermore, using bioinformatics, we analyzed the biochemical parameters, molecular evolution, and protein–protein interaction network for the Wnt family. Application of recombinant Wnt3a showed an anti-proliferative effect on keratinocytes in a dose-dependent manner. After treatment with TNF?, Wnt3a still demonstrated an anti-proliferative effect on human keratinocytes. Exogenous treatment of Wnt3a was unable to alter mRNA expression of differentiation markers of keratinocytes, whereas an altered expression was observed in TNF?-stimulated keratinocytes. In silico phylogenetic, biochemical, and protein–protein interaction analysis showed several close relationships among the family members of the Wnt family. Moreover, a close phylogenetic and biochemical similarity was observed between Wnt3a and Wnt5a. Finally, we proposed a hypothetical mechanism to illustrate how the Wnt3a protein may inhibit the process of proliferation in keratinocytes, which would be useful for future researchers. PMID:24686518

Nam, Ju-Suk; Chakraborty, Chiranjib; Sharma, Ashish Ranjan; Her, Young; Bae, Kee-Jeong; Sharma, Garima; Doss, George Priya; Lee, Sang-Soo; Hong, Myung-Sun; Song, Dong-Keun

2014-01-01

95

An ideal preparation for dermal regeneration: skin renewal growth factors, the growth factor composites from porcine platelets.  

PubMed

The use of growth factor composites from platelets has been introduced to many areas of clinical applications and studies. With the richest source of growth factors (GFs), beneficial effects have been shown on tissue regeneration and wound healing. However, animal and clinical studies have revealed inconsistent outcomes with the use of platelet-derived growth factors (PDGFs), which were likely due to variations in the presence and concentrations of GFs between various sources. Autologous PDGFs are considered to be safer, but they are limited by the feasibility of large-scale production to be used extensively in the acute phase, greater surface area, or general cosmetic applications. This study employed a simple process to obtain growth factor composites from activated platelets of porcine origin, namely skin renewal growth factors (SRGF). The functions of SRGF were subsequently evaluated on cultured human fibroblasts, keratinocytes, and melanocytes. Our data revealed that SRGF significantly promoted the proliferation of fibroblasts, accompanied by increased expression of collagens (types I, III, IV, and VIII) and proteoglycans. Diminished proliferation and arrested differentiation of keratinocytes were evidenced by the attenuated expression of laminin V and keratin 10. In addition, SRGF also suppressed the growth of melanocytes and reduced the expression of microphthalmia-associated transcription factor (MITF), tyrosinase, and paired box 3 (PAX3), which mediates melanogensis. Our results suggest that SRGF possesses beneficial properties and is a promising and cost-effective composition for the development of a safe cosmetic agent or topical products for skin regeneration. The development of SRGF may also provide an alternative strategy for tissue engineering. PMID:22950429

Wang, Kuo-Hsien; Wu, Yo-Ping Greg; Lo, Wen-Cheng

2012-12-01

96

Id1 and NF-?B promote the generation of CD133+ and BMI-1+ keratinocytes and the growth of xenograft tumors in mice  

PubMed Central

Id1 and NF-?B are highly expressed in oral squamous cell carcinoma (OSCC). Whether they have a synergistic role in the carcinogenesis of OSCC is unclear. The current study was designed to demonstrate the synergy of both Id1 and NF-?B in the underlying disease mechanisms of OSCC using in vitro and in vivo animal models. Id1 and NF-?B strengthened the expression of both CD133 and BMI-1 in OSCC cell cultures. CD133+ and BMI-1+ keratinocytes from OSCC tissues and cell cultures initiated the growth of xenograft tumors in SCID/Beige mice. Id1 and NF-?B regulate the expression of CD133 and BMI-1 in an additive or synergistic manner in OSCC, which is associated with the generation of naďve and self-renewable keratinocytes and initiate the growth of xenograft tumors in vivo. PMID:24572994

LAI, JINHUO; CAI, QIAN; BIEL, MERRILL A.; WANG, CHUAN; HU, XIAOHUA; WANG, SHAOYUAN; LIN, JIZHEN

2014-01-01

97

Keratinocyte chemoattractant (KC)/human growth-regulated oncogene (GRO) chemokines and pro-inflammatory chemokine networks in mouse and human ovarian epithelial cancer cells.  

PubMed

Chronic inflammation is an important underlying condition for ovarian tumor development, growth and progression. Since chemokine networks are activated by inflammation, patterns of chemokine gene expression were investigated in ovarian cancer cells. Chemokine specific microarrays were performed after mouse (ID8) and human (SKOV-3) ovarian surface epithelial cancer cells were exposed to the inflammatory agent bacterial endotoxin lipopolysaccharide (LPS, 10 microg/ml) and pro-inflammatory cytokines interleukin-1beta (IL-1, 10 ng/ml) and tumor necrosis factor-alpha (TNF, 10 ng/ml). In the mouse ID8 cells, LPS, IL-1 and TNF led to robust upregulation of keratinocyte chemoattractant (KC) chemokines CXCL1/2, mouse homologues of human growth-regulated oncogenes (GRO). Other chemokines, interferong inducible protein (IP)-10 (CXCL10), CCL7 and CCL20 were moderately upregulated. ID8 cells constitutively expressed CXCL16 and CCL2, but only CCL2 expression was enhanced by LPS, IL-1 and TNF. In the human SKOV-3 cells, LPS had no effect on chemokines expression due to the absence of the LPS receptor, toll-like receptor 4 (TLR4). However, IL-1 and TNF induced GROalpha/beta (CXCL1/2) in human SKOV-3 cells in a similar manner as observed with mouse ID8 cells. In SKOV-3 cells, IL-8 (CXCL8) was highly expressed and other chemokines GROgamma (CXCL3) and CCL20 were moderately expressed in response to IL-1 and TNF. The nuclear factor-kappaB (NF-kappaB) is a known mediator of cytokine and chemokines signaling. The NFkappaB inhibitor BAY 11-7082 attenuated expression of inflammatory-induced chemokines in the mouse and human ovarian cancer cells. Taken together, the results indicate that KC/GRO chemokines are the principal chemokines induced by LPS and pro-inflammatory cytokines IL-1 and TNF via NFkappaB signaling in ovarian surface epithelial cancer cells. PMID:17712227

Son, Deok-Soo; Parl, Angelika K; Rice, Valerie Montgomery; Khabele, Dineo

2007-08-01

98

Keratinocyte-derived follistatin regulates epidermal homeostasis and wound repair  

PubMed Central

Activin is a growth and differentiation factor that controls development and repair of several tissues and organs. Transgenic mice overexpressing activin in the skin were characterized by strongly enhanced wound healing, but also by excessive scarring. In this study, we explored the consequences of targeted activation of activin in the epidermis and hair follicles by generation of mice lacking the activin antagonist follistatin in keratinocytes. We observed enhanced keratinocyte proliferation in the tail epidermis of these animals. After skin injury, an earlier onset of keratinocyte hyperproliferation at the wound edge was observed in the mutant mice, resulting in an enlarged hyperproliferative epithelium. However, granulation tissue formation and scarring were not affected. These results demonstrate that selective activation of activin in the epidermis enhances reepithelialization without affecting the quality of the healed wound. PMID:19079322

Antsiferova, Maria; Klatte, Jennifer E; Bodó, Enikö; Paus, Ralf; Jorcano, José L; Matzuk, Martin M; Werner, Sabine; Kögel, Heidi

2014-01-01

99

Explaining Economic Growth: Factor Accumulation, Total Factor Productivity Growth, and Production Efficiency Improvement  

E-print Network

Explaining Economic Growth: Factor Accumulation, Total Factor Productivity Growth, and Production factor productivity growth, and production efficiency improvement. In addition, this paper incorporates quality of factors or total factor productivity growth in explaining output growth. The quality of capital

Ahmad, Sajjad

100

Periostin controls keratinocyte proliferation and differentiation by interacting with the paracrine IL-1?/IL-6 loop.  

PubMed

Proliferation and differentiation of keratinocytes are normally well balanced, but this balance can be perturbed in wound healing and is dysregulated in pathological conditions such as atopic dermatitis. Epithelial-mesenchymal interaction affects this event via the cross-talk of cytokines and growth factors. Periostin, a matricellular protein, has an important role during reepithelialization in wound healing and is critical for hyperproliferation of keratinocytes in atopic dermatitis. Here we investigated how periostin regulates proliferation and differentiation of keratinocytes in the epithelial-mesenchymal interactions using a three-dimensional organotypic air-liquid interface coculture system. The release of IL-1? from keratinocytes and subsequent IL-6 production from fibroblasts were critical for keratinocyte proliferation and differentiation. Periostin secreted from fibroblasts was required for IL-1?-induced IL-6 production and enhanced IL-6 production by activation of the NF-?B pathway synergistically with IL-1?. Thus, the combination of an autocrine loop of periostin and a paracrine loop composed of IL-1? and IL-6 regulates keratinocyte proliferation and differentiation in the epithelial-mesenchymal interactions, and periostin tunes the magnitude of keratinocyte proliferation and differentiation by interacting with the paracrine IL-1?/IL-6 loop. PMID:24352037

Taniguchi, Kazuto; Arima, Kazuhiko; Masuoka, Miho; Ohta, Shoichiro; Shiraishi, Hiroshi; Ontsuka, Kanako; Suzuki, Shoichi; Inamitsu, Masako; Yamamoto, Ken-ichi; Simmons, Olga; Toda, Shuji; Conway, Simon J; Hamasaki, Yuhei; Izuhara, Kenji

2014-05-01

101

Effects of Cerium Oxide Nanoparticles on the Growth of Keratinocytes, Fibroblasts and Vascular Endothelial Cells in Cutaneous Wound Healing  

PubMed Central

Rapid and effective wound healing requires a coordinated cellular response involving fibroblasts, keratinocytes and vascular endothelial cells (VECs). Impaired wound healing can result in multiple adverse health outcomes and, although antibiotics can forestall infection, treatments that accelerate wound healing are lacking. We now report that topical application of water soluble cerium oxide nanoparticles (Nanoceria) accelerates the healing of full-thickness dermal wounds in mice by a mechanism that involves enhancement of the proliferation and migration of fibroblasts, keratinocytes and VECs. The Nanoceria penetrated into the wound tissue and reduced oxidative damage to cellular membranes and proteins, suggesting a therapeutic potential for topical treatment of wounds with antioxidant nanoparticles. PMID:23266256

Chigurupati, Srinivasulu; Mughal, Mohamed R.; Okun, Eitan; Das, Soumen; Kumar, Amit; McCaffery, Michael; Seal, Sudipta; Mattson, Mark P.

2012-01-01

102

H2O2 Is an Important Mediator of UVB-Induced EGF-Receptor Phosphorylation in Cultured Keratinocytes  

Microsoft Academic Search

Exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) radiation induces phosphorylation of the epidermal growth factor receptor (EGFR). We demonstrate that H2O2 generated by UVB mediates EGFR phosphorylation. Using dihydrorhodamine 123 as a specific fluorescent dye probe, we show that UVB irradiation (50–800 J per m2) of keratinocytes leads within minutes to concentration-dependent intracellular production of H2O2.

Dominik Peus; Remus A. Vasa; Alexander Meves; Markus Pott; Astrid Beyerle; Karen Squillace; Mark R. Pittelkow

1998-01-01

103

Augmentation of granulocyte/macrophage colony-stimulating factor expression by ultraviolet irradiation is mediated by interleukin 1 in Pam 212 keratinocytes  

SciTech Connect

Keratinocytes are a potent source of a variety of cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF). In this study, we have shown that ultraviolet B (UVB) irradiation augments GM-CSF mRNA expression by murine keratinocytes. This is reflected in the increased production of GM-CSF protein by these cells. In the same cell population, exposure to UVB irradiation increases interleukin 1 alpha (IL-1 alpha) mRNA and IL-1 protein as detected by bioactivity. This increase in IL-1 alpha precedes the increase of GM-CSF mRNA. Addition of recombinant IL-1 alpha to the medium increases GM-CSF mRNA expression. Anti-IL-1 alpha antibodies can completely inhibit UV-augmented GM-CSF mRNA expression. These results demonstrate that UVB irradiation-induced augmentation of GM-CSF is mediated by UV-induced IL-1 alpha.

Nozaki, S.; Abrams, J.S.; Pearce, M.K.; Sauder, D.N. (Showa Univ., Tokyo (Japan))

1991-07-01

104

Human keratinocytes are a source for tumor necrosis factor alpha: Evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light  

SciTech Connect

Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human keratinocytes (HNK) and human epidermoid carcinoma cell lines (KB, A431) were tested both in a TNF-alpha-specific ELISA and a bioassay. In supernatants of untreated epidermal cells, no or minimal TNF-alpha activity was found, while after stimulation with lipopolysaccharide (LPS) or ultraviolet (UV) light, significant amounts were detected. Western blot analysis using an antibody directed against human TNF-alpha revealed a molecular mass of 17 kD for keratinocyte-derived TNF-alpha. These biological and biochemical data were also confirmed by Northern blot analysis revealing mRNA specific for TNF-alpha in LPS- or ultraviolet B (UVB)-treated HNK and KB cells. In addition, increased TNF-alpha levels were detected in the serum obtained from human volunteers 12 and 24 h after a single total body UVB exposure, which caused a severe sunburn reaction. These findings indicate that keratinocytes upon stimulation are able to synthesize and release TNF-alpha, which may gain access to the circulation. Thus, TNF-alpha in concert with other epidermal cell-derived cytokines may mediate local and systemic inflammatory reactions during host defense against injurious events caused by microbial agents or UV irradiation.

Koeck, A.S.; Schwarz, T.; Kirnbauer, R.; Urbanski, A.; Perry, P.; Ansel, J.C.; Luger, T.A. (Univ. of Vienna (Austria))

1990-12-01

105

UV radiation and prostaglandin E2 up-regulate vascular endothelial growth factor (VEGF) in cultured human fibroblasts  

Microsoft Academic Search

Objective and Design: Exposure to UV radiation is responsible for skin erythema and inflammation. PGE2 is an important inflammatory mediator involved in this process and vascular endothelial growth factor (VEGF) is a potent vascular permeability factor mainly produced by epidermal keratinocytes. This study was aimed at determining whether UVB\\/A1 radiation and prostaglandin E2 (PGE2) could modulate the production of VEGF

S. Trompezinski; I. Pernet; D. Schmitt; J. Viac

2001-01-01

106

Vitamin D receptor expression is linked to cell cycle control in normal human keratinocytes.  

PubMed

To improve our understanding of the cutaneous vitamin D system, we studied vitamin D receptor (VDR) gene regulation in cultured human keratinocytes. Because VDR and its ligand 1 alpha,25-dihydroxyvitamin D(3) have been implicated in epidermal growth control, we investigated VDR expression as related to cellular proliferation by using different cell cycle synchronization protocols. Keratinocytes, deprived of growth factors, were forced into quiescence and a concomitant loss of VDR expression was observed. Mitogenic stimulation of these G(0) cells however quickly upregulated VDR levels several hours ahead the G(1)-S transition point. Growth arrest at the G(1)-S border by mimosine treatment or at the metaphase by nocodazole also downregulated VDR levels but a restoration of VDR expression was again quickly achieved after reentering the cell cycle. These findings indicate that VDR expression in keratinocytes is restricted to actively cycling cells, but not limited to one particular phase of the cell cycle. PMID:11112422

Segaert, S; Degreef, H; Bouillon, R

2000-12-01

107

Transduction of the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papillomaviruses alters human keratinocyte growth and differentiation in organotypic cultures.  

PubMed

Epidermodysplasia-verruciformis-associated human papilloma virus DNA has been detected in skin cancers, in premalignant and benign skin lesions, and in plucked hairs from immunocompetent and immunosuppressed patients. The role of epidermodysplasia-verruciformis-associated human papilloma virus in the pathogenesis of nonmelanoma skin cancer is still enigmatic. In organotypic cultures we investigated the effects of retroviral transduction of the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papilloma virus types 5, 12, 15, 17, 20, and 38 on the growth and differentiation of human keratinocytes. Differentiation was disturbed to different degrees as revealed by histology and by the expression patterns of differentiation markers keratin 10 and small proline rich protein 2. Conversely, proliferating cell nuclear antigen was induced in some of the suprabasal, differentiated cells to varying extent. No unscheduled DNA synthesis was detected in these cells, however, as probed by 5'-bromo-2'-deoxyuridine incorporation. Most intriguingly, when the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papilloma virus types 15 and 17 were transduced, a broadening layer of basal cells and an accelerated differentiation were observed. In addition, "papilla-like structures" comprising basal-like keratinocytes arose from the basal layer into the differentiated layers. These cells did not express the differentiation markers keratin 10 and small proline rich protein 2, but did actively replicate DNA. These observations warrant further research by using this system to elucidate the replication strategy of epidermodysplasia-verruciformis-associated human papilloma virus types in keratinocytes and to shed light on the role of these human papilloma virus types in the pathogenesis of skin cancer. PMID:11886500

Boxman, I L; Mulder, L H; Noya, F; de Waard, V; Gibbs, S; Broker, T R; ten Kate, F; Chow, L T; ter Schegget, J

2001-12-01

108

IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes.  

PubMed

While the pro-differentiation and tumour suppressive functions of Notch signalling in keratinocytes are well established, the underlying mechanisms remain poorly understood. We report here that interferon regulatory factor 6 (IRF6), an IRF family member with an essential role in epidermal development, is induced in differentiation through a Notch-dependent mechanism and is a primary Notch target in keratinocytes and keratinocyte-derived SCC cells. Increased IRF6 expression contributes to the impact of Notch activation on growth/differentiation-related genes, while it is not required for induction of 'canonical' Notch targets like p21(WAF1/Cip1), Hes1 and Hey1. Down-modulation of IRF6 counteracts differentiation of primary human keratinocytes in vitro and in vivo, promoting ras-induced tumour formation. The clinical relevance of these findings is illustrated by the strikingly opposite pattern of expression of Notch1 and IRF6 versus epidermal growth factor receptor in a cohort of clinical SCCs, as a function of their grade of differentiation. Thus, IRF6 is a primary Notch target in keratinocytes, which contributes to the role of this pathway in differentiation and tumour suppression. PMID:21909072

Restivo, Gaetana; Nguyen, Bach-Cuc; Dziunycz, Piotr; Ristorcelli, Elodie; Ryan, Russell J H; Özuysal, Özden Yalçin; Di Piazza, Matteo; Radtke, Freddy; Dixon, Michael J; Hofbauer, Günther F L; Lefort, Karine; Dotto, G Paolo

2011-11-16

109

Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors  

PubMed Central

Although numerous epidemiological studies have shown that inorganic arsenicals cause skin cancers and hyperkeratoses in humans, there are currently no established mechanisms for their action or animal models. Previous studies in our laboratory using primary human keratinocyte cultures demonstrated that micromolar concentrations of inorganic arsenite increased cell proliferation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth factors, such as transforming growth factor (TGF)-?, promote the formation of skin tumors, we hypothesized that similar events may be responsible for those associated with arsenic skin diseases. Thus, the influence of arsenic in humans with arsenic skin disease and on mouse skin tumor development in transgenic mice was studied. After low-dose application of tetradecanoyl phorbol acetate (TPA), a marked increase in the number of skin papillomas occurred in Tg.AC mice, which carry the v-Ha-ras oncogene, that received arsenic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not receive TPA or arsenic/TPA-treated wild-type FVB/N mice. Consistent with earlier in vitro findings, increases in granulocyte/macrophage colony-stimulating factor (GM-CSF) and TGF-? mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-? overexpression to the hair follicles. Injection of neutralizing antibodies to GM-CSF after TPA application reduced the number of papillomas in Tg.AC mice. Analysis of gene expression in samples of skin lesions obtained from humans chronically exposed to arsenic via their drinking water also showed similar alterations in growth factor expression. Although confirmation will be required in nontransgenic mice, these results suggest that arsenic enhances development of skin neoplasias via the chronic stimulation of keratinocyte-derived growth factors and may be a rare example of a chemical carcinogen that acts as a co-promoter. PMID:9846968

Germolec, Dori R.; Spalding, Judson; Yu, Hsin-Su; Chen, G. S.; Simeonova, Petia P.; Humble, Michael C.; Bruccoleri, Alessandra; Boorman, Gary A.; Foley, Julie F.; Yoshida, Takahiko; Luster, Michael I.

1998-01-01

110

Keratinocytes from APP/APLP2-deficient mice are impaired in proliferation, adhesion and migration in vitro  

SciTech Connect

Growing evidence shows that the soluble N-terminal form (sAPP{alpha}) of the amyloid precursor protein (APP) represents an epidermal growth factor fostering keratinocyte proliferation, migration and adhesion. APP is a member of a protein family including the two mammalian amyloid precursor-like proteins APLP1 and APLP2. In the mammalian epidermis, only APP and APLP2 are expressed. APP and APLP2-deficient mice die shortly after birth but do not display a specific epidermal phenotype. In this report, we investigated the epidermis of APP and/or APLP2 knockout mice. Basal keratinocytes showed reduced proliferation in vivo by about 40%. Likewise, isolated keratinocytes exhibited reduced proliferation rates in vitro, which could be completely rescued by either exogenously added recombinant sAPP{alpha}, or by co-culture with dermal fibroblasts derived from APP knockout mice. Moreover, APP-knockout keratinocytes revealed reduced migration velocity resulting from severely compromised cell substrate adhesion. Keratinocytes from double knockout mice died within the first week of culture, indicating essential functions of APP-family members for survival in vitro. Our data indicate that sAPP{alpha} has to be considered as an essential epidermal growth factor which, however, in vivo can be functionally compensated to a certain extent by other growth factors, e.g., factors released from dermal fibroblasts.

Siemes, Christina [Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn (Germany); Quast, Thomas [Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn (Germany); Kummer, Christiane [Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn (Germany); Wehner, Sven [Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn (Germany); Kirfel, Gregor [Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn (Germany); Mueller, Ulrike [Max Planck Institute for Brain Research, Deutschordenstr. 46, 60528 Frankfurt (Germany) and Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg (Germany); Herzog, Volker [Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberlandstr. 61A, 53121 Bonn (Germany)]. E-mail: Herzog@uni-bonn.de

2006-07-01

111

Circulating Vascular Endothelial Growth Factor  

Microsoft Academic Search

Despite significant advances in early detection and treatment, breast cancer still remains the major cause of cancer-related\\u000a death in women. Many studies suggest a relationship between angiogenesis and breast cancer prognosis. Angiogenesis is the\\u000a complex process leading to the formation of new blood vessels from pre-existing vascular network. The VEGF is the most active\\u000a growth factor involved in angiogenesis; more

Roberta Sarmiento; Roberta Franceschini; Sabrina Meo; Massimo Gion; Raffaele Longo; Giampietro Gasparini

112

E2 Polyubiquitin-conjugating enzyme Ubc13 in keratinocytes is essential for epidermal integrity.  

PubMed

The E2 polyubiquitin-conjugating enzyme Ubc13 is a mediator of innate immune reactions. Ubc13 mediates the conjugation of keratin (K)63-linked polyubiquitin chains onto TNF receptor-associated factor 6 and IKK? during NF-?B activation. In contrast to K48-linked polyubiquitin chains, K63-linked polyubiquitin chains function in nonproteasomal biological processes. Although Ubc13 has been shown to be critical for Toll-like receptor (TLR) and IL-1 receptor signaling, the function of Ubc13 in the epidermis has not been studied. We generated keratinocyte-specific Ubc13-deficient mice (Ubc13(flox/flox)K5-Cre). At birth, the skin of the Ubc13(flox/flox)K5-Cre mice was abnormally shiny and smooth; in addition, the mice did not grow and died by postnatal day 2. Histological analysis showed atrophy of the epidermis with keratinocyte apoptosis. Immunohistochemical analyses revealed reduced proliferation, abnormal differentiation, and apoptosis of keratinocytes in the Ubc13(flox/flox)K5-Cre mouse epidermis. In culture, Ubc13(flox/flox)K5-Cre keratinocyte growth was impaired, and spontaneous cell death occurred. Moreover, the deletion of Ubc13 from cultured Ubc13(flox/flox) keratinocytes by means of an adenoviral vector carrying Cre recombinase also resulted in spontaneous cell death. Therefore, Ubc13 is essential for keratinocyte growth, differentiation, and survival. Analyses of intracellular signaling revealed that the IL-1 and TNF-induced activation of JNK, p38, and NF-?B pathways was impaired in Ubc13(flox/flox)K5-Cre keratinocytes. In conclusion, Ubc13 appears to be essential for epidermal integrity in mice. PMID:20663875

Sayama, Koji; Yamamoto, Masahiro; Shirakata, Yuji; Hanakawa, Yasushi; Hirakawa, Satoshi; Dai, Xiuju; Tohyama, Mikiko; Tokumaru, Sho; Shin, Myoung-Sook; Sakurai, Hiroaki; Akira, Shizuo; Hashimoto, Koji

2010-09-24

113

Human papillomavirus causes an angiogenic switch in keratinocytes which is sufficient to alter endothelial cell behavior  

SciTech Connect

One of the requirements for tumor growth is the ability to recruit a blood supply, a process known as angiogenesis. Angiogenesis begins early in the progression of cervical disease from mild to severe dysplasia and on to invasive cancer. We have previously reported that expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7) proteins in primary foreskin keratinocytes (HFKs) decreases expression of two inhibitors and increases expression of two angiogenic inducers [Toussaint-Smith, E., Donner, D.B., Roman, A., 2004. Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors. Oncogene 23, 2988-2995]. Here we report that HPV-induced early changes in the keratinocyte phenotype are sufficient to alter endothelial cell behavior both in vitro and in vivo. Conditioned media from HPV16 E6E7 expressing HFKs as well as from human cervical keratinocytes containing the intact HPV16 were able to stimulate proliferation and migration of human microvascular endothelial cells. In addition, introduction of the conditioned media into immunocompetent mice using a Matrigel plug model resulted in a clear angiogenic response. These novel data support the hypothesis that HPV proteins contribute not only to the uncontrolled keratinocyte growth seen following HPV infection but also to the angiogenic response needed for tumor formation.

Chen, W. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Li, F.; Mead, L.; White, H. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Walker, J. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States); Ingram, D.A. [Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Roman, A. [Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 635 Barnhill Drive, Indianapolis, IN 46202-5120 (United States)], E-mail: aroman@iupui.edu

2007-10-10

114

Hepatocyte Growth Factor By Alex Brown  

E-print Network

1 Hepatocyte Growth Factor By Alex Brown Nutritional Sciences Molecular Structure and Receptor Type Hepatocyte Growth Factor (HGF) is a glycoprotein which is expressed mainly by fibroblasts and by other non in detail below. Figure 1: Hepatocyte Growth Factor (Mizuno & Nakamura, 2007) #12;2 Figure 2: The tyrosine

Nottingham, University of

115

Antithrombin Regulates Matriptase Activity Involved in Plasmin Generation, Syndecan Shedding, and HGF Activation in Keratinocytes  

PubMed Central

Matriptase, a membrane-associated serine protease, plays an essential role in epidermal barrier function through activation of the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin. The matriptase-prostasin proteolytic cascade is tightly regulated by hepatocyte growth factor activator inhibitor (HAI)-1 such that matriptase autoactivation and prostasin activation occur simultaneously and are followed immediately by the inhibition of both enzymes by HAI-1. However, the mechanisms whereby matriptase acts on extracellular substrates remain elusive. Here we report that some active matriptase can escape HAI-1 inhibition by being rapidly shed from the cell surface. In the pericellular environment, shed active matriptase is able to activate hepatocyte growth factor (HGF), accelerate plasminogen activation, and shed syndecan 1. The amount of active matriptase shed is inversely correlated with the amount of antithrombin (AT) bound to the surface of the keratinocytes. Binding of AT to the surface of keratinocytes is dependent on a functional heparin binding site, Lys-125, and that the N-glycosylation site Asn-135 be unglycosylated. This suggests that ?-AT, and not ?-AT, is responsible for regulation of pericellular matriptase activity in keratinocytes. Keratinocytes appear to rely on AT to regulate the level of pericellular active matriptase much more than breast and prostate epithelial cells in which AT regulation of matriptase activity occurs at much lower levels than keratinocytes. These results suggest that keratinocytes employ two distinct serine protease inhibitors to control the activation and processing of two different sets of matriptase substrates leading to different biological events: 1) HAI-1 for prostasin activation/inhibition, and 2) AT for the pericellular proteolysis involved in HGF activation, accelerating plasminogen activation, and shedding of syndecans. PMID:23675430

Chen, Ya-Wen; Xu, Zhenghong; Baksh, Adrienne N. H.; Wang, Jehng-Kang; Chen, Chiu-Yuan; Swanson, Richard; Olson, Steve T.; Kataoka, Hiroaki; Johnson, Michael D.; Lin, Chen-Yong

2013-01-01

116

B-Myb enhances proliferation and suppresses differentiation of keratinocytes in three-dimensional cell culture.  

PubMed

B-Myb (Mybl2) is a member of the Myb gene family of transcription factors involved in the control of cell growth, differentiation, and apoptosis. The effects of B-Myb on keratinocyte proliferation and differentiation have not yet been clarified. The present study was performed to examine the role of B-Myb in proliferation and differentiation of the spontaneously immortalized human skin keratinocyte cell line HaCaT and normal human keratinocytes with formation of a stratified epidermoid structure in air-liquid interface three-dimensional culture. B-Myb was expressed specifically in undifferentiated normal keratinocytes and downregulated during differentiation. The constitutive overexpression of B-Myb in HaCaT cells during air exposure-induced differentiation resulted in an undifferentiated phenotype, i.e., thickening of the stratified layers, suppression of differentiation marker expression, and retention of proliferative activity with activation of cell cycle regulatory proteins in the S and G2/M phases. In contrast, suppression of B-Myb caused their downregulation and constrained proliferation with retention of differentiation capacity. These findings suggested that B-Myb plays an important role in maintenance of the undifferentiated phenotype of keratinocytes in the basal epidermal layer. PMID:24515894

Maruyama, Hiroshi; Ishitsuka, Yosuke; Fujisawa, Yasuhiro; Furuta, Junichi; Sekido, Mitsuru; Kawachi, Yasuhiro

2014-05-01

117

Persea americana Mill. Seed: Fractionation, Characterization, and Effects on Human Keratinocytes and Fibroblasts  

PubMed Central

Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes. PMID:24371457

Ramos-Jerz, Maria del R.; Villanueva, Socorro; Jerz, Gerold; Winterhalter, Peter; Deters, Alexandra M.

2013-01-01

118

Persea americana Mill. Seed: Fractionation, Characterization, and Effects on Human Keratinocytes and Fibroblasts.  

PubMed

Methanolic avocado (Persea americana Mill., Lauraceae) seed extracts were separated by preparative HSCCC. Partition and HSCCC fractions were principally characterized by LC-ESI-MS/MS analysis. Their in vitro influence was investigated on proliferation, differentiation, cell viability, and gene expression on HaCaT and normal human epidermal keratinocytes (NHEK) and normal human dermal fibroblasts (NHDF). The methanol-water partition (M) from avocado seeds and HSCCC fraction 3 (M.3) were mostly composed of chlorogenic acid and its isomers. Both reduced NHDF but enhanced HaCaT keratinocytes proliferation. HSCCC fraction M.2 composed of quinic acid among chlorogenic acid and its isomers inhibited proliferation and directly induced differentiation of keratinocytes as observed on gene and protein level. Furthermore, M.2 increased NHDF proliferation via upregulation of growth factor receptors. Salidrosides and ABA derivatives present in HSCCC fraction M.6 increased NHDF and keratinocyte proliferation that resulted in differentiation. The residual solvent fraction M.7 contained among low concentrations of ABA derivatives high amounts of proanthocyanidins B1 and B2 as well as an A-type trimer and stimulated proliferation of normal cells and inhibited the proliferation of immortalized HaCaT keratinocytes. PMID:24371457

Ramos-Jerz, Maria Del R; Villanueva, Socorro; Jerz, Gerold; Winterhalter, Peter; Deters, Alexandra M

2013-01-01

119

Double-Stranded RNA-Exposed Human Keratinocytes Promote Th1 Responses by Inducing a Type1 Polarized Phenotype in Dendritic Cells: Role of Keratinocyte-Derived Tumor Necrosis Factor ?, Type I Interferons, and Interleukin18  

Microsoft Academic Search

Dendritic cells play a key role in establishing the class of immune response against invading pathogens. Upon engagement with double-stranded RNA, a major bioactive constituent of many virus types, immature dendritic cells develop into type 1 immunostimulatory dendritic cells that promote Th1 responses. Immature dendritic cells reside in the epithelia and are in close contact with keratinocytes. We studied to

M Cristina Lebre; Jeanine C Antons; Pawel Kalinski; Joost H N Schuitemaker; Toni M M van Capel; Martien L Kapsenberg; Esther C de Jong

2003-01-01

120

Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization  

PubMed Central

Many peptide growth factors, including epidermal growth factor receptor (EGFR) ligands, accelerate wound reepithelialization in vivo and in vitro. Furthermore, EGFR expression is transiently increased at wound margins, suggesting an active role for this receptor in wound repair. During reepithelialization of cutaneous wounds, keratinocytes display a phenotypic plasticity resembling aspects of epithelial-mesenchymal transformation (EMT). The transcription factor Slug is a regulator of EMT during development, and we reported previously that Slug expression is elevated in keratinocytes bordering cutaneous wounds in vivo, ex vivo, and in vitro. In this study we provide evidence that Slug expression is necessary for an EGFR-stimulated reepithelialization response. EGF induces Slug expression and the response to EGFR activation is more robust than to other receptor tyrosine kinase ligands. EGFR-stimulated reepithelialization is highly dependent on Slug, as demonstrated by the absence of EGF-stimulated outgrowth in explants derived from Slug null mice. In vitro reepithelialization stimulated by ectopic Slug expression was not impaired by an inhibitor of EGFR catalytic activity suggesting that Slug is a downstream mediator of this EGFR-stimulated response. Our findings provide evidence that Slug is an essential component of the pathway leading to EGFR-mediated epithelial outgrowth. PMID:18685621

Kusewitt, Donna F.; Choi, Changsun; Newkirk, Kimberly M.; Leroy, Pascale; Li, Yafan; Chavez, Miquella; Hudson, Laurie G.

2013-01-01

121

Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization.  

PubMed

Many peptide growth factors, including EGFR ligands, accelerate wound reepithelialization in vivo and in vitro. Furthermore, EGFR expression is transiently increased at wound margins, suggesting an active role for this receptor in wound repair. During reepithelialization of cutaneous wounds, keratinocytes display a phenotypic plasticity resembling aspects of epithelial-mesenchymal transformation. The transcription factor Slug/Snai2 is a regulator of epithelial-mesenchymal transformation during development, and we previously reported that Slug expression is elevated in keratinocytes bordering cutaneous wounds in vivo, ex vivo, and in vitro. In this study we provide evidence that Slug expression is necessary for an EGFR-stimulated reepithelialization response. Epidermal growth factor (EGF) induces Slug expression and the response to EGFR activation is more robust than to other receptor tyrosine kinase ligands. EGFR-stimulated reepithelialization is highly dependent on Slug, as demonstrated by the absence of EGF-stimulated outgrowth in explants derived from Slug null mice. In vitro reepithelialization stimulated by ectopic Slug expression was not impaired by an inhibitor of EGFR catalytic activity, suggesting that Slug is a downstream mediator of this EGFR-stimulated response. Our findings provide evidence that Slug is an essential component of the pathway leading to EGFR-mediated epithelial outgrowth. PMID:18685621

Kusewitt, Donna F; Choi, Changsun; Newkirk, Kimberly M; Leroy, Pascale; Li, Yafan; Chavez, Miquella G; Hudson, Laurie G

2009-02-01

122

Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia  

Microsoft Academic Search

Objective: The aim of this study was to determine whether plasma concentrations of vascular endothelial growth factor and placental growth factor are altered in women with severe preeclampsia. Study Design: We performed a case-control study to compare plasma concentrations of vascular endothelial growth factor and placental growth factor between women with severe preeclampsia and normotensive women admitted for delivery. Twenty-one

Jeffrey C. Livingston; Robert Chin; Bassam Haddad; Elizabeth T. McKinney; Robert Ahokas; Baha M. Sibai

2000-01-01

123

Growth and growth factors in diabetes mellitus.  

PubMed Central

Growth of 79 children with diabetes was analysed at diagnosis and again after one to 10.7 years of treatment with insulin. Both sexes were tall at onset, whereas at the last observation boys alone showed significant growth retardation. Height standard deviation score (SDS), however, showed no significant fall either in 32 subjects reassessed after five years of disease or in 18 subjects examined at full stature. Skeletal maturity was not significantly impaired after treatment. Pubertal growth spurt was reduced, especially in girls and in subjects with onset of disease at or around puberty. We found no significant correlation between height and height velocity SDS and glycosylated haemoglobin values or secretion of growth hormone during the arginine test. Somatomedin C values were correlated with height velocity SDS in prepubertal boys. The results of this study suggest that there are interferences in the growth of children with diabetes but that they do not seem to have a significant influence on adult height. PMID:3813637

Salardi, S; Tonioli, S; Tassoni, P; Tellarini, M; Mazzanti, L; Cacciari, E

1987-01-01

124

Gamma Interferon Reduces the Synthesis of Fibronectin by Human Keratinocytes,  

National Technical Information Service (NTIS)

Recombinant gamma interferon has a variety of effects on human keratinocytes including the induction of synthesis and expression of HLA-DR antigen as well as growth inhibition. In order to ascertain whether rIFN-y affects the keratinocytes capacity to int...

J. N. Mansbridge, S. T. Huang, V. B. Morhenn

1988-01-01

125

Transforming growth factor-? and fibrosis  

PubMed Central

Transforming growth factor-? (TGF-?), a prototype of multifunctional cytokine, is a key regulator of extracellular matrix (ECM) assembly and remodeling. Specifically, TGF-? isoforms have the ability to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. Elevated TGF-? expression in affected organs, and subsequent deregulation of TGF-? functions, correlates with the abnormal connective tissue deposition observed during the onset of fibrotic diseases. During the last few years, tremendous progress has been made in the understanding of the molecular aspects of intracellular signaling downstream of the TGF-? receptors. In particular, Smad proteins, TGF-? receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, have been studied extensively. The role of Smad3 in the transcriptional regulation of typeIcollagen gene expression and in the development of fibrosis, demonstrated both in vitro and in animal models with a targeted deletion of Smad3, is of critical importance because it may lead to novel therapeutic strategies against these diseases. This review focuses on the mechanisms underlying Smad modulation of fibrillar collagen expression and how it relates to fibrotic processes. PMID:17589920

Verrecchia, Franck; Mauviel, Alain

2007-01-01

126

Growth factors and antimicrobial factors of bovine colostrum  

Microsoft Academic Search

Colostrum is the first natural food produced by female mammals during the first 24–36h directly after giving birth. Chemically, colostrum is a very complex fluid rich in nutrients, antibodies and growth factors. In cows the antibodies provide passive immunity to the new born calf, whereas the growth factors especially stimulate the growth of the gut. The other antimicrobial components of

R. Pakkanen; J. Aalto

1997-01-01

127

The importance of both fibroblasts and keratinocytes in a bilayered living cellular construct used in wound healing  

PubMed Central

Cross talk between fibroblasts and keratinocytes, which maintains skin homeostasis, is disrupted in chronic wounds. For venous leg ulcers and diabetic foot ulcers, a bilayered living cellular construct (BLCC), containing both fibroblasts and keratinocytes that participate in cross talk, is a safe and effective product in healing chronic wounds. To show the importance of both cell types in BLCC, constructs were generated containing only fibroblasts or only keratinocytes and compared directly to BLCC via histology, mechanical testing, gene/protein analysis, and angiogenesis assays. BLCC contained a fully differentiated epithelium and showed greater tensile strength compared with one-cell-type constructs, most likely due to formation of intact basement membrane and well-established stratum corneum in BLCC. Furthermore, expression of important wound healing genes, cytokines, and growth factors was modulated by the cells in BLCC compared with constructs containing only one cell type. Finally, conditioned medium from BLCC promoted greater endothelial network formation compared with media from one-cell-type constructs. Overall, this study characterized a commercially available wound healing product and showed that the presence of both fibroblasts and keratinocytes in BLCC contributed to epithelial stratification, greater tensile strength, modulation of cytokine and growth factor expression, and increased angiogenic properties compared with constructs containing fibroblasts or keratinocytes alone. PMID:24635175

Wojtowicz, Abigail M; Oliveira, Steve; Carlson, Mark W; Zawadzka, Agatha; Rousseau, Cecile F; Baksh, Dolores

2014-01-01

128

Design and Synthesis of Binding Growth Factors  

PubMed Central

Growth factors play important roles in tissue regeneration. However, because of their instability and diffusible nature, improvements in their performance would be desirable for therapeutic applications. Conferring binding affinities would be one way to improve their applicability. Here we review techniques for conjugating growth factors to polypeptides with particular affinities. Conjugation has been designed at the level of gene fusion and of polypeptide ligation. We summarize and discuss the designs and applications of binding growth factors prepared by such conjugation approaches. PMID:22754349

Tada, Seiichi; Kitajima, Takashi; Ito, Yoshihiro

2012-01-01

129

Differential Utilization and Localization of ErbB Receptor Tyrosine Kinases in Skin Compared to Normal and Malignant Keratinocytes  

Microsoft Academic Search

Induction of heparin -binding epidermal growth factor - like growth factor (HB -EGF ) mRNA in mouse skin organ culture was blocked by two pan-ErbB receptor tyrosine kinase ( RTK ) inhibitors but not by genetic ablation of ErbB1, suggesting involvement of multiple ErbB species in skin physiology. Human skin, cultured normal keratinocytes, and A431 skin carcinoma cells expressed ErbB1,

Stefan W. Stoll; Sanjay Kansra; Scott Peshick; David W. Fry; Wilbur R. Leopold; Jane F. Wiesen; Maria Sibilia; Tong Zhang; Zena Werb; Rik Derynck; Erwin F. Wagner; James T. Elder

2001-01-01

130

Proliferation and motility of HaCaT keratinocyte derivatives is enhanced by fibroblast nemosis  

SciTech Connect

The role of paracrine tumor-stroma regulation in the progression of cancer is under intense investigation. Activated fibroblasts are key components of the tumor microenvironment providing the soluble factors mediating the regulation. Nemosis is an experimental model to study these parameters: formation of a multicellular spheroid activates fibroblasts and leads to increased production of soluble factors involved in the promotion of growth and motility. Role of nemosis was investigated in the tumorigenesis of HaCaT derivatives representing skin carcinoma progression. Conditioned medium from fibroblast spheroids increased proliferation rate of HaCaT derivatives. Expression of proliferation marker Ki-67 increased significantly in benign A5 and low-grade malignant II-4 cells, but did not further increase in the metastatic RT3 cells. Expression of p63, keratinocyte stem cell marker linked to cancer progression, was augmented by medium from nemotic fibroblasts; this increase was also seen in RT3 cells. Scratch-wound healing of the keratinocytes was enhanced in response to fibroblast nemosis. Neutralizing antibodies against growth factors inhibited wound healing to some extent; the response varied between benign and malignant keratinocytes. Migration and invasion were enhanced by conditioned medium from nemotic fibroblasts in benign and low-grade malignant cells. RT3 keratinocyte migration was further augmented, but invasion was not, indicating their intrinsic capacity to invade. Our data demonstrate that fibroblast nemosis increases proliferation and motility of HaCaT keratinocyte derivatives, and thus nemosis can be used as a model to study the role of soluble factors secreted by fibroblasts in tumor progression.

Raesaenen, Kati, E-mail: kati.rasanen@helsinki.fi [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)] [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland); Vaheri, Antti, E-mail: antti.vaheri@helsinki.fi [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)] [Haartman Institute, POB 21, FI-00014 University of Helsinki (Finland)

2010-06-10

131

Pulmonary effects of keratinocyte growth factor in newborn rats exposed to hyperoxia  

E-print Network

alveolar development characterize bronchopulmonary dysplasia (BPD) of the premature neonate. High levels distress syndrome, BPD has considerably evolved with changes in the care of VLBW infants and because of survival of lower gestational age infants than in the original description. It is now usually considered

Paris-Sud XI, Université de

132

Potential prognostic and diagnostic application of a novel monoclonal antibody against keratinocyte growth factor receptor.  

PubMed

KGFR is involved in the pathogenesis of several human cancers. In this study, we generated and characterized a monoclonal antibody specific to KGFR (SC-101 mAb) and evaluated its potential use in basic research and as a diagnostic and prognostic tool. The specificity and biological activity of the SC-101 mAb were evaluated by Western blotting, immunofluorescence, and immunoprecipitation analyses on various cell lines. KGFR expression in breast, pancreatic, and thyroid carcinoma was assessed by immunohistochemistry (IHC) with SC-101 mAb. KGFR expression levels revealed by SC-101 mAb resulted to increase proportionally with tumor grade in breast and pancreatic cancer. In addition, SC-101 mAb was able to detect KGFR down-modulation in thyroid cancer. SC-101 mAb might represent a useful tool for basic research applications, and it could also contribute to improve the accuracy of diagnosis and prognosis of epithelial tumors. PMID:24899248

Ceccarelli, Simona; Bei, Roberto; Vescarelli, Enrica; D'Amici, Sirio; di Gioia, Cira; Modesti, Andrea; Romano, Ferdinando; Redler, Adriano; Marchese, Cinzia; Angeloni, Antonio

2014-10-01

133

Regulation of Growth Factor Receptors by Gangliosides  

NSDL National Science Digital Library

Growth factor receptors are important in controlling many cellular functions, such as growth, differentiation, and disease. Growth factor receptors activate numerous signal transduction pathways within cells; however, how one growth factor receptor orchestrates multiple signal transduction pathways is not clear. This review focuses on a ubiquitous component of the plasma membrane, called "gangliosides," and how they modulate growth factor receptors at the cell membrane. Gangliosides are complex structures that consist of two parts--a lipid ceramide moiety and a carbohydrate head structure. Studies over the past two decades have demonstrated that different gangliosides can enhance or inhibit growth factor receptor activity. However, ganglioside modulation of growth factor receptors is more complex than simply stimulation or inhibition. We present and discuss three models of how gangliosides regulate growth factor receptors: (i) modulation of ligand binding, (ii) regulation of receptor dimerization, and (iii) regulation of receptor activation state and subcellular distribution. On the basis of these models, we speculate about the physiological consequences of ganglioside regulation of growth factor receptors.

Erik A. Miljan (Chicago;Children's Memorial Medical Center REV); Eric G. Bremer (Chicago;Children's Memorial Medical Center REV)

2002-11-26

134

Roles for Growth Factors in Cancer Progression  

NSDL National Science Digital Library

Under physiological conditions, cells receive fate-determining signals from their tissue surroundings, primarily in the form of polypeptide growth factors. Integration of these extracellular signals underlies tissue homeostasis. Although departure from homeostasis and tumor initiation are instigated by oncogenic mutations rather than by growth factors, the latter are the major regulators of all subsequent steps of tumor progression, namely clonal expansion, invasion across tissue barriers, angiogenesis, and colonization of distant niches. Here, we discuss the relevant growth factor families, their roles in tumor biology, as well as the respective downstream signaling pathways. Importantly, cancer-associated activating mutations that impinge on these pathways often relieve, in part, the reliance of tumors on growth factors. On the other hand, growth factors are frequently involved in evolvement of resistance to therapeutic regimens, which extends the roles for polypeptide factors to very late phases of tumor progression and offers opportunities for cancer therapy.

Esther Witsch (Weizmann Institute of Science); Michael Sela (Weizmann Institute of Science); Yosef Yarden (The Weizmann Institute of Science)

2010-04-01

135

Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing  

PubMed Central

Significance This review highlights the critical role of transforming growth factor beta (TGF-?)1–3 within different phases of wound healing, in particular, late-stage wound healing. It is also very important to identify the TGF-?1–controlling factors involved in slowing down the healing process upon wound epithelialization. Recent Advances TGF-?1, as a growth factor, is a known proponent of dermal fibrosis. Several strategies to modulate or regulate TGF's actions have been thoroughly investigated in an effort to create successful therapies. This study reviews current discourse regarding the many roles of TGF-?1 in wound healing by modulating infiltrated immune cells and the extracellular matrix. Critical Issues It is well established that TGF-?1 functions as a wound-healing promoting factor, and thereby if in excess it may lead to overhealing outcomes, such as hypertrophic scarring and keloid. Thus, the regulation of TGF-?1 in the later stages of the healing process remains as critical issue of which to better understand. Future Directions One hypothesis is that cell communication is the key to regulate later stages of wound healing. To elucidate the role of keratinocyte/fibroblast cross talk in controlling the later stages of wound healing we need to: (1) identify those keratinocyte-released factors which would function as wound-healing stop signals, (2) evaluate the functionality of these factors in controlling the outcome of the healing process, and (3) formulate topical vehicles for these antifibrogenic factors to improve or even prevent the development of hypertrophic scarring and keloids as a result of deep trauma, burn injuries, and any type of surgical incision. PMID:24527344

Pakyari, Mohammadreza; Farrokhi, Ali; Maharlooei, Mohsen Khosravi; Ghahary, Aziz

2013-01-01

136

Development and bioevaluation of nanofibers with blood-derived growth factors for dermal wound healing.  

PubMed

The aim of our work was to produce a modern nanomaterial with incorporated blood-derived growth factors, produced by electrospinning, applicable in treatment of chronic wounds. Platelet-rich plasma was chosen as a natural source of growth factors. Results showed that platelet-rich plasma stimulates keratinocyte and fibroblast cell growth in vitro. Its optimal concentration in growth medium was 2% (v/v) for both types of skin cells, while higher concentrations caused alterations in cell morphology, with reduced cell mobility and proliferation. In the next step hydrophilic nanofibers loaded with platelet-rich plasma were produced from chitosan and poly(ethylene oxide), using electrospinning. The morphology of nanofibers was stable in aqueous conditions for 72 h. It was shown that electrospinning does not adversely affect the biological activity of platelet-rich plasma. The effects of nanofibers with incorporated platelet-rich plasma on cell proliferation, survival, morphology and mobility were examined. Nanofibers limited cell mobility, changed morphology and stimulated cell proliferation. Despite of the small amount of blood-derived growth factors introduced in cell culture via platelet-rich plasma-loaded nanofibers, such nanofibrillar support significantly induced cell proliferation, indicating synergistic effect of nanotopography and incorporated growth factors. The overall results confirm favorable in vitro properties of produced nanofibers, indicating their high potential as a nanomaterial suitable for delivery of platelet-rich plasma in wound healing applications. PMID:24931341

Bertoncelj, Valentina; Pelipenko, Jan; Kristl, Julijana; Jeras, Matjaž; Cukjati, Marko; Kocbek, Petra

2014-09-01

137

Growth factor involvement in tension-induced skeletal muscle growth  

NASA Technical Reports Server (NTRS)

Long-term manned space travel will require a better understanding of skeletal muscle atrophy which results from microgravity. Astronaut strength and dexterity must be maintained for normal mission operations and for emergency situations. Although exercise in space slows the rate of muscle loss, it does not prevent it. A biochemical understanding of how gravity/tension/exercise help to maintain muscle size by altering protein synthesis and/or degradation rate should ultimately allow pharmacological intervention to prevent muscle atrophy in microgravity. The overall objective is to examine some of the basic biochemical processes involved in tension-induced muscle growth. With an experimental in vitro system, the role of exogenous and endogenous muscle growth factors in mechanically stimulated muscle growth are examined. Differentiated avian skeletal myofibers can be 'exercised' in tissue culture using a newly developed dynamic mechanical cell stimulator device which simulates different muscle activity patterns. Patterns of mechanical activity which significantly affect muscle growth and metabolic characteristics were found. Both exogenous and endogenous growth factors are essential for tension-induced muscle growth. Exogenous growth factors found in serum, such as insulin, insulin-like growth factors, and steroids, are important regulators of muscle protein turnover rates and mechanically-induced muscle growth. Endogenous growth factors are synthesized and released into the culture medium when muscle cells are mechanically stimulated. At least one family of mechanically induced endogenous factors, the prostaglandins, help to regulate the rates of protein turnover in muscle cells. Endogenously synthesized IGF-1 is another. The interaction of muscle mechanical activity and these growth factors in the regulation of muscle protein turnover rates with our in vitro model system is studied.

Vandenburgh, Herman H.

1993-01-01

138

Characterization of growth factors in human cartilage.  

PubMed

Growth factor activity has been identified in the chondrocytes and extracellular matrix (ECM) fractions of human costal cartilage. There was about five times more growth factor activity in the ECM than was found to be associated with the chondrocytes. The growth factor activity in chondrocytes was found to be associated with chromatin. Both the chromatin-associated growth factor (CAGF) activity and extracellular matrix growth factor (EMGF) activity were characterized for molecular weight, charge, and the effect of reduction by sulfhydryl reducing reagents. Biorex cation exchange chromatography showed that both CAGF and EMGF were cationic. CAGF and EMGF have molecular weights between 15,000 and 18,000 as determined by size exclusion chromatography on HPLC TSK 3000 columns equilibrated with guanidine-HCl and dithiothreitol. PMID:7169497

Bekoff, M C; Klagsbrun, M

1982-01-01

139

Transforming growth factor ? and epidermal growth factor expression in experimental murine polycystic kidney disease  

Microsoft Academic Search

Cystic change in polycystic kidney disease (PKD) is associated with epithelial hyperplasia, altered fluid and electrolyte transport, and de-differentiation of renal tubular epithelium. The role of polypeptide growth factors as potential modulators of cystic change remains an area of controversy. In this study, the expression of epidermal growth factor (EGF) and transforming growth factor-a (TGFa) were assessed by immunohistochemistry and

Malcolm R. Ogborn; Sanjay Sareen

1996-01-01

140

Genistein and curcumin block TGF-beta 1-induced u-PA expression and migratory and invasive phenotype in mouse epidermal keratinocytes.  

PubMed

Transforming growth factor-beta 1 (TGF-beta 1) stimulates migration/invasion of mouse transformed keratinocytes and increases urokinase (u-PA) expression/secretion. In this report, we analyzed the biological behavior of two naturally occurring inhibitors of protein tyrosine kinases, genistein and curcumin, that could abrogate the enhancement of u-PA levels induced by TGF-beta 1 in transformed keratinocytes. Our results showed that genistein and curcumin blocked this response in a dose-dependent manner and also inhibited the TGF-beta 1-induced synthesis of fibronectin, an early responsive gene to the growth factor. Both compounds also reduced TGF-beta 1-stimulated cell migration and invasiveness. These results suggest that a tyrosine kinase-signaling pathway should be involved in TGF-beta 1-mediated increased malignancy of transformed keratinocytes and that genistein and curcumin could play an important role in inhibiting tumor progression. PMID:10965519

Santibáńez, J F; Quintanilla, M; Martínez, J

2000-01-01

141

Nerve Growth Factor/Receptor Complex.  

National Technical Information Service (NTIS)

The invention relates to a complex comprising nerve growth factor (NGF) and tyrosine receptor kinase (trk) proto-oncogene protein and a complex comprising neurotrophic factors, neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF), and trkB pr...

L. Parada, D. Soppet, D. Kaplan, D. Martin-Zanca

1991-01-01

142

Growth factors, muscle function, and doping.  

PubMed

This article discusses the inevitable use of growth factors for enhancing muscle strength and athletic performance. Much effort has been expended on developing a treatment of muscle wasting associated with a range of diseases and aging. Frailty in the aging population is a major socioeconomic and medical problem. Emerging molecular techniques have made it possible to gain a better understanding of the growth factor genes and how they are activated by physical activity. The ways that misuse of growth factors may be detected and verified in athletes and future challenges for detecting manipulation of signaling pathways are discussed. PMID:20122457

Goldspink, Geoffrey; Wessner, Barbara; Tschan, Harald; Bachl, Norbert

2010-03-01

143

Environmental factors influencing growth and pubertal development.  

PubMed Central

Postnatal growth is based on hereditary signals and environmental factors in a complex regulatory network. Each factor must be in an optimal state for normal growth of the child. Fetal conditions may also have consequences on postnatal height. Intrauterine growth retardation can be recovered postnatally, although postnatal growth remains depressed in about one-third of cases. After birth, the environment may exert either a positive or negative effect on growth. In underdeveloped countries, malnutrition plays a major role in inhibiting the growth process. Children from families of higher socioeconomic classes are taller than their coevals in the lower socioeconomic groups. Urbanization also has a positive effect on growth. Better child care is supported by sufficient food supply, appropriate health and sanitation services, and a higher level of education. Over the last century, these factors have induced a taller stature and a more rapid maturity in Europe, North America, and Australia; a phenomenon which has been referred to as "the secular trend" in growth. Recently, a secular trend has also been reported in some developing countries. Although urbanization in general appears to be associated with better conditions of living, this is not the case in the slums of South America or in Africa where rural children are better off than children living in the poor cities. This paper describes in more detail the different hereditary and environmental factors that act during the fetal period and postnatally, and which play a role in human growth and pubertal development. PMID:8243404

Delemarre-van de Waal, H A

1993-01-01

144

Calcium-Regulated Differentiation of Normal Human Epidermal Keratinocytes in Chemically Defined Clonal Culture and Serum-Free Serial Culture  

Microsoft Academic Search

An improved serum-free culture system has been developed for normal human epidermal keratinocytes (HK), Short-term clonal growth and differentiation studies are routinely performed in a defined medium consisting of optimized nutrient medium MCDB 153 supplemented with epidermal growth factor, insulin, hydrocortisone, ethanolamine, and phosphoethanolamine. A small amount of whole bovine pituitary extract (wBPE) is added for initiation of primary cultures,

Steven T. Boyce; Richard G. Ham

1983-01-01

145

The inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes.  

PubMed

Rac1 is a Rho subfamily small GTPase which is highly expressed in epidermal keratinocytes. In mice the significance of Rac1 for the maintenance of the epidermis has been controversial. In keratinocytes from human origin, the role of Rac1 in the control of growth/differentiation is still obscure. In this study we used RNA interference to induce specific inhibition of Rac1 expression in cultured human keratinocytes and analyzed the consequences on proliferation and differentiation. We found that the autocrine proliferation of keratinocytes is unaltered by Rac1 silencing. However, the suppression of Rac1 induced premature differentiation as revealed by the expression of markers (keratin 10, involucrin), but the involved mechanism is independent of the activity of p38 mitogen-activated protein kinase. Rather, we found that the effects of Rac1 silencing on keratinocytes differentiation are concomitant with negative regulation of the Ser62/Thr58 phosphorylation on the transcription factor c-myc, a mechanism known to control post-translational stability of the c-myc protein. Thus, in growing human keratinocytes, Rac1 could impede the expression of premature differentiation markers, probably by exerting positive control on c-myc activity and its binding to specific promoters. PMID:17615554

Nikolova, Ekaterina; Mitev, Vanio; Minner, Frédéric; Deroanne, Christophe F; Poumay, Yves

2008-02-15

146

Autologous keratinocyte suspension in platelet concentrate accelerates and enhances wound healing - a prospective randomized clinical trial on skin graft donor sites: platelet concentrate and keratinocytes on donor sites  

PubMed Central

Background Wound healing involves complex mechanisms, which, if properly chaperoned, can enhance patient recovery. The abilities of platelets and keratinocytes may be harnessed in order to stimulate wound healing through the formation of platelet clots, the release of several growth factors and cytokines, and cell proliferation. The aim of the study was to test whether autologous keratinocyte suspensions in platelet concentrate would improve wound healing. The study was conducted at the Lausanne University Hospital, Switzerland in 45 patients, randomized to three different topical treatment groups: standard treatment serving as control, autologous platelet concentrate (PC) and keratinocytes suspended in autologous platelet concentrate (PC?+?K). Split thickness skin graft donor sites were chosen on the anterolateral thighs of patients undergoing plastic surgery for a variety of defects. Wound healing was assessed by the duration and quality of the healing process. Pain intensity was evaluated at day five. Results Healing time was reduced from 13.9?±?0.5 days (mean?±?SEM) in the control group to 7.2?±?0.2 days in the PC group (P?keratinocytes in suspension further reduced the healing time to 5.7?±?0.2 days. Pain was reduced in both the PC and PC?+?K groups. Data showed a statistically detectable advantage of using PC?+?K over PC alone (P?keratinocytes in stimulating wound healing and reducing pain. This strikingly simple approach could have a significant impact on patient care, especially critically burned victims for whom time is of the essence. Clinical trial registry information Protocol Record Identification Number: 132/03 Registry URL: http://www.clinicaltrials.gov PMID:23570605

2013-01-01

147

Transforming Growth Factor-?1-Mediated Slug and Snail Transcription Factor Up-Regulation Reduces the Density of Langerhans Cells in Epithelial Metaplasia by Affecting E-Cadherin Expression  

PubMed Central

Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a+ LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-?1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-?1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis. PMID:18385519

Herfs, Michael; Hubert, Pascale; Kholod, Natalia; Hubert Caberg, Jean; Gilles, Christine; Berx, Geert; Savagner, Pierre; Boniver, Jacques; Delvenne, Philippe

2008-01-01

148

Activated protein C: A regulator of human skin epidermal keratinocyte function  

PubMed Central

Activated protein C (APC) is a physiological anticoagulant, derived from its precursor protein C (PC). Independent of its anticoagulation, APC possesses strong anti-inflammatory, anti-apoptotic and barrier protective properties which appear to be protective in a number of disorders including chronic wound healing. The epidermis is the outermost skin layer and provides the first line of defence against the external environment. Keratinocytes are the most predominant cells in the epidermis and play a critical role in maintaining epidermal barrier function. PC/APC and its receptor, endothelial protein C receptor (EPCR), once thought to be restricted to the endothelium, are abundantly expressed by skin epidermal keratinocytes. These cells respond to APC by upregulating proliferation, migration and matrix metalloproteinase-2 activity and inhibiting apoptosis/inflammation leading to a wound healing phenotype. APC also increases barrier function of keratinocyte monolayers by promoting the expression of tight junction proteins and re-distributing them to cell-cell contacts. These cytoprotective properties of APC are mediated through EPCR, protease-activated receptors, epidermal growth factor receptor or Tie2. Future preventive and therapeutic uses of APC in skin disorders associated with disruption of barrier function and inflammation look promising. This review will focus on APC’s function in skin epidermis/keratinocytes and its therapeutical potential in skin inflammatory conditions. PMID:24921007

McKelvey, Kelly; Jackson, Christopher John; Xue, Meilang

2014-01-01

149

Combined treatment with sodium butyrate and PD153035 enhances keratinocyte differentiation.  

PubMed

Epidermal growth factor (EGF) receptor (EGFR) signalling is a critical determinant of keratinocyte proliferation and differentiation in both normal and diseased skin. Here we explore the effects of combined treatment with the differentiation-promoting agent sodium butyrate (SB) and the EGFR inhibitor (EGFRI) PD153035 on terminal differentiation of normal human epidermal keratinocytes (NHEKs). Cells treated with SB showed increased expression of the levels of mRNA and protein of the differentiation markers filaggrin and transglutaminase 1. Cotreatment with EGF significantly blunted these effects of SB. Combined treatment with SB and PD153035 alleviated these inhibitory actions of EGF, resulting in improved effects of decreased cell growth and increased terminal differentiation, relative to the individual treatments. These results indicate that the combined use of a differentiation-promoting agent and an EGFR inhibitor may offer an additional approach to the management of hyperproliferative skin diseases. PMID:24451036

Leon Carrion, Sandra; Sutter, Carrie Hayes; Sutter, Thomas R

2014-03-01

150

Luteolin inhibits human keratinocyte activation and decreases NF-?B induction that is increased in psoriatic skin.  

PubMed

Psoriasis (Ps) is an autoimmune disease characterized by keratinocyte hyperproliferation and chronic inflammation, with increased expression of tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF). Anti-TNF biologic agents are effective in treating Ps, but are associated with increased risk of infections and blood malignancies. Moreover, keratinocyte hyperproliferation and activation have yet to be addressed. Flavonoids, such as luteolin, are natural compounds with potent anti-inflammatory properties, but their actions on keratinocytes remain unknown. We show that TNF (50 ng/mL) triggers significant production of inflammatory mediators interleukin-6, interleukin-8 and VEGF from both human HaCaT and primary keratinocytes. Pretreatment with the flavonoid luteolin (10-100 µM) significantly inhibits mRNA expression and release of all three mediators in a concentration-dependent manner. More importantly, luteolin decreases TNF-induced phosphorylation, nuclear translocation and DNA binding of the nuclear factor-kappa B (NF-?B) typically involved in inflammatory mediator transcription. We also report that luteolin reduces TNF-induced mRNA expression of two genes (NFKB1 and RELA) encoding two NF-?B subunits (NF-?B p50 and NF-?B p65, respectively). Interestingly, we show that gene expression of RELA is increased in human psoriatic skin. Keratinocyte proliferation, which is a characteristic feature of psoriatic skin, is effectively reduced by luteolin in HaCaT cells, but not in primary keratinocytes. Finally, luteolin does not affect intracellular ATP production or viability. Appropriate formulations of luteolin and related flavones may be promising candidates to be developed into local and systemic treatments for Ps and other inflammatory skin diseases. PMID:24587411

Weng, Zuyi; Patel, Arti B; Vasiadi, Magdalini; Therianou, Anastasia; Theoharides, Theoharis C

2014-01-01

151

Original article Effect of growth factors on proliferation, apoptosis  

E-print Network

the local production of insulin-like growth factors type I or II (IGF-I, IGF-II) or epidermal growth factor, Alexander V. MAKAREVICHa, Alojz KĂ?BEKb a Research Institute of Animal Production, 949 92 Nitra, Slovak of action. insulin-like growth factor I / insulin-like growth factor II / epidermal growth factor / cumulus

Boyer, Edmond

152

Predictive factors for intrauterine growth restriction  

PubMed Central

Abstract Reduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies. Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; ?-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer–Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient

Albu, AR; Anca, AF; Horhoianu, VV; Horhoianu, IA

2014-01-01

153

Fracture induces keratinocyte activation, proliferation, and expression of pro-nociceptive inflammatory mediators.  

PubMed

Tibia fracture in rats results in chronic vascular and nociceptive changes in the injured limb resembling complex regional pain syndrome (CRPS) and up-regulates expression of interleukin 1? (IL-1?), interleukin IL-6 (IL-6), tumor necrosis factor-? (TNF-?), and nerve growth factor-? (NGF-?) in the hindpaw skin. When fractured rats are treated with cytokine or NGF inhibitors nociceptive sensitization is blocked. Because there is no leukocyte infiltration in the hindpaw skin we postulated that resident skin cells produce the inflammatory mediators causing nociceptive sensitization after fracture. To test this hypothesis rats underwent distal tibia fracture and hindlimb casting for 4 weeks, then the hindpaw skin was harvested and immunostained for keratin, cytokines and NGF. BrdU staining was used to evaluate cell proliferation. Hindpaw nociceptive thresholds, edema, and temperature were tested before and up to 96h after intraplantar injections of IL-6 and TNF-?. Tibia fracture caused keratinocyte activation, proliferation, and up-regulated IL-1?, IL-6, TNF-? and NGF-? protein expression in the hindpaw keratinocytes. Local injections of IL-6 and TNF-? induced hindpaw mechanical allodynia lasting for several days and modest increases in temperature and edema. These data indicate that activated keratinocytes proliferate and express IL-1?, IL-6, TNF-?, and NGF-? after fracture and that excess amounts of inflammatory mediators in the skin cause sustained nociceptive sensitization. This is the first study demonstrating in vivo keratinocyte expression of IL-6, TNF-? and NGF-? in a CRPS model and we postulate that the keratinocyte is the primary cellular source for the inflammatory signals mediating cutaneous nociceptive sensitization in early CRPS. PMID:20934254

Li, Wen-Wu; Guo, Tian-Zhi; Li, Xiang-qi; Kingery, Wade S; Clark, J David

2010-12-01

154

Nerve growth factor: from neurotrophin to neurokine  

Microsoft Academic Search

Nerve growth factor (NGF) is largely known as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurones and basal forebrain cholinergic nuclei during development and maturation. However, NGF also exerts a modulatory role on sensory, nociceptive nerve physiology during adulthood that appears to correlate with hyperalgesic phenomena occurring in tissue inflammation.

Rita Levi-Montalcini; Stephen D. Skaper; Roberto Dal Toso; Lucia Petrelli; Alberta Leon

1996-01-01

155

Role of Platelet-derived Growth Factor and Vascular Endothelial Growth Factor in Obliterative Airway Disease  

Microsoft Academic Search

Rationale: Platelet-derived growth factor (PDGF) is an important smoothmusclecellmitogen,and vascularendothelialgrowth factor (VEGF) is a known angiogenic and proinflammatory growth factor. We hypothesized that specific therapy aimed at these growth fac- tors might inhibit the development of experimental obliterative airway disease (OAD). Methods: In fully mismatched rat tracheal allografts, we used ima- tinibandPTK\\/ZK,eitheraloneor incombination, toblockPDGFand VEGF receptor protein tyrosine kinase (RTK)

Jussi M. Tikkanen; Maria Hollmen; Antti I. Nykanen; Jeanette Wood; Petri K. Koskinen; Karl B. Lemstrom

2006-01-01

156

AP1-dependent repression of TGF?-mediated MMP9 upregulation by PPAR? agonists in keratinocytes.  

PubMed

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that function mainly in the regulation of glucose and lipid homeostasis. PPAR agonists have been shown to control inflammation by inhibition of distinct proinflammatory genes. Aberrant activation of the epidermal growth factor receptor and/or overexpression of its ligand, transforming growth factor-? (TGF?), are key features of both neoplastic and inflammatory hyperproliferative epithelia. Matrix metalloproteinase 9 (MMP9) belongs to the set of genes that are effectively induced by TGF? in keratinocytes. Induction of MMP9 expression is strongly linked to regenerative skin repair mechanisms, inflammatory skin diseases and tumor metastasis. We explored whether the known anti-inflammatory effects of PPAR? ligands involve inhibiting the TGF?-mediated upregulation of MMP9. The PPAR? agonists potently inhibited TGF?-induced MMP9 expression in human keratinocytes. This inhibition was observed at both the protein and mRNA levels. Transcriptional activation studies with deletion constructs of a reporter gene revealed that PPAR? agonists mediate their inhibitory effects via an AP1-binding site. Electromobility shift assay analysis indicated that MMP9 gene expression is inhibited by repressing site-dependent DNA binding and transactivation by c-fos. In conclusion, our data provide the first evidence that MMP9 expression induced by TGF? is a valid target of PPAR? ligands in keratinocytes. PMID:21496113

Meissner, Markus; Berlinski, Barbara; Doll, Monika; Hrgovic, Igor; Laubach, Vesselina; Reichenbach, Gabi; Kippenberger, Stefan; Gille, Jens; Kaufmann, Roland

2011-05-01

157

Mechanical Stretch Inhibits Lipopolysaccharide-induced Keratinocyte-derived Chemokine and Tissue Factor Expression While Increasing Procoagulant Activity in Murine Lung Epithelial Cells*  

PubMed Central

Previous studies have shown that the innate immune stimulant LPS augments mechanical ventilation-induced pulmonary coagulation and inflammation. Whether these effects are mediated by alveolar epithelial cells is unclear. The alveolar epithelium is a key regulator of the innate immune reaction to pathogens and can modulate both intra-alveolar inflammation and coagulation through up-regulation of proinflammatory cytokines and tissue factor (TF), the principal initiator of the extrinsic coagulation pathway. We hypothesized that cyclic mechanical stretch (MS) potentiates LPS-mediated alveolar epithelial cell (MLE-12) expression of the chemokine keratinocyte-derived cytokine (KC) and TF. Contrary to our hypothesis, MS significantly decreased LPS-induced KC and TF mRNA and protein expression. Investigation into potential mechanisms showed that stretch significantly reduced LPS-induced surface expression of TLR4 that was not a result of increased degradation. Decreased cell surface TLR4 expression was concomitant with reduced LPS-mediated NF-?B activation. Immunofluorescence staining showed that cyclic MS markedly altered LPS-induced organization of actin filaments. In contrast to expression, MS significantly increased LPS-induced cell surface TF activity independent of calcium signaling. These findings suggest that cyclic MS of lung epithelial cells down-regulates LPS-mediated inflammatory and procoagulant expression by modulating actin organization and reducing cell surface TLR4 expression and signaling. However, because LPS-induced surface TF activity was enhanced by stretch, these data demonstrate differential pathways regulating TF expression and activity. Ultimately, loss of LPS responsiveness in the epithelium induced by MS could result in increased susceptibility of the lung to bacterial infections in the setting of mechanical ventilation. PMID:23362270

Sebag, Sara C.; Bastarache, Julie A.; Ware, Lorraine B.

2013-01-01

158

Distinct effects of different phosphatidylglycerol species on mouse keratinocyte proliferation.  

PubMed

We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16?0/20?4), palmitoyl-linoleoyl-PG (16?0/18?2), dilinoleoyl-PG (18?2/18?2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16?0/18?1) and dioleoyl-PG (18?1/18?1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation. PMID:25233484

Xie, Ding; Seremwe, Mutsa; Edwards, John G; Podolsky, Robert; Bollag, Wendy B

2014-01-01

159

Distinct Effects of Different Phosphatidylglycerol Species on Mouse Keratinocyte Proliferation  

PubMed Central

We have previously shown that liposomes composed of egg-derived phosphatidylglycerol (PG), with a mixed fatty acid composition (comprising mainly palmitate and oleate), inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16?0/20?4), palmitoyl-linoleoyl-PG (16?0/18?2), dilinoleoyl-PG (18?2/18?2) and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16?0/18?1) and dioleoyl-PG (18?1/18?1) were especially effective proproliferative PG species. This result represents the first demonstration of opposite effects of different species of a single class of phospholipid and suggests that these different PG species may signal to diverse effector enzymes to differentially affect keratinocyte proliferation and normalize keratinocyte proliferation. Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation. PMID:25233484

Xie, Ding; Seremwe, Mutsa; Edwards, John G.; Podolsky, Robert; Bollag, Wendy B.

2014-01-01

160

Transforming Growth Factor-?1Antisense Modulates the Expression of Hepatocyte Growth Factor\\/Scatter Factor in Keloid Fibroblast Cell Culture  

Microsoft Academic Search

Abnormal wound healing processes can result in hypertrophic scars and keloids. Transforming growth factor-?1 (TGF-?1) and\\u000a hepatocyte growth factor\\/scatter factor (HGF\\/SF) are biphasic growth factor cytokines in physiologic and pathophysiologic\\u000a conditions. Findings have shown TGF-?1 to be pivotal in the formation of keloid tissue. Therefore, neutralizing antibodies\\u000a may allow wound healing without keloid formation. As reported, TGF-?1 is antagonized by

R. Naim; A. Naumann; J. Barnes; A. Sauter; K. Hormann; D. Merkel; W. Aust; T. Braun; M. Bloching

2008-01-01

161

Transforming growth factor-? regulates production of proteoglycans by mesangial cells  

Microsoft Academic Search

Transforming growth factor-? regulates production of proteoglycans by mesangial cells. Accumulation of glomerular extracellular matrix is a prominent feature of most forms of progressive glomerular disease. Since some growth factors may play a role in extracellular matrix production, we examined the effects of transforming growth factor-? (TGF-?), interleukin 1, platelet derived growth factor, and tumor necrosis factor on the production

Wayne A Border; Seiya Okuda; Lucia R Languino; Erkki Ruoslahti

1990-01-01

162

Effect of laser phototherapy on the release of fibroblast growth factors by human gingival fibroblasts.  

PubMed

The effects of laser phototherapy on the release of growth factors by human gingival fibroblasts were studied in vitro. Cells from a primary culture were irradiated twice (6 h interval), with continuous diode laser [gallium-aluminum-arsenium (GaAlAs), 780 nm, or indium-gallium-aluminum-phosphide (InGaAlP),_660 nm] in punctual and contact mode, 40 mW, spot size 0.042 cm(2), 3 J/cm(2) and 5 J/cm(2) (3 s and 5 s, respectively). Positive [10% fetal bovine serum (FBS)] and negative (1%FBS) controls were not irradiated. Production of keratinocyte growth factor (KGF) and basic fibroblast growth factor (bFGF) was quantified by enzyme-linked immunosorbent assay (ELISA). The data were statistically compared by analysis of variance (ANOVA) followed by Tukey's test (P

Damante, Carla Andreotti; De Micheli, Giorgio; Miyagi, Sueli Patrícia Harumi; Feist, Ilíria Salomăo; Marques, Márcia Martins

2009-11-01

163

Antagonism of epidermal growth factor receptor tyrosine kinase ameliorates the psoriatic phenotype in organ-cultured skin.  

PubMed

Psoriatic plaque skin incubated for eight days in organ culture in the presence of a potent epidermal growth factor (EGF) receptor tyrosine kinase (RTK) antagonist reverted to a more normal histological appearance, while untreated psoriatic plaque skin retained histological features associated with the psoriatic phenotype. In concomitant studies it was shown that the EGF-RTK antagonist had no significant effect on histological features of non-psoriatic skin and no effect on dermal function, i.e. elaboration of both type I procollagen and matrix metalloproteinase-1 (MMP-1; interstitial collagenase). When human epidermal keratinocytes were treated with the EGF-RTK antagonist in monolayer culture, growth inhibition was seen (ED(50) = approximately 0.06 microM). When dermal fibroblasts were exposed to the EGF-RTK antagonist in monolayer culture, proliferation, MMP-1 and type I procollagen production were essentially unaffected at concentrations which interfered with keratinocyte growth (up to 1 microM). The capacity of the EGF-RTK antagonist to modulate the histological features of psoriatic skin in organ culture under conditions in which normal skin architecture and dermal function are largely unaffected suggests a potential for anti-psoriatic therapy. PMID:15897684

Varani, J; Lateef, H; Fay, K; Elder, J T

2005-01-01

164

Reprogramming human adipose tissue stem cells using epidermal keratinocyte extracts  

PubMed Central

Human adipose tissue stem cells (ATSCs) can differentiate into various types of cell in response to lineage-specific induction factors. Reprogramming cells using nuclear and cytoplasmic extracts derived from another type of somatic cell is an effective method of producing specific types of differentiated cell. In the present study, the ability of reprogrammed ATSCs to acquire epidermal keratinocyte properties following transient exposure to epidermal keratinocyte extracts was demonstrated. Reversibly permeabilized ATSCs were incubated for 1 h in nuclear and cytoplasmic extracts from epidermal keratinocytes, resealed with CaCl2 and cultured. ATSC reprogramming is demonstrated by nuclear uptake of epidermal keratinocyte extracts. After one week of exposure to extracts, ATSCs underwent changes in cell morphology, cell-specific genes were activated, and epidermal keratinocyte markers including K19 and K1/K10 (markers of stem cells and terminally differentiated keratinocytes, respectively) were expressed. This study indicates that the reprogramming of ATSCs using nuclear and cytoplasmic extracts from epidermal keratinocytes is a viable option for the production of specific types of cell. PMID:25333210

XIE, FENG; TANG, XINJIE; ZHANG, QUN; DENG, CHENLIANG

2015-01-01

165

Reprogramming human adipose tissue stem cells using epidermal keratinocyte extracts.  

PubMed

Human adipose tissue stem cells (ATSCs) can differentiate into various types of cell in response to lineage?specific induction factors. Reprogramming cells using nuclear and cytoplasmic extracts derived from another type of somatic cell is an effective method of producing specific types of differentiated cell. In the present study, the ability of reprogrammed ATSCs to acquire epidermal keratinocyte properties following transient exposure to epidermal keratinocyte extracts was demonstrated. Reversibly permeabilized ATSCs were incubated for 1 h in nuclear and cytoplasmic extracts from epidermal keratinocytes, resealed with CaCl2 and cultured. ATSC reprogramming is demonstrated by nuclear uptake of epidermal keratinocyte extracts. After one week of exposure to extracts, ATSCs underwent changes in cell morphology, cell?specific genes were activated, and epidermal keratinocyte markers including K19 and K1/K10 (markers of stem cells and terminally differentiated keratinocytes, respectively) were expressed. This study indicates that the reprogramming of ATSCs using nuclear and cytoplasmic extracts from epidermal keratinocytes is a viable option for the production of specific types of cell. PMID:25333210

Xie, Feng; Tang, Xinjie; Zhang, Qun; Deng, Chenliang

2015-01-01

166

Activated keratinocytes in the epidermis of hypertrophic scars.  

PubMed Central

The etiology of hypertrophic scarring, a pathological end point of wound healing, is unknown. The scars most commonly occur when epithelialization has been delayed during, for example, the healing of deep dermal burn wounds. Hypertrophic scars are conventionally described as a dermal pathology in which the epidermis has only a passive role. In this study, the expression of keratin intermediate filament proteins and filaggrin has been investigated in the epidermis of hypertrophic scars and site-matched controls from the same patients. Hypertrophic scar epidermis was found to express the hyperproliferative keratins K6 and K16 in interfollicular epidermis in association with K17 and precocious expression of filaggrin. K16 mRNA was localized by in situ hybridization using a highly specific cRNA probe. In contrast to the immunohistochemical location of K16 protein, the K16 mRNA was found to be expressed in the basal cell layer of normal skin. In hypertrophic scars the mRNA distribution corroborated the abnormal K16 protein distribution. These results suggest the keratinocytes in hypertrophic scar epidermis have entered an alternative differentiation pathway and are expressing an activated phenotype. Activated keratinocytes are a feature of the early stages of wound healing producing growth factors that influence fibroblasts, endothelial cells, and the inflammatory response. We propose that cellular mechanisms in the pathogenesis of hypertrophic scarring are more complex than isolated dermal phenomena. The persistence of activated keratinocytes in hypertrophic scar epidermis implicates abnormal epidermal-mesenchymal interactions. Images Figure 1 Figure 3 PMID:9588880

Machesney, M.; Tidman, N.; Waseem, A.; Kirby, L.; Leigh, I.

1998-01-01

167

Transforming Growth Factor-? in Cutaneous Tissue Repair  

Microsoft Academic Search

Transforming growth factor-?s and their family are important components of the injury response. By far, the best studied of\\u000a these multifunctional peptides is TGF-?1. Evidence accumulated over the last two decades shows that TGF-?s have a profound\\u000a stimulatory effect on overall extracellular matrix production, on the development of tensile strength after wounding, and\\u000a on the formation of a stable scar.

Jisun Cha; Vincent Falanga

168

FGF-P improves barrier function and proliferation in human keratinocytes after radiation  

PubMed Central

Purpose Epidermal keratinocytes, which can be severely damaged after ionizing radiation (IR), are rapid turnover cells that function as a barrier protecting the host from pathogenic invasion and fluid loss. We tested fibroblast growth factor-peptide (FGF-P), a small peptide derived from the receptor-binding domain of FGF-2, as a potential mitigator of radiation effects via proliferation and the barrier function of keratinocytes. Methods and Materials Keratinocytes isolated from neonatal foreskin were grown on transwells. After 0, 5, or 10-Gy, the cells were treated with a vehicle or FGF-P. The permeability of IR cells was assessed through transepithelial electrical resistance (TEER) and a paracellular tracer flux of fluorescein isothiocyanate-conjugated bovine serum albumin (FITC-BSA) with Ussing chambers. The cell proliferation was measured with yellow tetrazolium salt (MTT) and tritiated thymidine (3H-TdR) assays. The phosphorylation of extracellular signal-regulated kinases (ERK) was measured in an enzyme-linked immunosorbent (ELISA)-like assay, and the proteins related to tight junctions (TJ) and adherens junctions (AJ) were examined with Western blotting. We used a mouse model to assess the ability of FGF-P to promote the healing of skin ?-burns created with a strontium applicator. Results 1) FGF-P reduced the permeability of irradiated keratinocytes, as evidenced by increased TEER and decreased diffusion of FITC-BSA both associated with the regulation of different proteins and levels of TJ and AJ; 2) FGF-P enhanced the proliferation of irradiated keratinocytes, as evidenced by increased MTT activity and 3H-TdR incorporation, which was associated with activation of the ERK pathway; and 3) FGF-P promoted the healing of skin ?-burns. Conclusions FGF-P enhances the barrier function, including up-regulation of TJ proteins, increases proliferation of human keratinocytes, and accelerates the healing of skin ?-burns. FGF-P is a promising mitigator that improves the proliferation and barrier function of keratinocytes after IR. PMID:21489707

Zhang, Kunzhong; Tian, Yeping; Yin, Liangjie; Zhang, Mei; Beck, Lisa A.; Zhang, Bingrong; Okunieff, Paul; Zhang, Lurong; Vidyasagar, Sadasivan

2011-01-01

169

Platelet-derived growth factors and fibroblast growth factors are mitogens for rat Schwann cells  

Microsoft Academic Search

Rat sciatic nerve Schwann cells in culture respond to a limited range of mitogens, including glial growth factor, transforming growth factors beta-1 and beta-2 (TGF-fll, TGF-\\/~2), some cell mem- brane-associated factors, and to agents such as cholera toxin and forskolin which raise intracellular levels of cAME These responses require the presence of FCS, which exhibits little or no mitogenic activity

John B. Davis; Paul Stroobant

1990-01-01

170

PCB153 reduces telomerase activity and telomere length in immortalized human skin keratinocytes (HaCaT) but not in human foreskin keratinocytes (NFK)  

SciTech Connect

Polychlorinated biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24 days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism. -- Highlights: ? Human immortal (HaCaT) and primary (NFK) keratinocytes were exposed to PCB153. ? PCB153 significantly reduced telomerase activity and telomere length in HaCaT. ? No effect on telomere length and telomerase activity was found in NFK. ? Increased intracellular superoxide levels and reduced cell growth was seen in both. ? PCB153 may damage telomerase expressing cells like stem cells.

Senthilkumar, P.K. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States)] [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Robertson, L.W. [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States) [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA (United States); Ludewig, G., E-mail: Gabriele-ludewig@uiowa.edu [Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA (United States); Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA (United States)

2012-02-15

171

Vascular endothelial growth factor B, a novel growth factor for endothelial cells.  

PubMed Central

We have isolated and characterized a novel growth factor for endothelial cells, vascular endothelial growth factor B (VEGF-B), with structural similarities to vascular endothelial growth factor (VEGF) and placenta growth factor. VEGF-B was particularly abundant in heart and skeletal muscle and was coexpressed with VEGF in these and other tissues. VEGF-B formed cell-surface-associated disulfide-linked homodimers and heterodimerized with VEGF when coexpressed. Conditioned medium from transfected 293EBNA cells expressing VEGF-B stimulated DNA synthesis in endothelial cells. Our results suggest that VEGF-B has a role in angiogenesis and endothelial cell growth, particularly in muscle. Images Fig. 3 Fig. 4 Fig. 5 PMID:8637916

Olofsson, B; Pajusola, K; Kaipainen, A; von Euler, G; Joukov, V; Saksela, O; Orpana, A; Pettersson, R F; Alitalo, K; Eriksson, U

1996-01-01

172

UVB Activates ERK1\\/2 and p38 Signaling Pathways via Reactive Oxygen Species in Cultured Keratinocytes  

Microsoft Academic Search

We have previously shown that hydrogen peroxide is an important mediator of ultraviolet B induced phosphorylation of the epidermal growth factor receptor in human keratinocytes. Here we demonstrate that physiologic doses of ultraviolet B and hydrogen peroxide stimulate activation of two related but distinct mitogen-activated protein kinase pathways: extracellular regulated kinase 1 and 2 (ERK1\\/2), as well as p38, the

Dominik Peus; Remus A. Vasa; Astrid Beyerle; Alexander Meves; Carsten Krautmacher; Mark R. Pittelkow

1999-01-01

173

Nerve growth factor promotes human hemopoietic colony growth and differentiation  

SciTech Connect

Nerve growth factor (NGF) is a neurotropic polypeptide necessary for the survival and growth of some central neurons, as well as sensory afferent and sympathetic neurons. Much is now known of the structural and functional characteristics of NGF, whose gene has recently been clones. Since it is synthesized in largest amounts by the male mouse submandibular gland, its role exclusively in nerve growth is questionable. These experiments indicate that NGF causes a significant stimulation of granulocyte colonies grown from human peripheral blood in standard hemopoietic methylcellulose assays. Further, NGF appears to act in a relatively selective fashion to induce the differentiation of eosinophils and basophils/mast cells. Depletion experiments show that the NGF effect may be T-cell dependent and that NGF augments the colony-stimulating effect of supernatants from the leukemic T-cell (Mo) line. The hemopoietic activity of NGF is blocked by {sup 125}I-polyclonal and monoclonal antibodies to NGF. The authors conclude that NGF may indirectly act as a local growth factor in tissues other than those of the nervous system by causing T cells to synthesize or secrete molecules with colony-stimulating activity. In view of the synthesis of NGF in tissue injury, the involvement of basophils/mast cells and eosinophils in allergic and other inflammatory processes, and the association of mast cells with fibrosis and tissue repair, they postulate that NGF plays an important biological role in a variety of repair processes.

Matsuda, H.; Coughlin, M.D.; Bienenstock, J.; Denburg, J.A. (McMaster Univ. Health Sciences Center, Hamilton, Ontario (Canada))

1988-09-01

174

Altered (/sup 125/I)epidermal growth factor binding and receptor distribution in psoriasis  

SciTech Connect

Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyperproliferative disease such as psoriasis vulgaris is unclear. To study the pathogenesis of psoriasis, 4-mm2 punch biopsy specimens of normal, uninvolved, and involved psoriatic skin were assayed for EGF receptors by autoradiographic, immunohistochemical, and biochemical methods. Using autoradiographic and immunohistochemical methods, basal keratinocytes were found to contain the greatest number of EGF binding sites and immunoreactive receptors as compared to the upper layers of the epidermis in both normal epidermis and psoriatic skin. No EGF receptor differences between normal and psoriatic epidermis were observed in this layer. In the upper layers of the epidermis, a 2-fold increase in EGF binding capacity was observed in psoriatic skin as compared with normal thin or thick skin. Biochemical methods indicated that (/sup 125/I)EGF binding was increased in psoriatic epidermis as compared with similar thickness normal epidermis when measured on a protein basis. Epidermal growth factor was shown to increase phosphorylation of the EGF receptor in skin. EGF receptors retained in the nonmitotic stratum spinosum and parakeratotic stratum corneum may reflect the incomplete, abnormal differentiation that occurs in active psoriatic lesions. Alternatively, retained EGF receptors may play a direct role in inhibiting cellular differentiation in the suprabasal layers.

Nanney, L.B.; Stoscheck, C.M.; Magid, M.; King, L.E. Jr.

1986-03-01

175

Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice  

PubMed Central

Vascular endothelial growth factor receptor-3 (VEGFR-3) has an essential role in the development of embryonic blood vessels; however, after midgestation its expression becomes restricted mainly to the developing lymphatic vessels. The VEGFR-3 ligand VEGF-C stimulates lymphangiogenesis in transgenic mice and in chick chorioallantoic membrane. As VEGF-C also binds VEGFR-2, which is expressed in lymphatic endothelia, it is not clear which receptors are responsible for the lymphangiogenic effects of VEGF-C. VEGF-D, which binds to the same receptors, has been reported to induce angiogenesis, but its lymphangiogenic potential is not known. In order to define the lymphangiogenic signalling pathway we have created transgenic mice overexpressing a VEGFR-3-specific mutant of VEGF-C (VEGF-C156S) or VEGF-D in epidermal keratinocytes under the keratin 14 promoter. Both transgenes induced the growth of lymphatic vessels in the skin, whereas the blood vessel architecture was not affected. Evidence was also obtained that these growth factors act in a paracrine manner in vivo. These results demonstrate that stimulation of the VEGFR-3 signal transduction pathway is sufficient to induce specifically lymphangiogenesis in vivo. PMID:11250889

Veikkola, Tanja; Jussila, Lotta; Makinen, Taija; Karpanen, Terhi; Jeltsch, Michael; Petrova, Tatiana V.; Kubo, Hajime; Thurston, Gavin; McDonald, Donald M.; Achen, Marc G.; Stacker, Steven A.; Alitalo, Kari

2001-01-01

176

Senataxin modulates neurite growth through fibroblast growth factor 8 signalling.  

PubMed

Senataxin is encoded by the SETX gene and is mainly involved in two different neurodegenerative diseases, the dominant juvenile form of amyotrophic lateral sclerosis type 4 and a recessive form of ataxia with oculomotor apraxia type 2. Based on protein homology, senataxin is predicted to be a putative DNA/RNA helicase, while senataxin interactors from patients' lymphoblast cell lines suggest a possible involvement of the protein in different aspects of RNA metabolism. Except for an increased sensitivity to oxidative DNA damaging agents shown by some ataxia with neuropathy patients' cell lines, no data are available about possible functional consequences of dominant SETX mutations and no studies address the function of senataxin in neurons. To start elucidating the physiological role of senataxin in neurons and how disease-causing mutations in this protein lead to neurodegeneration, we analysed the effect of senataxin on neuronal differentiation in primary hippocampal neurons and retinoic acid-treated P19 cells by modulating the expression levels of wild-type senataxin and three different dominant mutant forms of the protein. Wild-type senataxin overexpression was required and sufficient to trigger neuritogenesis and protect cells from apoptosis during differentiation. These actions were reversed by silencing of senataxin. In contrast, overexpression of the dominant mutant forms did not affect the regular differentiation process in primary hippocampal neurons. Analysis of the cellular pathways leading to neuritogenesis and cytoprotection revealed a role of senataxin in modulating the expression levels and signalling activity of fibroblast growth factor 8. Silencing of senataxin reduced, while overexpression enhanced, fibroblast growth factor 8 expression levels and the phosphorylation of related target kinases and effector proteins. The effects of senataxin overexpression were prevented when fibroblast growth factor 8 signalling was inhibited, while exogenous fibroblast growth factor 8 reversed the effects of senataxin silencing. Overall, these results reveal a key role of senataxin in neuronal differentiation through the fibroblast growth factor 8 signalling and provide initial molecular bases to explain the neurodegeneration associated with loss-of-function mutations in senataxin found in recessive ataxia. The lack of effect on neuritogenesis observed with the overexpression of the dominant mutant forms of senataxin apparently excludes a dominant negative effect of these mutants while favouring haploinsufficiency as the pathogenic mechanism implicated in the amyotrophic lateral sclerosis 4-related degenerative condition. Alternatively, a different protein function, other than the one involved in neuritogenesis, may be implicated in these dominant degenerative processes. PMID:21576111

Vantaggiato, Chiara; Bondioni, Sara; Airoldi, Giovanni; Bozzato, Andrea; Borsani, Giuseppe; Rugarli, Elena I; Bresolin, Nereo; Clementi, Emilio; Bassi, Maria Teresa

2011-06-01

177

Expression of dominant negative Jun inhibits elevated AP1 and NF-?B transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes  

Microsoft Academic Search

AP-1 transactivation appears to be required for mouse JB6 cell neoplastic transformation induced by the tumor promoter TPA or epidermal growth factor (EGF). Exposure to AP-1 transrepressing retinoids and glucocorticoids and expression of a dominant negative c-jun (TAM67) blocked tumor promoter-induced AP-1 transactivation and neoplastic transformation. The aim of the present study was to extend the inquiry of the role

Jian-Jian Li; Johng S Rhim; Richard Schlegel; Karen H Vousden; Nancy H Colburn; J-J Li

1998-01-01

178

Growth factor signalling in endocrine and anti-growth factor resistant breast cancer  

Microsoft Academic Search

Growth factors provide powerful mitogenic and survival signals to breast cancer cells and it is therefore not surprising that\\u000a they are able to subvert inhibitory responses to anti-hormonal drugs. In this review we discuss several mechanisms by which\\u000a this may be achieved and expand our observations to encompass recently emerging anti-growth factor treatments. The information\\u000a presented is underpinned by inhibitor

R. I. Nicholson; I. R. Hutcheson; H. E. Jones; S. E. Hiscox; M. Giles; K. M. Taylor; J. M. W. Gee

2007-01-01

179

Epidermal growth factor receptor signaling in tissue  

SciTech Connect

Abstract: A peptide purified from the salivary gland of a mouse was shown few years ago to accelerate incisor eruption and eyelid opening in newborn mice, and was named epidermal growth factor (EGF). The members of this family of peptide growth factors had been identified in numerous physiological and pathological contexts. EGF binds to a cell surface EGF receptor, which induces a biochemical modification (phosphorylation) of the receptor's cytoplasmic tail. There is a growing consensus in the research community that, in addition to cellular and molecular studies, the dynamics of the EGFR network and its operation must be examined in tissues. A key challenge is to integrate the existing molecular and cellular information into a system-level description of the EGFR network at the tissue and organism level. In this paper, the two examples of EGFR signaling in tissues are described, and the recent efforts to model EGFR autocrine loops, which is a predominant mode of EGFR activation in vivo, are summarized.

Shvartsman, Stanislav; Wiley, H. S.; Lauffenburger, Douglas A.

2004-08-01

180

Growth Factors and Tension-Induced Skeletal Muscle Growth  

NASA Technical Reports Server (NTRS)

The project investigated biochemical mechanisms to enhance skeletal muscle growth, and developed a computer based mechanical cell stimulator system. The biochemicals investigated in this study were insulin/(Insulin like Growth Factor) IGF-1 and Steroids. In order to analyze which growth factors are essential for stretch-induced muscle growth in vitro, we developed a defined, serum-free medium in which the differentiated, cultured avian muscle fibers could be maintained for extended periods of time. The defined medium (muscle maintenance medium, MM medium) maintains the nitrogen balance of the myofibers for 3 to 7 days, based on myofiber diameter measurements and myosin heavy chain content. Insulin and IGF-1, but not IGF-2, induced pronounced myofiber hypertrophy when added to this medium. In 5 to 7 days, muscle fiber diameters increase by 71 % to 98% compared to untreated controls. Mechanical stimulation of the avian muscle fibers in MM medium increased the sensitivity of the cells to insulin and IGF-1, based on a leftward shift of the insulin dose/response curve for protein synthesis rates. (54). We developed a ligand binding assay for IGF-1 binding proteins and found that the avian skeletal muscle cultures produced three major species of 31, 36 and 43 kD molecular weight (54) Stretch of the myofibers was found to have no significant effect on the efflux of IGF-1 binding proteins, but addition of exogenous collagen stimulated IGF-1 binding protein production 1.5 to 5 fold. Steroid hormones have a profound effect on muscle protein turnover rates in vivo, with the stress-related glucocorticoids inducing rapid skeletal muscle atrophy while androgenic steroids induce skeletal muscle growth. Exercise in humans and animals reduces the catabolic effects of glucocorticoids and may enhance the anabolic effects of androgenic steroids on skeletal muscle. In our continuing work on the involvement of exogenrus growth factors in stretch-induced avian skeletal muscle growth, we have performed experiments to determine whether mechanical stimulation of cultured avian muscle cells alters their response to anabolic steroids or glucocorticoids. In static cultures, testosterone had no effect on muscle cell growth, but 5alpha-dihydrotestosterone and the synthetic steroid stanozolol increased cell growth by up to 18% and 30%, respectively, after a three day exposure. We completed development of a new IBM-based mechanical cell stimulator system to provide greater flexibility in operating and monitoring our experiments. Our previous long term studies on myofiber growth were designed around a perfusion system of our own design. We have recently changed to performing these studies using a modified CELLCO cartridge bioreactor system Z since it has been certified as the ground-based model for the Shuttle's Space Tissue Loss (STL) F= Cell Culture Module. The current goals of this aspect of the project are three fold: 1) to design a Z cell culture system for studying avian skeletal myofiber atrophy on the Shuttle and Space Station; 0 2) to expand the use of bioreactors to cells which do not grow in either suspension or attached to the hollow fibers; and 3) to combine the bioreactor system with our computerized mechanical cell stimulator to have a better in vitro model to study tension/gravity/stretch regulation of skeletal muscle size. Preliminary studies also reported on involved : (1) how release of tension can induce rapid atrophy of tissues cultured avian skeletal muscle cells, and (2) a mechanism to transfer and maintain avian skeletal muscle organoids in modified cartridges in the Space Tissue Loss Module.

Vandenburgh, Herman H.

1994-01-01

181

Growth factors and corneal epithelial wound healing  

PubMed Central

In this article, we briefly review recent findings in the effects of growth factors including the EGF family, KGF, HGF, IGF, insulin, and TGF-? on corneal epithelial wound healing. We discuss the essential role of EGFR in inter-receptor cross-talk in response to wounding in corneal epithelium and bring forward a concept of “alarmins” to the field of wound healing research. PMID:19733636

Yu, Fu-Shin X.; Yin, Jia; Xu, Keping; Huang, Jenny

2010-01-01

182

Formulation Design of Acidic Fibroblast Growth Factor  

Microsoft Academic Search

The design of an aqueous formulation for acidic fibroblast growth factor (aFGF) requires an understanding of the type of compounds that can either directly or indirectly stabilize the protein. To this end, spectrophotometric turbidity measurements were initially employed to screen the ability of polyanionic ligands, less specific compounds, and variations in solution conditions (temperature and pH) to stabilize aFGF against

P. K. Tsai; David B. Volkin; Jonathan M. Dabora; Karen C. Thompson; Mark W. Bruner; Jacqueline O. Gress; Bozena Matuszewska; Martina Keogan; Joseph V. Bondi; C. Russell Middaugh

1993-01-01

183

Id-1 delays senescence but does not immortalize keratinocytes.  

PubMed

Defining the molecular basis responsible for regulating the proliferative potential of keratinocytes has important implications for normal homeostasis and neoplasia of the skin. Under current culture conditions, neonatal foreskin-derived human keratinocytes possess a relatively short replicative lifespan. Recently it was reported that forced overexpression of the helix-loop-helix protein Id-1 was capable of immortalizing keratinocytes, secondary to activation of telomerase activity and suppression of p16/Rb-mediated growth arrest pathways. To investigate the relationship between Id-1, telomerase activity, telomere length, p16, Rb cell cycle regulators, and senescence, whole populations of keratinocytes were infected with a retrovirus to induce overexpression of Id-1. In these unselected cultures, enhanced Id-1 levels clearly extended the lifespan of keratinocytes, but Id-1 did not prevent the onset of replicative senescence. Under these experimental conditions, Id-1 expression did not trigger induction of telomerase activity, and there was progressive shortening of the telomeres that was accompanied by elevated p16 levels and prevalence of active Rb. The ability of Id-1 to postpone, but not prevent, senescence may be related to partial inhibition of p16 expression, as the Id-1-overexpressing cultures displayed a decreased capacity for 12-O-tetradecanoylphorbol-13-acetate-mediated p16 induction. Thus, while no immortalization was observed, Id-1 could delay the onset of replicative senescence in unselected human keratinocyte populations. PMID:10908559

Nickoloff, B J; Chaturvedi, V; Bacon, P; Qin, J Z; Denning, M F; Diaz, M O

2000-09-01

184

The suppression of fibroblast growth factor 2/fibroblast growth factor 4-dependent tumour angiogenesis and growth by the anti-growth factor activity of dextran derivative (CMDB7).  

PubMed Central

Our previous studies showed that carboxymethyl benzylamide dextran (CMDB7) blocks basic fibroblast growth factor (FGF-2)-dependent cell proliferation of a human breast epithelial line (HBL100), suggesting its potential role as a potent antiangiogenic substance. The derived cell line (HH9), which was transformed with the hst/FGF4 gene, has been shown to be highly proliferative in vitro and to induce angiogenic tumours in nude mice. We show here that CMDB7 inhibits the mitogenic activities of the conditioned media from HBL 100 and HH9 cells in a dose-dependent manner. When HH9 cells were injected s.c. into nude mice, CMDB7 treatment (300 mg kg(-1) week(-1)) suppressed the tumour take and the tumour growth by about 50% and 80% respectively. Immunohistochemical analysis showed a highly significant decrease, by more than threefold, in the endothelial density of viable tumour regions, together with a significant increase in the necrosis area. This antiangiogenic activity of CMDB7 was further demonstrated by direct inhibition of calf pulmonary artery (CPAE) and human umbilical vein (HUVEC) endothelial cell proliferation and migration in vitro. In addition, we showed that CMDB7 inhibits specifically the mitogenic effects of the growth factors that bind to heparin such as FGF-2, FGF-4, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-beta1), but not those of epidermal growth factor (EGF) and insulin-like growth factor (IGF-1). These results demonstrate that CMDB7 inhibits FGF-2/FGF-4-dependent tumour growth and angiogenesis, most likely by disrupting the autocrine and paracrine effects of growth factors released from the tumour cells. Images Figure 4 PMID:9662260

Bagheri-Yarmand, R.; Kourbali, Y.; Mabilat, C.; Morere, J. F.; Martin, A.; Lu, H.; Soria, C.; Jozefonvicz, J.; Crepin, M.

1998-01-01

185

Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair  

PubMed Central

Significance: Angiogenesis, the growth of new blood vessels from existing vessels, is an important aspect of the repair process. Restoration of blood flow to damaged tissues provides oxygen and nutrients required to support the growth and function of reparative cells. Vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic growth factors in the skin, and the amount of VEGF present in a wound can significantly impact healing. Recent Advances: The activity of VEGF was once considered to be specific for endothelial cells lining the inside of blood vessels, partly because VEGF receptor (VEGFR) expression was believed to be restricted to endothelial cells. It is now known, however, that VEGFRs can be expressed by a variety of other cell types involved in wound repair. For example, keratinocytes and macrophages, which both carry out important functions during wound healing, express VEGFRs and are capable of responding directly to VEGF. Critical Issues: The mechanisms by which VEGF promotes angiogenesis are well established. Recent studies, however, indicate that VEGF can directly affect the activity of several nonendothelial cell types present in the skin. The implications of these extra-angiogenic effects of VEGF on wound repair are not yet known, but they suggest that this growth factor may play a more complex role during wound healing than previously believed. Future Directions: Despite the large number of studies focusing on VEGF and wound healing, it is clear that the current knowledge of how VEGF contributes to the repair of skin wounds is incomplete. Further research is needed to obtain a more comprehensive understanding of VEGF activities during the wound healing process. PMID:25302139

Johnson, Kelly E.; Wilgus, Traci A.

2014-01-01

186

Nerve growth factor promotes human hemopoietic colony growth and differentiation.  

PubMed Central

Nerve growth factor (NGF) is a neurotropic polypeptide necessary for the survival and growth of some central neurons, as well as sensory afferent and sympathetic neurons. Much is now known of the structural and functional characteristics of NGF, whose gene has recently been cloned. Since it is synthesized in largest amounts by the male mouse submandibular gland, its role exclusively in nerve growth is questionable. NGF also causes histamine release from rat peritoneal mast cells in vitro, and we have shown elsewhere that it causes significant, dose-dependent, generalized mast cell proliferation in the rat in vivo when administered neonatally. Our experiments now indicate that NGF causes a significant stimulation of granulocyte colonies grown from human peripheral blood in standard hemopoietic methylcellulose assays. Further, NGF appears to act in a relatively selective fashion to induce the differentiation of eosinophils and basophils/mast cells. Depletion experiments show that the NGF effect may be T-cell dependent and that NGF augments the colony-stimulating effect of supernatants from the leukemic T-cell (Mo) line. The hemopoietic activity of NGF is blocked by polyclonal and monoclonal antibodies to NGF. We conclude that NGF may indirectly act as a local growth factor in tissues other than those of the nervous system by causing T cells to synthesize or secrete molecules with colony-stimulating activity. In view of the synthesis of NGF in tissue injury, the involvement of basophils/mast cells and eosinophils in allergic and other inflammatory processes, and the association of mast cells with fibrosis and tissue repair, we postulate that NGF plays an important biological role in a variety of repair processes. PMID:3413109

Matsuda, H; Coughlin, M D; Bienenstock, J; Denburg, J A

1988-01-01

187

Governing epidermal homeostasis by coupling cell-cell adhesion to integrin and growth factor signaling, proliferation, and apoptosis.  

PubMed

Cadherin/catenin-based adhesions coordinate cellular growth, survival, migration, and differentiation within a tissue by mechanically anchoring cells to their neighbors. They also intersect with diverse signaling pathways in development and cancer. Although the adhesive functions of adherens junction proteins are well characterized, their contribution to other signaling pathways is less well understood. Here, we show that ablation of ?-catenin in the epidermis selectively induces apoptosis in suprabasal differentiating keratinocytes while sparing basal cell progenitors. This protection from death is coupled to elevated focal adhesion signaling, faster migration, and an altered distribution of growth factor receptors. We show that simultaneous depletion of ?-catenin and focal adhesion kinase or p21-activated kinase eliminates basal cell protection as well as the elevated migration and proliferation of cells. The increased dependency of cells upon matrix interactions for their survival when cell-cell adhesions are destabilized has important implications for cancer progression and metastasis. PMID:22411810

Livshits, Geulah; Kobielak, Agnieszka; Fuchs, Elaine

2012-03-27

188

Governing epidermal homeostasis by coupling cell-cell adhesion to integrin and growth factor signaling, proliferation, and apoptosis  

PubMed Central

Cadherin/catenin-based adhesions coordinate cellular growth, survival, migration, and differentiation within a tissue by mechanically anchoring cells to their neighbors. They also intersect with diverse signaling pathways in development and cancer. Although the adhesive functions of adherens junction proteins are well characterized, their contribution to other signaling pathways is less well understood. Here, we show that ablation of ?-catenin in the epidermis selectively induces apoptosis in suprabasal differentiating keratinocytes while sparing basal cell progenitors. This protection from death is coupled to elevated focal adhesion signaling, faster migration, and an altered distribution of growth factor receptors. We show that simultaneous depletion of ?-catenin and focal adhesion kinase or p21-activated kinase eliminates basal cell protection as well as the elevated migration and proliferation of cells. The increased dependency of cells upon matrix interactions for their survival when cell–cell adhesions are destabilized has important implications for cancer progression and metastasis. PMID:22411810

Livshits, Geulah; Kobielak, Agnieszka; Fuchs, Elaine

2012-01-01

189

Epidermal growth factor receptor and bladder cancer  

PubMed Central

Muscle-invasive bladder cancer is a disease which causes significant morbidity and mortality. The two main forms of treatment for this disease include radical cystectomy and radical radiotherapy, but five year survival after treatment remains low at 40%. Many clinical and molecular risk factors have been shown to be associated with poor prognosis. One such factor is the expression of epidermal growth factor receptor (EGFR), which is overexpressed by many epithelial tumours, including bladder cancers. There are several methods of inhibiting the activity of EGFR and it may be that use of an anti-EGFR therapy, in combination with more conventional treatment, provides a method of improving the prognosis for muscle-invasive bladder cancer. PMID:12415079

Colquhoun, A; Mellon, J

2002-01-01

190

Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements  

SciTech Connect

Human papilloma virus (HPV) types 16 and 18 are most commonly associated with cervical carcinoma in patients and induce immortalization of human keratinocytes in culture. HPV has not been associated with breast cancer. This report describes the immortalization of normal human mammary epithelial cells (76N) by plasmid pHPV18 or pHPV16, each containing the linearized viral genome. Transfectants were grown continuously for more than 60 passages, whereas 76N cells senesce after 18-20 passages. The transfectants also differ from 76N cells in cloning in a completely defined medium called D2 and growing a minimally supplemented defined medium (D3) containing epidermal growth factor. All transfectant tested contain integrated HPV DNA, express HPV RNA, and produce HPV E7 protein. HPV transfectants do not form tumors in a nude mouse assay. It is concluded that products of the HPV genome induce immortalization of human breast epithelial cells and reduce their growth factor requirements. This result raises the possibility that HPV might be involved in breast cancer. Furthermore, other tissue-specific primary epithelial cells that are presently difficult to grown and investigate may also be immortalized by HPV.

Band, V.; Zajchowski, D.; Kulesa, V.; Sager, R. (Dana-Farber Cancer Institute, Boston, MA (USA))

1990-01-01

191

Proteolytic Processing Regulates Placental Growth Factor Activities*  

PubMed Central

Placental growth factor (PlGF) is a critical mediator of blood vessel formation, yet mechanisms of its action and regulation are incompletely understood. Here we demonstrate that proteolytic processing regulates the biological activity of PlGF. Specifically, we show that plasmin processing of PlGF-2 yields a protease-resistant core fragment comprising the vascular endothelial growth factor receptor-1 binding site but lacking the carboxyl-terminal domain encoding the heparin-binding domain and an 8-amino acid peptide encoded by exon 7. We have identified plasmin cleavage sites, generated a truncated PlGF118 isoform mimicking plasmin-processed PlGF, and explored its biological function in comparison with that of PlGF-1 and -2. The angiogenic responses induced by the diverse PlGF forms were distinct. Whereas PlGF-2 increased endothelial cell chemotaxis, vascular sprouting, and granulation tissue formation upon skin injury, these activities were abrogated following plasmin digestion. Investigation of PlGF/Neuropilin-1 binding and function suggests a critical role for heparin-binding domain/Neuropilin-1 interaction and its regulation by plasmin processing. Collectively, here we provide new mechanistic insights into the regulation of PlGF-2/Neuropilin-1-mediated tissue vascularization and growth. PMID:23645683

Hoffmann, Daniel C.; Willenborg, Sebastian; Koch, Manuel; Zwolanek, Daniela; Muller, Stefan; Becker, Ann-Kathrin A.; Metzger, Stephanie; Ehrbar, Martin; Kurschat, Peter; Hellmich, Martin; Hubbell, Jeffrey A.; Eming, Sabine A.

2013-01-01

192

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth  

Microsoft Academic Search

Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET proto- oncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190 MEt) made of a 50 kD (o0 subunit disulfide linked to a 145-kD

F. Bussolino; M. E Di Renzo; M. Ziche; E. Bocchietto; M. Olivero; L. Naldini; G. Gaudino; L. Tamagnone; A. Coffer; P. M. Comoglio

1992-01-01

193

Genes for Epidermal Growth Factor Receptor, Transforming Growth Factor a, and Epidermal Growth Factor and Their Expression in Human Gliomas in Vivo  

Microsoft Academic Search

Anomalies of the epidermal growth factor receptor (EGFR) gene, including amplification, rearrangement, and overexpression, have been reported in malignant human gliomas in t'ivo. In vitro glioma cell lines coexpress EGFR and at least one of its ligands, transforming growth factor a, suggesting the existence of an autocrine growth stimulatory loop. \\\\Ve have studied the tumor tissue from 62 human glioma

A. Jonas Ekstrand; C. David James; Webster K. Cavenee; Barbara Seliger; Ralf F. Pettersson; V. Peter Collins

194

Epidermal Expression of Neuropilin 1 Protects Murine keratinocytes from UVB-induced apoptosis  

PubMed Central

Background Neuropilin 1 (NRP1) is expressed on several cell types including neurons and endothelial cells, where it functions as an important regulator in development and during angiogenesis. As a cell surface receptor, NRP1 is able to bind to members of the VEGF family of growth factors and to secreted class 3 semaphorins. Neuropilin 1 is also highly expressed in keratinocytes, but the function of NRP1 in epidermal physiology and pathology is still unclear. Methods and Results To elucidate the role of NRP1 in skin in vivo we generated an epidermis-specific neuropilin 1 knock out mouse model by using the Cre-LoxP-System. Mice were viable and fertile and did not display any obvious skin or hair defects. After challenge with UVB irradiation, we found that deletion of epidermal NRP1 leads to increased rates of apoptosis both in vitro and in vivo. NRP1-deficient primary keratinocytes cultured in vitro showed significantly higher rates of apoptosis 24 hours after UVB. Likewise, there is a significant increase of active caspase 3 positive cells in the epidermis of Keratin 14-Cre-NRP1 (?/?) mice 24 hours after UVB irradiation. By Western Blot analysis we could show that NRP1 influences the cytosolic levels of Bcl-2, a pro-survival member of the Bcl-2 family. After UVB irradiation the amounts of Bcl-2 decrease in both protein extracts from murine epidermis and in NRP1-deficient keratinocytes in vitro, whereas wild type cells retain their Bcl-2 levels. Likewise, levels of phospho-Erk and Rac1 were lower in NRP1-knock out keratinocytes, whereas levels of pro-apoptotic p53 were higher. Conclusion NRP1 expression in keratinocytes is dispensable for normal skin development. Upon UVB challenge, NRP1 contributes to the prevention of keratinocyte apoptosis. This pro-survival function of NRP1 is accompanied by the maintenance of high levels of the antiapoptotic regulator Bcl-2 and by lower levels of pro-apoptotic p53. PMID:23251405

Riese, Anna; Eilert, Yvonne; Meyer, Yvonne; Arin, Meral; Baron, Jens M.; Eming, Sabine; Krieg, Thomas; Kurschat, Peter

2012-01-01

195

c-Rel downregulation affects cell cycle progression of human keratinocytes.  

PubMed

The c-Rel protein, a member of the NF-?B transcription factor family, exerts unique and distinctive functions in various cell types. Although c-Rel is expressed in human epidermis, its functions in keratinocytes are poorly understood. Our small interfering RNA-based approach of c-Rel silencing in HaCaT keratinocytes induced altered cell morphology toward a spindle-shaped appearance. In addition, c-Rel downregulation resulted in increased apoptosis and significantly reduced proliferation towing to G2/M cell cycle delay, concomitant aberrant mitotic spindle formation, and induction of phospho-aurora A(Thr288). The relevance of c-Rel in epithelial carcinogenesis was further supported by detection of c-Rel expression in squamous cell carcinomas of the skin. Our studies indicate that c-Rel is a key regulator of cell fate decisions in keratinocytes such as cell growth and death and may have a role in epidermal carcinogenesis. PMID:23892589

Lorenz, Verena N; Schön, Michael P; Seitz, Cornelia S

2014-02-01

196

N-Glycosylation of ss4 Integrin Controls the Adhesion and Motility of Keratinocytes  

PubMed Central

?6ß4 integrin is an essential component of hemidesmosomes and modulates cell migration in wound healing and cancer invasion. To elucidate the role of N-glycosylation on ß4 integrin, we investigated keratinocyte adhesion and migration through the re-expression of wild-type or N-glycosylation-defective ß4 integrin (?Nß4) in ß4 integrin null keratinocytes. N-glycosylation of ß4 integrin was not essential for the heterodimer formation of ß4 integrin with ?6 integrin and its expression on a cell surface, but N-glycosylation was required for integrin-mediated cell adhesion and migration. Concomitantly with the reduction of ß4 integrin in the membrane microdomain, the intracellular signals of Akt and ERK activation were decreased in cells expressing ?Nß4 integrin. Forced cross-linking of ß4 integrin rescued the decreased ERK activation in ?Nß4 integrin-expressing cells to a similar extent in wild-type ß4 integrin-expressing cells. Surprisingly, compared with cells expressing wild-type ß4 integrin, an alternation in N-glycan structures expressed on epidermal growth factor receptor (EGFR), and the induction of a stronger association between EGFR and ß4 integrin were observed in ?Nß4 integrin-expressing cells. These results clearly demonstrated that N-glycosylation on ß4 integrin plays an essential role in keratinocyte cellular function by allowing the appropriate complex formation on cell surfaces. PMID:22073258

Kariya, Yoshinobu; Gu, Jianguo

2011-01-01

197

Control of Growth Factor Networks by Heparan Sulfate Proteoglycans  

Microsoft Academic Search

Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding\\u000a of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with\\u000a heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different\\u000a growth factors may allow for cross regulation. Here we demonstrate,

Kimberly Forsten-Williams; Chia Lin Chu; Michael Fannon; Jo Ann Buczek-Thomas; Matthew A. Nugent

2008-01-01

198

Staphylococcus aureus Infection of Epidermal Keratinocytes Promotes Expression of Innate Antimicrobial Peptides  

Microsoft Academic Search

Received 21 October 2004\\/Returned for modification 26 January 2005\\/Accepted 5 April 2005 Keratinocytes upregulate expression of endogenous antimicrobial peptides in response to inflammatory stimuli. We show that both viable and heat-inactivated Staphylococcus aureus and lipoteichoic acid differentially alter expression of these peptides upon contact with human keratinocytes. The findings indicate a diversity of staphylococcal factors involved in upregulation of antimicrobial

Barbara E. Menzies; Aimee Kenoyer

2005-01-01

199

Quantitative analysis of basic fibroblast growth factor and vascular endothelial growth factor in human colorectal cancer.  

PubMed Central

Tumour growth is angiogenesis dependent. Some authors suggest a prognostic role of microvessel count in colorectal cancer. We tested the role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the switch to the angiogenic phenotype in 35 patients with colorectal cancer at different stages of disease. We evaluated the two angiogenic factors, by enzyme-linked immunosorbent assay (ELISA), in tumour, peritumoral mucosa, pathological mesenteric and peripheral blood. We used ten endoscopic intestinal biopsies and ten peripheral blood samples from healthy subjects as control. bFGF was significantly lower in tumour tissues and in peritumoral mucosas than in healthy mucosas, whereas VEGF was up-regulated in tumours but not in peritumoral mucosa. Both angiogenic factors were greatly increased in mesenteric blood. VEGF tumour and serum levels were significantly correlated with the stage of disease. bFGF tumour and serum concentration were not correlated with the stage of disease. The high levels of bFGF in mesenteric blood suggest that this growth factor might be abnormally released from tumour tissue and peritumoral mucosa and could function as an early effector in the switch to the angiogenic phenotype. In contrast, VEGF, whose levels show a significant correlation with the stage of disease, could act in a following step, supporting tumour progression. PMID:9743297

Landriscina, M.; Cassano, A.; Ratto, C.; Longo, R.; Ippoliti, M.; Palazzotti, B.; Crucitti, F.; Barone, C.

1998-01-01

200

A decorin-deficient matrix affects skin chondroitin/dermatan sulfate levels and keratinocyte function.  

PubMed

Decorin is a small leucine-rich proteoglycan harboring a single glycosaminoglycan chain, which, in skin, is mainly composed of dermatan sulfate (DS). Mutant mice with targeted disruption of the decorin gene (Dcn(-/-)) exhibit an abnormal collagen architecture in the dermis and reduced tensile strength, collectively leading to a skin fragility phenotype. Notably, Ehlers-Danlos patients with mutations in enzymes involved in the biosynthesis of DS display a similar phenotype, and recent studies indicate that DS is involved in growth factor binding and signaling. To determine the impact of the loss of DS-decorin in the dermis, we analyzed the glycosaminoglycan content of Dcn(-/-) and wild-type mouse skin. The total amount of chondroitin/dermatan sulfate (CS/DS) was increased in the Dcn(-/-) skin, but was overall less sulfated with a significant reduction in bisulfated ?DiS2,X (X=4 or 6) disaccharide units, due to the reduced expression of uronyl 2-O sulfotransferase (Ust). With increasing age, sulfation declined; however, Dcn(-/-) CS/DS was constantly undersulfated vis-ŕ-vis wild-type. Functionally, we found altered fibroblast growth factor (Fgf)-7 and -2 binding due to changes in the micro-heterogeneity of skin Dcn(-/-) CS/DS. To better delineate the role of decorin, we used a 3D Dcn(-/-) fibroblast cell culture model. We found that the CS/DS extracts of wild-type and Dcn(-/-) fibroblasts were similar to the skin sugars, and this correlated with the lack of uronyl 2-O sulfotransferase in the Dcn(-/-) fibroblasts. Moreover, Ffg7 binding to total CS/DS was attenuated in the Dcn(-/-) samples. Surprisingly, wild-type CS/DS significantly reduced the binding of Fgf7 to keratinocytes in a concentration dependent manner unlike the Dcn(-/-) CS/DS that only affected the binding at higher concentrations. Although binding to cell-surfaces was quite similar at higher concentrations, keratinocyte proliferation was differentially affected. Higher concentration of Dcn(-/-) CS/DS induced proliferation in contrast to wild-type CS/DS. 3D co-cultures of fibroblasts and keratinocytes showed that, unlike Dcn(-/-) CS/DS, wild-type CS/DS promoted differentiation of keratinocytes. Collectively, our results provide novel mechanistic explanations for the reported defects in wound healing in Dcn(-/-) mice and possibly Ehlers-Danlos patients. Moreover, the lack of decorin-derived DS and an altered CS/DS composition differentially influence keratinocyte behavior. PMID:24447999

Nikolovska, Katerina; Renke, Jana K; Jungmann, Oliver; Grobe, Kay; Iozzo, Renato V; Zamfir, Alina D; Seidler, Daniela G

2014-04-01

201

Keratinocyte galvanotaxis in combined DC and AC electric fields supports an electromechanical transduction sensing mechanism.  

PubMed

Sedentary keratinocytes at the edge of a skin wound migrate into the wound, guided by the generation of an endogenous electric field (EF) generated by the collapse of the transepithelial potential. The center of the wound quickly becomes more negative than the surrounding tissue and remains the cathode of the endogenous EF until the wound is completely re-epithelialized. This endogenous guidance cue can be studied in vitro. When placed in a direct current (DC) EF of physiological strength, 100 V/m, keratinocytes migrate directionally toward the cathode in a process known as galvanotaxis. Although a number of membrane-bound (e.g., epidermal growth factor receptor (EGFR), integrins) and cytosolic proteins (cAMP, ERK, PI3K) are known to play a role in the downstream signaling mechanisms underpinning galvanotaxis, the initial sensing mechanism for this response is not understood. To investigate the EF sensor, we studied the migration of keratinocytes in a DC EF of 100 V/m, alternating current (AC) EFs of 40 V/m at either 1.6 or 160 Hz, and combinations of DC and AC EFs. In the AC EFs alone, keratinocytes migrated randomly. The 1.6 Hz AC EF combined with the DC EF suppressed the direction of migration but had no effect on speed. In contrast, the 160 Hz AC EF combined with the DC EF did not affect the direction of migration but increased the migration speed compared to the DC EF alone. These results can be understood in terms of an electromechanical transduction model, but not an electrodiffusion/osmosis or a voltage-gated channel model. PMID:22907479

Hart, Francis X; Laird, Mhairi; Riding, Aimie; Pullar, Christine E

2013-02-01

202

The role of the tetraspanin CD151 in primary keratinocyte and fibroblast functions: Implications for wound healing  

SciTech Connect

Previous studies showed that CD151-null mice have a skin wound healing deficit. To gain an understanding of the role of CD151 in re-epithelialisation and dermal contraction, keratinocyte and fibroblast functions were assayed. Primary CD151-null keratinocytes displayed defective migration on Matrigel (a basement membrane equivalent) and laminin-332, the primary adhesion component of basement membranes, but not on collagen-I. Adhesion, spreading and proliferation were also deficient on laminin-332, but not collagen-I. The data suggest that loss of CD151 impairs the function of its primary interaction partners, integrin {alpha}3{beta}1- and/or {alpha}6{beta}4 which bind to laminin-332. Skin fibroblasts also produce CD151 mRNA. CD151-null fibroblasts migrated significantly faster on collagen I than wild type fibroblasts, confirming that they possess functional collagen receptors. However, no significant decrease in the ability of CD151-null fibroblasts to cause contraction in floating collagen gel assays in response to transforming growth factor beta-1 (TGF-{beta}1) or platelet derived growth factor (PDGF-BB) was observed, nor was there an effect on fibroblast adhesion or proliferation on collagen-I. The data implicate CD151 as a facilitator of laminin-332-mediated keratinocyte functions that impact on the re-epithelialisation process intrinsic to wound healing and further suggest a potential novel role for CD151 in fibroblast migration.

Geary, Sean M. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Cowin, Allison J. [Child Health Research Institute, North Adelaide, South Australia (Australia); Department of Paediatrics, University of Adelaide, South Australia (Australia); Copeland, Ben; Baleato, Rosa M. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Miyazaki, Kaoru [Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokohama (Japan); Ashman, Leonie K. [School of Biomedical Sciences, University of Newcastle, New South Wales (Australia); Hunter Medical Research Institute, Newcastle, New South Wales (Australia)], E-mail: leonie.ashman@newcastle.edu.au

2008-07-01

203

Characterization of insulin-like growth factor I and epidermal growth factor receptors in meningioma  

SciTech Connect

Receptors for insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) were localized and characterized in eight samples of human meningioma (four fibrous, two meningothelial, and two angioblastic types), using quantitative autoradiographic techniques. Effects of both growth factors on deoxyribonucleic acid (DNA) synthesis in the cultured meningioma cells were examined. High numbers of specific binding sites for both IGF-I and EGF were homogeneously present in tissue sections derived from fibrous and meningothelial types of meningiomas, whereas binding sites for these growth factors were not detectable in adjacent leptomeninges. While relatively large numbers of IGF-I binding sites were located in the wall of the intratumoral vasculature, the number of binding sites in the stromal component was lower in angioblastic-type meningiomas, including a low number of EGF binding sites detected only in the stromal portion. Scatchard analysis revealed the presence of a single class of high-affinity binding sites for both IGF-I and EGF in the meningiomas examined (dissociation constant (Kd) = 0.6 to 2.9 nM, and the maximum number of binding sites (Bmax) = 16 to 80 fmol/mg for IGF-I; and Kd = 0.6 to 4.0 nM, Bmax = 3 to 39 fmol/mg for EGF). Both growth factors increased the synthesis of DNA, in a dose-dependent manner, as measured by 3H-thymidine incorporation. The combination of IGF-I and EGF synergistically stimulated the synthesis of DNA, and the effects seen with 10% fetal bovine serum could be reproduced at a concentration of 10(-10) M. These observations can be interpreted to mean that both IGF-I and EGF may be involved in the growth modulation of meningiomas, possibly through paracrine or autocrine mechanisms.

Kurihara, M.; Tokunaga, Y.; Tsutsumi, K.; Kawaguchi, T.; Shigematsu, K.; Niwa, M.; Mori, K. (Nagasaki Univ. School of Medicine (Japan))

1989-10-01

204

Heparin-Binding Epidermal Growth Factor Cleavage Mediates Zinc-Induced Epidermal Growth Factor Receptor Phosphorylation  

Microsoft Academic Search

We have previously shown that exposure to zinc ions can acti- vate epidermal growth factor (EGF) receptor (EGFR) signaling in murine fibroblasts and A431 cells through a mechanism in- volving Src kinase. While studying the effects of zinc ions in normal human bronchial epithelial cell, we uncovered evidence for an additional mechanism of Zn 2 -induced EGFR activation. Exposure to

Weidong Wu; James M. Samet; Robert Silbajoris; Lisa A. Dailey; Dean Sheppard; Philip A. Bromberg; Lee M. Graves

2004-01-01

205

Aspirin decreases vascular endothelial growth factor release during myocardial ischemia  

Microsoft Academic Search

Background: Vascular Endothelial Growth Factor (VEGF) is an important angiogenesis factor involved in pathophysiology of cardiovascular diseases. Controlling this factor's level in the serum might have significant prognostic outcomes. Methods: Twenty-four patients undergoing coronary artery bypass grafting were prospectively categorized into two groups according to aspirin administration before surgery. Vascular Endothelial Growth Factor levels were compared and correlated and adjusted

Rabin Gerrah; Mina Fogel; Dan Gilon

2004-01-01

206

Scatter factor\\/hepatocyte growth factor is essential for liver development  

Microsoft Academic Search

POLYPEPTIDE growth factors are important effectors of cell growth and differentiation in vitro and are thought to be critical for processes such as specification of cell fate, tissue growth and organogenesis in vivo. Scatter factor1-3\\/hepatocyte growth factor4,5 (SF\\/HGF) is the prototype of an emerging family of growth factors that resemble in their domain structure and mechanism of activation the blood

Claudia Schmidt; Friedhelm Bladt; Stefanie Goedecke; Volker Brinkmann; Wolfgang Zschiesche; Melanie Sharpe; Ermanno Gherardi; Carmen Birchmeler

1995-01-01

207

Latent TGF?1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder  

PubMed Central

Transforming growth factor ?1 (TGF?1), a potent keratinocyte growth inhibitor, has been shown to be overexpressed in keratinocytes in certain inflammatory skin diseases and has been thought to counteract the effects of other growth factors at the site of inflammation. Surprisingly, our transgenic mice expressing wild-type TGF?1 in the epidermis using a keratin 5 promoter (K5.TGF?1wt) developed inflammatory skin lesions, with gross appearance of psoriasis-like plaques, generalized scaly erythema, and Koebner's phenomenon. These lesions were characterized by epidermal hyperproliferation, massive infiltration of neutrophils, T lymphocytes, and macrophages to the epidermis and superficial dermis, subcorneal microabscesses, basement membrane degradation, and angiogenesis. K5.TGF?1wt skin exhibited multiple molecular changes that typically occur in human Th1 inflammatory skin disorders, such as psoriasis. Further analyses revealed enhanced Smad signaling in transgenic epidermis and dermis. Our study suggests that certain pathological condition-induced TGF?1 overexpression in the skin may synergize with or induce molecules required for the development of Th1 inflammatory skin disorders. PMID:15057277

Li, Allen G; Wang, Donna; Feng, Xin-Hua; Wang, Xiao-Jing

2004-01-01

208

Matrix control of transforming growth factor-? function  

PubMed Central

The cytokine transforming growth factor-beta (TGF-?) has multiple effects in both physiological and pathological conditions. TGF-? is secreted as part of a tripartite complex from which it must be released in order to bind to its receptor. Sequestration of latent TGF-? in the extracellular matrix (ECM) is crucial for proper mobilization of the latent cytokine and its activation. However, contrary to expectation, loss-of-function mutations in genes encoding certain matrix proteins that bind TGF-? yield elevated, rather than decreased, TGF-? levels, posing a ‘TGF-? paradox.’ In this review, we discuss recent findings concerning the relationship of TGF-?, ECM molecules, and latent TGF-? activation and propose a model to resolve the ‘TGF-? paradox.’ PMID:22923731

Horiguchi, Masahito; Ota, Mitsuhiko; Rifkin, Daniel B.

2012-01-01

209

Expression of fibroblast growth factor gene family and its receptor gene family in the human upper gastrointestinal tract.  

PubMed

All of 13 human esophageal cancer cell lines contained mRNAs for both basic fibroblast growth factor (bFGF) and its receptor, FGFR1/N-sam protein, while they did not have mRNAs for keratinocyte growth factor (KGF) despite the presence of mRNAs for the KGF receptor gene, K-sam. The results indicate that in human esophageal cancer, bFGF plays roles in an autocrine manner, while KGF acts as a paracrine mediator. In contrast, only one of seven human gastric cancer cell lines contained bFGF mRNAs, while three out of the seven had mRNAs for FGFR1/N-sam protein. The KGF gene was not expressed in any of the gastric cancer cell lines, while K-sam mRNAs were detected in six out of the seven. The results demonstrate that in most human gastric cancers, bFGF does not act as an autocrine mediator, while KGF acts as a paracrine factor. The mRNAs for the other four members of the fibroblast growth factor (FGF) family, including acidic FGF, int-2 protein, hst-1 protein, FGF5 protein and FGF6/hst-2 protein could not be detected in the esophageal and gastric cancer cell lines. PMID:7511892

Iida, S; Katoh, O; Tokunaga, A; Terada, M

1994-03-30

210

Proliferation of normal human keratinocytes on silicone substrates.  

PubMed

Several polydimethylsiloxane elastomers and gels were tested as culture substrates for proliferating normal human epidermal keratinocytes. Growth kinetics of normal human keratinocytes (NHK) and dermal fibroblasts were compared on 'very soft', 'soft' and 'hard' silicone gels, as well as on standard cell culture polystyrene dishes. Water contact angles and chemical compositions (IRFT-HATR) of the different silicone surfaces were found to be equivalent, although very different from standard cell culture polystyrene. The topography of the surfaces as well as the shape of the keratinocytes and fibroblasts grown on the different substrates were visualized by scanning electron microscopy, and compared. Although the surface softness and topography of the substrates differed markedly, dermal fibroblasts proliferated in serum-containing medium in equivalent manner on all substrates. Again no correlation could be found between the characteristics and the attachment of the substrates and rapid proliferation of the epidermal keratinocytes in defined medium. The epidermal keratinocytes spread, secreted a structured extracellular matrix network and grew up to confluence on all silicone substrates (elastomers and gels), except the relatively 'hard' silicone gel; this could be due to a direct interference by the waves observed on the silicone gel surfaces. PMID:1654138

Rosdy, M; Grisoni, B; Clauss, L C

1991-07-01

211

Pigment-independent cAMP-mediated epidermal thickening protects against cutaneous UV injury by keratinocyte proliferation  

PubMed Central

The epidermis increases pigmentation and epidermal thickness in response to ultraviolet exposure to protect against UV-associated carcinogenesis; however, the contribution of epidermal thickness has been debated. In a humanized skin mouse model that maintains interfollicular epidermal melanocytes, we found that forskolin, a small molecule that directly activates adenylyl cyclase and promotes cAMP generation, up-regulated epidermal eumelanin accumulation in fair-skinned melanocortin-1-receptor (Mc1r)-defective animals. Forskolin-induced pigmentation was associated with a reproducible expansion of epidermal thickness irrespective of melanization or the presence of epidermal melanocytes. Rather, forskolin-enhanced epidermal thickening was mediated through increased keratinocyte proliferation, indirectly through secreted factor(s) from cutaneous fibroblasts. We identified keratinocyte growth factor (Kgf) as a forskolin-induced fibroblast-derived cytokine that promoted keratinocyte proliferation, as forskolin induced Kgf expression both in the skin and in primary fibroblasts. Lastly, we found that even in the absence of pigmentation, forskolin-induced epidermal thickening significantly diminished the amount of UVA and UVB that passed through whole skin and reduced the amount of UVB-associated epidermal sunburn cells. These findings suggest the possibility of pharmacologic-induced epidermal thickening as a novel UV-protective therapeutic intervention, particularly for individuals with defects in pigmentation and adaptive melanization. PMID:23078399

Scott, Timothy L.; Christian, P.A.; Kesler, M.; Donohue, Kevin M.; Shelton, Brent; Wakamatsu, Kazumasa; Ito, Shosuke; D'Orazio, John

2012-01-01

212

Transforming growth factor-?1 in plaque morphea  

PubMed Central

Introduction Morphea (localized scleroderma) is a rare cutaneous disease characterized by skin fibrosis of unknown pathogenesis. Transforming growth factor-? (TGF-?) is a potent profibrotic factor. The role of TGF-? in morphea remains unclear. Aim The goal of this study was to estimate the expression level of TGF-?1 in skin and peripheral blood mononuclear cells as well as the plasma levels of TGF-?1 in plaque morphea (MEP). Material and methods The study involved 20 MEP patients. Three control groups were involved: 1 – plasma: 36 healthy volunteers; 2 – PBMC: 47 healthy volunteers; 3 – skin biopsies: 13 samples collected during mastectomy (breast cancer was not skin involved). The analysis of TGF-?1 plasma levels was performed with the use an adequate ELISA kit, while real-time polymerase chain reaction was employed for the expression of TGF-?1 in peripheral blood mononuclear cells (PBMC) and skin. Results In our study we have not detected differences in TGF-? 1 expression in PBMC, skin, nor in plasma levels of TGF-?1 between MEP patients and healthy controls, regardless of disease activity and its duration. Conclusions The results of our study contradict the claim of the substantial role of TGF-?1 in the most common morphea subtype – MEP. PMID:24493995

Kowalczyk, Michal J.; Szramka-Pawlak, Beata; Gornowicz-Porowska, Justyna; Szewczyk, Aleksandra; Silny, Wojciech; Molinska-Glura, Marta; Olewicz-Gawlik, Anna; Zaba, Ryszard; Pazdrowski, Jakub; Hrycaj, Pawel

2013-01-01

213

Effect of gamma-hydroxybutyrate on keratinocytes proliferation: A preliminary prospective controlled study in severe burn patients  

PubMed Central

Background: Hypermetabolism and hyposomatotropism related to severe burns lead to impaired wound healing. Growth hormone (GH) boosts wound healing notably following stimulation of the production of insulin-like growth factor-1 (IGF1), a mitogen factor for keratinocytes. Gamma-hydroxybutyrate (GHB) stimulates endogenous GH secretion. Aim: To assess effects of GHB sedation on keratinocytes proliferation (based on immunohistochemical techniques). Design: Monocentric, prospective, controlled trial. Materials and Methods: Patients (aging 18-65 years, burn surface area >30%, expected to be sedated for at least one month) were alternately allocated, at the 5th day following injury, in three groups according to the intravenous GHB dose administered for 21 days: Evening bolus of 50 mg/kg (Group B), continuous infusion at the rate of 10 mg/kg/h (Group C), or absence of GHB (Group P). They all received local standard cares. Immunohistochemistry (Ki67/MIB-1, Ulex europaeus agglutinin-1 and Mac 387 antibodies) was performed at D21 on adjacent unburned skin sample for assessing any keratinocyte activation. Serum IGF1 levels were measured at initiation and completion of the protocol. Statistical Analysis: Categorical variables were compared with Chi-square test. Comparisons of medians were made using Kruskal-Wallis test. Post hoc analyses were performed using Mann-Whitney test with Bonferroni correction for multiple comparisons. A P < 0.05 was considered to be statistically significant. Results: A total of 14 patients completed the study (Group B: n = 5, Group C: n = 5, Group P: n = 4). Continuous administration of GHB was associated with a significant higher Ki67 immunolabeling at D21 (P = 0.049) and with a significant higher increase in the IGF1 concentrations at D21 (P = 0.024). No adverse effects were disclosed. Conclusions: Our preliminary data support a positive effect of GHB on keratinocyte proliferation and are encouraging enough to warrant large prospective studies. PMID:25024938

Rousseau, Anne-Françoise; Bargues, Laurent; Bever, Hervé Le; Vest, Philippe; Cavalier, Etienne; Ledoux, Didier; Piérard, Gérald E.; Damas, Pierre

2014-01-01

214

Gene Expression of Growth Factors and Growth Factor Receptors for Potential Targeted Therapy of Canine Hepatocellular Carcinoma  

PubMed Central

ABSTRACT The purpose of this study was to evaluate the gene expression of growth factors and growth factor receptors of primary hepatic masses, including hepatocellular carcinoma (HCC) and nodular hyperplasia (NH), in dogs. Quantitative real-time reverse transcriptase-polymerase chain reaction was performed to measure the expression of 18 genes in 18 HCCs, 10 NHs, 11 surrounding non-cancerous liver tissues and 4 healthy control liver tissues. Platelet-derived growth factor-B (PDGF-B), transforming growth factor-?, epidermal growth factor receptor, epidermal growth factor and hepatocyte growth factor were found to be differentially expressed in HCC compared with NH and the surrounding non-cancerous and healthy control liver tissues. PDGF-B is suggested to have the potential to become a valuable ancillary target for the treatment of canine HCC. PMID:24189579

IIDA, Gentoku; ASANO, Kazushi; SEKI, Mamiko; SAKAI, Manabu; KUTARA, Kenji; ISHIGAKI, Kumiko; KAGAWA, Yumiko; YOSHIDA, Orie; TESHIMA, Kenji; EDAMURA, Kazuya; WATARI, Toshihiro

2013-01-01

215

Opioid growth factor - opioid growth factor receptor axis inhibits proliferation of triple negative breast cancer.  

PubMed

Triple negative breast cancer (TNBC) represents approximately 15% of the newly diagnosed cancers worldwide and is characterized by tissue lacking in estrogen, progesterone and human epidermal growth factor receptors. TNBC disproportionately affects younger women and women of colour, and new treatments are needed. The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a determinant of cell proliferation in neoplasia, and OGF is an endogenously produced pentapeptide that inhibits cell replication by interacting with OGFr and upregulating cyclin-dependent inhibitory kinase pathways thus reducing DNA synthesis. In these studies we investigated the presence and function of the OGF-OGFr axis in two human TNBC cell lines, as well as in breast cancer cell lines containing hormonal receptors. TNBC cell lines MDA-MD-231 and BT-20, as well as human breast cancer cells SK-BR-3 and MCF-7, were examined for the presence of pentapeptide and receptors, as well as their response to OGF. Specificity of peptide and receptor was confirmed by antibody neutralization and molecular studies to knockdown classical receptor protein. The requirement for protein transcription and translation and RNA transcription were investigated. Growth of TNBC cells in the presence of OGF and standard of care chemotherapeutic agent paclitaxel was evaluated to determine both efficacy and protective effects against toxicity. OGF treatment inhibited TNBC cells in a dosage related, receptor mediated, and reversible manner. OGF was the specific endogenous opioid to inhibit cell proliferation, and this was mediated by p21 cyclin dependent inhibitory kinase pathways, and required protein and RNA synthesis. OGFr was the specific receptor involved; both peptide and receptor were detected in all four cell lines. OGF treatment inhibited growth of all cancer cell lines evaluated, and reduced cell death in cultures exposed to paclitaxel. The OGF-OGFr axis is present and functioning in TNBC cell lines, and provides a novel biological pathway as potential therapy. PMID:23918871

Zagon, Ian S; Porterfield, Nancy K; McLaughlin, Patricia J

2013-06-01

216

The wind rose of human keratinocyte cell fate.  

PubMed

Extensive efforts have been made to understand the molecular actors that control epithelial cell fate. Although pieces of information have been obtained from single-gene function investigations, the entire picture of the molecular mechanisms involved in the regulation of epithelial homeostasis is still mysterious. Growing data indicate that gene networks rather than single "master" genes dictate cell fate. In an attempt to characterize such gene networks, we have been investigating the human keratinocyte proliferation and differentiation genes that act downstream of the transcription factor p63, a major regulator of epidermal homeostasis. We identified two networks: the cell cycle network that controls cell proliferation and the keratinocyte cell fate network. Through further analysis of the existing data on epithelial tumorigenesis and induced pluripotent stem cells, we propose a wind rose model of cell fate that is based on a balance between these two different networks that ultimately control human keratinocyte fate and epidermal homeostasis. PMID:25326028

Wu, Ning; Gidrol, Xavier

2014-12-01

217

Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes.  

PubMed

The USA300 strains of Staphylococcus aureus are the major cause of skin and soft tissue infection in the United States. Invasive USA300 infection has been attributed to several virulence factors, including protein A and the ?-hemolysin (Hla), which cause pathology by activating host signaling cascades. Here we show that S. aureus exploits the proinflammatory bias of human keratinocytes to activate pyroptosis, a caspase 1-dependent form of inflammatory cell death, which was required for staphylococci to penetrate across a keratinocyte barrier. Keratinocyte necrosis was mediated by calpains, Ca(2+)-dependent intracellular proteases whose endogenous inhibitor, calpastatin, is targeted by Hla-induced caspase 1. Neither Panton-Valentine leukocidin nor protein A expression was essential, but inhibition of either calpain or caspase 1 activity was sufficient to prevent staphylococcal invasion across the keratinocytes. These studies suggest that pharmacological interruption of specific keratinocyte signaling cascades as well as targeting the Hla might prevent invasive skin infection by staphylococci. PMID:22457275

Soong, Grace; Chun, Jarin; Parker, Dane; Prince, Alice

2012-05-15

218

Vascular Endothelial Growth Factor in Eye Disease  

PubMed Central

Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis. PMID:18653375

Penn, J.S.; Madan, A.; Caldwell, R.B.; Bartoli, M.; Caldwell, R.W.; Hartnett, M.E.

2012-01-01

219

Nerve growth factor: structure/function relationships.  

PubMed Central

Nerve growth factor (NGF), which has a tertiary structure based on a cluster of 3 cystine disulfides and 2 very extended, but distorted beta-hairpins, is the prototype of a larger family of neurotrophins. Prior to the availability of cloning techniques, the mouse submandibular gland was the richest source of NGF and provided sufficient material to enable its biochemical characterization. It binds as a dimer to at least 2 cell-surface receptor types expressed in a variety of neuronal and non-neuronal cells. Residues involved in these interactions and in the maintenance of tertiary and quaternary structure have been identified by chemical modification and site-directed mutagenesis, and this information can be related to their location in the 3-dimensional structure. For example, interactions between aromatic residues contribute to the stability of the NGF dimer, and specific surface lysine residues participate in receptor contacts. The conclusion from these studies is that receptor interactions involve broad surface regions, which may be composed of residues from both promoters in the dimer. PMID:7703837

Bradshaw, R. A.; Murray-Rust, J.; Ibanez, C. F.; McDonald, N. Q.; Lapatto, R.; Blundell, T. L.

1994-01-01

220

Fibroblast growth factor receptor expression investibular schwannoma  

PubMed

INTRODUCTION: The family of fibroblast growth factor (FGF) and their receptors (FGFRs) play a critical role in nervous system development. Aberrant expression or a change in the pattern of their expression may contribute to neural tumour formation. The FGFR expression status in vestibular schwannoma is unknown. AIM: To characterize the pattern of FGFR-1, FGFR-3 and FGFR-4 expression in resection vestibular schwannoma. METHOD: Fifty paraffin-embedded archival specimens of vestibular schwannomas were immunostained fro FGFR-1, FGFR-3 and FGFR-4 using specific rabbit polyclonal antibodies. signals were graded as weak, moderate or strong by two independent observers. Normal tissues and appropriate positive and negative controls were included. RESULTS: FGFR-1 and FGFR-3 appeared to have similar patterns of immunoreactivity with predominantly membrane and cytoplasmic signals in control tissues. In contrast, in vestibular schwannomas, FGFR-1 and FGFR-3, preferentially localize to the nucleau, with moderate to strong signals in 80% and 76% of the specimens, respectively. FGFR-4 expression was upregulated in 70% of vestibular schwannomas to a moderate level, localizing to the perinuclear and cytoplasmic area. Differential cellular localization of receptor proteins has been demonstrated in vestibular schwannomas. CONCLUSION: This is the first comprehensive study characterizing FGFR expression in vestibular schwannoma. The development of vestibular schwannomas is associated with an altered pattern and level of FGFR expression. Our ongoing work aims to examine their significance in the pathogenesis of vestibular schwannomas. PMID:11123169

Nair; Leung; Ince; Ramsden; Wilson

2000-12-01

221

Oncogenic Human Papillomaviruses Activate the Tumor-Associated Lens Epithelial-Derived Growth Factor (LEDGF) Gene  

PubMed Central

The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic. PMID:24604027

Leitz, Jenny; Reuschenbach, Miriam; Lohrey, Claudia; Honegger, Anja; Accardi, Rosita; Tommasino, Massimo; Llano, Manuel; von Knebel Doeberitz, Magnus; Hoppe-Seyler, Karin; Hoppe-Seyler, Felix

2014-01-01

222

Growth factor involvement in tension-induced skeletal muscle growth  

NASA Technical Reports Server (NTRS)

New muscle tissue culture techniques were developed to grow embryonic skeletal myofibers which are able to differentiate into more adultlike myofibers. Studies on mechanical simulation of cultured muscle cell growth will now be more directly applicable to mechanically-induced growth in adult muscle, and lead to better models for understanding muscle tissue atrophy caused by disuse in the microgravity of space.

Vandenburgh, Herman W.

1987-01-01

223

Novel Drosophila receptor that binds multiple growth factors  

SciTech Connect

The authors have recently reported the identification of a novel growth factor receptor from Drosophila cell cultures that has dual binding specificity for both insulin and epidermal growth factor (EGF). This 100 kDa protein is also antigenically related to the cytoplasmic region of the mammalian EGF receptor-tyrosine kinase. They now report that this protein binds to mammalian nerve growth factor and human transforming growth factor alpha as well as insulin and EGF with apparent dissociation constants ranging from 10/sup -6/ to 10/sup -8/ M. The 100 kDa protein can be affinity-labeled with these /sup 125/I-labeled growth factors after immunoprecipitation with anti-EGF receptor antiserum. These four growth factors appear to share a common binding site, as evidenced by their ability to block affinity labelling by /sup 125/I-insulin. No significant binding to the 100 kDa protein was observed with platelet-derived growth factor, transforming growth factor beta, or glucagon. The 100 kDa Drosophila protein has a unique ligand-binding spectrum with no direct counterpart in mammalian cells and may represent an evolutionary precursor of the mammalian receptors for these growth factors.

Rosner, M.R.; Thompson, K.L.; Garcia, V.; Decker, S.J.

1986-05-01

224

Markedly elevated levels of vascular endothelial growth factor, fibroblast growth factor, and interleukin 6 in Meigs syndrome  

Microsoft Academic Search

Analysis of serum and peritoneal and pleural fluid from a patient with Meigs’ syndrome revealed high levels of vascular endothelial growth factor, fibroblast growth factor, and interleukin 6. Serum levels declined after removal of the ovarian tumor, along with resolution of ascites and hydrothorax. These findings suggest the involvement of these vasoactive factors in ascites and pleural fluid formation in

Yoram Abramov; Shaoul O. Anteby; Sozos J. Fasouliotis; Vivian Barak

2001-01-01

225

Induction of Hair Growth by Insulin-Like Growth Factor-1 in 1,763 MHz Radiofrequency-Irradiated Hair Follicle Cells  

PubMed Central

Radiofrequency (RF) radiation does not transfer high energy to break the covalent bonds of macromolecules, but these low energy stimuli might be sufficient to induce molecular responses in a specific manner. We monitored the effect of 1,763 MHz RF radiation on cultured human dermal papilla cells (hDPCs) by evaluating changes in the expression of cytokines related to hair growth. The expression of insulin-like growth factor-1 (IGF-1) mRNA in hDPCs was significantly induced upon RF radiation at the specific absorption rate of 10 W/kg, which resulted in increased expression of B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) and cyclin D1 (CCND1) proteins and increased phosphorylation of MAPK1 protein. Exposure to 10 W/kg RF radiation 1 h per day for 7 days significantly enhanced hair shaft elongation in ex vivo hair organ cultures. In RF-exposed follicular matrix keratinocytes in the hair bulb, the expression of Ki-67 was increased, while the signal for terminal deoxynucleotidyl transferase dUTP nick end labeling was reduced. From these results, we suggest that 1,763 MHz RF exposure stimulates hair growth in vitro through the induction of IGF-1 in hDPCs. PMID:22164296

Jo, Seong Jin; Cho, A-Ri; Jeon, Soon-Ik; Choi, Hyung-Do; Kim, Kyu Han; Park, Gun-Sik; Pack, Jeong-Ki; Kwon, Oh Sang; Park, Woong-Yang

2011-01-01

226

Extracts of Sarcoptes scabiei De Geer downmodulate secretion of IL-8 by skin keratinocytes and fibroblasts and of GM-CSF by fibroblasts in the presence of proinflammatory cytokines.  

PubMed

Previous in vitro studies showed that molecules in an extract of the mite Sarcoptes scabiei variety canis De Geer could modulate the secretion of cytokines from cultured normal human epidermal keratinocytes and dermal fibroblasts in the absence of proinflammatory cytokines in the cell culture media. The purpose of this study was to investigate whether scabies extract could also modulate cytokine and chemokine secretion from epidermal keratinocytes and dermal fibroblasts in the presence of proinflammatory cytokines that are likely present in the scabietic lesion in vivo. In particular, could the downmodulating properties of this ectoparasitic mite on skin cells be maintained in the presence of proinflammatory cytokines? We found that even in the presence of the proinflammatory cytokines interleukin (IL)-1alpha, IL-beta, and a mixture of tumor necrosis factor (TNF)alpha + IL-17, scabies extract still downregulated the levels of IL-8 secretion from keratinocytes and fibroblasts and of granulocyte/macrophage-colony stimulating factor (GM-CSF) secretion from fibroblasts that were induced by stimulation of the cells with proinflammatory cytokines alone. This study also showed that scabies molecules induced secretions of growth-related oncogene alpha (GROalpha), transforming growth factor alpha (TGFalpha), and cutaneous T-cell attracting chemokine (CTACK) from keratinocytes and IL-6 and granulocyte-colony stimulating factor (G-CSF) from fibroblasts. These findings, coupled with the previous findings that molecules in scabies extract could downregulate expression of intracellular adhesion molecule-1 (ICAM-1) and E-selectin by normal dermal microvascular endothelial cells and secretion of IL-1alpha from keratinocytes, suggest that multiple factors from scabies mites play a role in the characteristic delayed inflammatory response to a primary infestation with S. scabiei. These are adaptations that favor invasion of the host by the parasite. PMID:19645287

Mullins, Jeremi S; Arlian, Larry G; Morgan, Marjorie S

2009-07-01

227

Control of Growth Factor Networks by Heparan Sulfate Proteoglycans  

PubMed Central

Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different growth factors may allow for cross regulation. Here we demonstrate, using experiments and computer simulations, that the HB-GFs FGF-2 and heparin-binding EGF-like growth factor (HB-EGF) can cross regulate receptor binding of the other despite having unique receptors. The ability of HSPG to stabilize HB-GF receptor binding is critical for competing growth factors to modulate receptor binding with both enhanced and reduced binding possible depending on this stabilization process. HSPG density and affinity for HB-GF are also critical factors for HB-GF cross regulation. Simulations further reveal that HB-GF can regulate receptor binding of non-HB-GFs such as EGF even when the two proteins share no binding sites when other HB-GF are present within the network. Proliferation studies demonstrate potentiation of HB-EGF-induced growth by FGF-2 indicating that competition networks can alter biological response. Exogenous manipulation of cellular responses to growth factors in complex living systems will require understanding the HSPG-controlled network. PMID:18839312

Forsten-Williams, Kimberly; Chu, Chia Lin; Fannon, Michael; Buczek-Thomas, Jo Ann; Nugent, Matthew A.

2008-01-01

228

Control of growth factor networks by heparan sulfate proteoglycans.  

PubMed

Growth factor binding to transmembrane protein receptors is generally understood to initiate cell signaling. Receptor binding of heparin-binding growth factors (HB-GFs), such as fibroblast growth factor-2 (FGF-2), is regulated by interactions with heparan sulfate proteoglycans. While there is some specificity for binding to heparan sulfate, overlap in sites for different growth factors may allow for cross regulation. Here we demonstrate, using experiments and computer simulations, that the HB-GFs FGF-2 and heparin-binding EGF-like growth factor (HB-EGF) can cross regulate receptor binding of the other despite having unique receptors. The ability of HSPG to stabilize HB-GF receptor binding is critical for competing growth factors to modulate receptor binding with both enhanced and reduced binding possible depending on this stabilization process. HSPG density and affinity for HB-GF are also critical factors for HB-GF cross regulation. Simulations further reveal that HB-GF can regulate receptor binding of non-HB-GFs such as EGF even when the two proteins share no binding sites when other HB-GF are present within the network. Proliferation studies demonstrate potentiation of HB-EGF-induced growth by FGF-2 indicating that competition networks can alter biological response. Exogenous manipulation of cellular responses to growth factors in complex living systems will require understanding the HSPG-controlled network. PMID:18839312

Forsten-Williams, Kimberly; Chu, Chia Lin; Fannon, Michael; Buczek-Thomas, Jo Ann; Nugent, Matthew A

2008-12-01

229

REVIEW ARTICLE Fibroblast growth factor signaling in mammalian tooth  

E-print Network

in tooth number, morphology or enamel structure. The parallel roles of FGF signaling in mouse and humanREVIEW ARTICLE Fibroblast growth factor signaling in mammalian tooth development Chun-Ying Li · Jan In this review, we discuss the central role of fibroblast growth factor (FGF) signaling in mammalian tooth

Klein, Ophir

230

Autologous fibrin glue with growth factors in reconstructive maxillofacial surgery  

Microsoft Academic Search

The aim of this paper was to describe a method for the preparation of autologous fibrin glue with platelet growth factors and to report its use with particulate cancellous bone in reconstructive maxillofacial surgery. The fibrin glue is a two-component glue, where the one component is a concentrated fibrinogen solution with platelet growth factors and the other component is a

J. J. Thorn; H. Sřrensen; U. Weis-Fogh; M. Andersen

2004-01-01

231

Differential Effect of Growth Factors on Intestinal Wall Components  

Microsoft Academic Search

Both the mucosal and muscle layers respond to surgical manipulation of the small intestine. Various growth factors influence the mucosal response but less is known about changes in the muscle layers. Our aim was to evaluate the effect of epidermal growth factor (EGF) and octreotide (OCT) on changes in the intestinal wall induced by serosal patching. Twenty-four New Zealand white

J. S. Thompson

1996-01-01

232

The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes.  

PubMed

Monomethylfumarate (MMF) is thought to be the bioactive ingredient of the drug Fumaderm (Biogen Idec, Cambridge, MA), licensed in Germany since 1994 for the treatment of moderate-to-severe psoriasis. Psoriasis is a common inflammatory hyperproliferative skin disorder that involves cross-talk between different cell types, including immune cells and keratinocytes. Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation, and inflammation, with the psoriatic cytokine network maintained by communication between immune cells and keratinocytes. Recently, there is increasing evidence regarding the pivotal role of keratinocytes in mediating the disease process, and these cells can be regarded as safe therapeutic targets. From the data available on human subjects treated with Fumaderm, MMF is an effective antipsoriatic agent with known effects on immune cells. However, little is known about its direct effects on keratinocytes. We hypothesized that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. Indeed, MMF dose-dependently inhibited [(3)H]thymidine incorporation into DNA, indicating a direct antiproliferative action on keratinocytes. MMF significantly increased the protein level of keratin 10, the early keratinocyte differentiation marker, and the activity of transglutaminase, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced keratinocytes, MMF significantly inhibited the expression of the proinflammatory cytokines, tumor necrosis factor-? (TNF?), interleukin-6, and interleukin-1? as well as the production of TNF?. Our results support the notion that MMF has direct antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes, highlighting its potential use as a multifactorial antipsoriatic agent. PMID:25332455

Helwa, Inas; Patel, Ravi; Karempelis, Peter; Kaddour-Djebbar, Ismail; Choudhary, Vivek; Bollag, Wendy B

2015-01-01

233

Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation.  

PubMed Central

The endothelial cell-specific mitogen vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) represents a central regulator of cutaneous angiogenesis. Increased VPF/VEGF expression has recently been reported in psoriatic skin and healing wounds, both conditions in which transforming growth factor-alpha (TGF alpha) and its ligand, the epidermal growth factor receptor, are markedly up-regulated. Since TGF alpha strongly induces VPF/VEGF synthesis in keratinocytes, TGF alpha-mediated VPF/VEGF expression is likely to play a significant role in the initiation and maintenance of increased vascular hyperpermeability and hyperproliferation in skin biology. The objectives of the present studies were to determine the molecular mechanisms responsible for TGF alpha-induced transcriptional activation of the VPF/VEGF gene. We have identified a GC-rich TGF alpha-responsive region between -88 bp and -65 bp of the VPF/VEGF promoter that is necessary for constitutive and TGF alpha-inducible transcriptional activation. In electrophoretic mobility shift assays, this region binds Sp1-dependent protein complexes constitutively and an additional TGF alpha-inducible protein complex that is distinct from Sp1 protein. Both AP-2 and Egr-1 transcription factors were detected as components of the TGF alpha-inducible protein complex in supershift EMSA studies. In co-transfection studies, an AP-2 but not an Egr-1 expression vector activated VPF/VEGF transcription, thus indicating that AP-2 protein is functionally important in TGF alpha-induced VPF/VEGF gene expression. By clarifying regulatory mechanisms that are critical for angiogenic processes in the skin, these studies may form the basis for new therapeutic strategies to modulate VPF/VEGF expression in cutaneous inflammation and wound healing. PMID:9049304

Gille, J; Swerlick, R A; Caughman, S W

1997-01-01

234

Extracellular matrix and growth factors in branching morphogenesis  

NASA Technical Reports Server (NTRS)

The unifying hypothesis of the NSCORT in gravitational biology postulates that the ECM and growth factors are key interrelated components of a macromolecular regulatory system. The ECM is known to be important in growth and branching morphogenesis of embryonic organs. Growth factors have been detected in the developing embryo, and often the pattern of localization is associated with areas undergoing epithelial-mesenchymal interactions. Causal relationships between these components may be of fundamental importance in control of branching morphogenesis.

Hardman, P.; Spooner, B. S.

1993-01-01

235

Vascular Endothelial Growth Factor is a Secreted Angiogenic Mitogen  

NASA Astrophysics Data System (ADS)

Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.

Leung, David W.; Cachianes, George; Kuang, Wun-Jing; Goeddel, David V.; Ferrara, Napoleone

1989-12-01

236

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth  

PubMed Central

Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET protooncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190MET) made of a 50 kD (alpha) subunit disulfide linked to a 145-kD (beta) subunit. HGF binding to endothelial cells identifies two sites with different affinities. The higher affinity binding site (Kd = 0.35 nM) corresponds to the p190MET receptor. Sub- nanomolar concentrations of HGF, but not of a recombinant inactive precursor, stimulate the receptor kinase activity, cell proliferation and motility. HGF induces repairs of a wound in endothelial cell monolayer. HGF stimulates the scatter of endothelial cells grown on three-dimensional collagen gels, inducing an elongated phenotype. In the rabbit cornea, highly purified HGF promotes neovascularization at sub-nanomolar concentrations. HGF lacks activities related to hemostasis-thrombosis, inflammation and endothelial cells accessory functions. These data show that HGF is an in vivo potent angiogenic factor and in vitro induces endothelial cells to proliferate and migrate. PMID:1383237

1992-01-01

237

TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)  

EPA Science Inventory

TITLE: TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

238

Adiponectin induces breast cancer cell migration and growth factor expression.  

PubMed

Adiponectin, the hormone produced and secreted by adipocytes, has been shown to promote migration of the epithelial cells and angiogenesis in these cells. We sought to determine if adiponectin could induce the cellular migration and growth factor expression in breast cancer cells grown in vitro. The breast cancer cell lines MDA-MB-436 and MFM-223 (estrogen-independent) were treated with adiponectin for different time periods. Supernatants of the cell cultures were obtained by centrifugation and were assayed for growth factor expression by the enzyme-linked immunosorbent assay (ELISA). Becton-Dickinson-Falcon Transwell systems were used to assay adiponectin-induced migration. Adiponectin significantly induced the expression of various growth factors, including vascular endothelial growth factor, transforming growth factor-?1, and basic fibroblast growth factor in MDA-MB-436 and MFM-223 cells. Adiponectin also enhanced the migration of breast cancer cells which were inhibited about 50-70 % by the inhibitors of mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K). Adiponectin treatment of the cancer cell induced an increased expression of different growth factors and migration of the cells. These effects are likely to contribute to the progression of breast cancer, implying that change in adiponectin levels associated with obesity may be considered as a high risk factor in breast cancer patients. PMID:24906235

Jia, Zhongming; Liu, Yan; Cui, Shouyong

2014-11-01

239

Growth Hormone-Releasing Hormone: An Autocrine Growth Factor for Small Cell Lung Carcinoma  

Microsoft Academic Search

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of various cancers in vivo. This effect is thought to be exerted through suppression of the pituitary growth hormone-hepatic insulin-like growth factor I (IGF-I) axis and direct inhibition of autocrine\\/paracrine production of IGF-I and -II in tumors. However, other evidence points to a direct effect of GHRH antagonists on tumor growth

H. Kiaris; A. V. Schally; J. L. Varga; K. Groot; P. Armatis

1999-01-01

240

Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer  

Microsoft Academic Search

Solid tumors must induce a vascular stroma to grow beyond a minimal size, and the intensity of the angiogenic response has been correlated with prognosis in breast cancer patients. Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a secreted protein that has been implicated in tumor-associated angiogenesis. Vascular permeability factor directly stimulates endothelial cell growth

Lawrence F Brown; Brygida Berse; Robert W Jackman; Kathi Tognazzi; Anthony J Guidi; Harold F Dvorak; Donald R Senger; James L Connolly; Stuart J Schnitt

1995-01-01

241

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice  

PubMed Central

The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis. PMID:24503019

Schafer, Matthias; Willrodt, Ann-Helen; Kurinna, Svitlana; Link, Andrea S; Farwanah, Hany; Geusau, Alexandra; Gruber, Florian; Sorg, Olivier; Huebner, Aaron J; Roop, Dennis R; Sandhoff, Konrad; Saurat, Jean-Hilaire; Tschachler, Erwin; Schneider, Marlon R; Langbein, Lutz; Bloch, Wilhelm; Beer, Hans-Dietmar; Werner, Sabine

2014-01-01

242

Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma.  

PubMed

Vascular endothelial growth factor (VEGF) is an angiogenic hormone that is produced by and supports the growth of many types of malignancies. The present study shows that insulin-like growth factor 1 (IGF-I), a mitogen that promotes the propagation of cancers through autocrine and paracrine mechanisms, increases the expression of mRNA for VEGF and production of VEGF protein by COLO 205 colon carcinoma cells. IGF-I also induces expression of VEGF mRNA in SW620, LSLiM6, and HCT15 colon carcinoma cells showing that this is a common response to IGF-I. Whereas IGF-I induced VEGF mRNA in each cell line examined (2.3-12-fold), it induced proliferation only in COLO 205 and LSLiM6 cells. Thus, the proliferative response induced by IGF-I and its ability to induce VEGF occur through distinguishable mechanisms. IGF-I increases the cellular content of VEGF mRNA by increasing the rate of transcription (5-fold after 4 h) and also by increasing the half-life of VEGF mRNA (0.6 +/- 0.07 h in control cells to 2.0 +/- 0.37 h in IGF-I-treated cells). Monoclonal antibody (alphaIR3) directed against the type 1 IGF receptor significantly attenuated the ability of IGF-I to promote expression of VEGF mRNA. Interestingly, by itself alphaIR3 acted as a weak agonist and induced a modest increase in the cellular content of VEGF mRNA. alphaIR3 also promoted tyrosine phosphorylation of the beta subunit of the IGF-I receptor, and the magnitude of this response was comparable with that induced by IGF-I. These observations point to a nonlinear relationship between activation of the IGF-I receptor and induction of VEGF mRNA. Thus, in addition to its direct, growth stimulatory effect on transformed cells, IGF-I induces the expression of VEGF which can promote the progression of cancer by regulating the development of new blood vessels. PMID:8910616

Warren, R S; Yuan, H; Matli, M R; Ferrara, N; Donner, D B

1996-11-15

243

Reduced growth factor requirement of keloid-derived fibroblasts may account for tumor growth  

SciTech Connect

Keloids are benign dermal tumors that form during an abnormal wound-healing process is genetically susceptible individuals. Although growth of normal and keloid cells did not differ in medium containing 10% (vol/vol) fetal bovine serum, keloid culture grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) fetal bovine serum, keloid cultures grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) plasma or 1% fetal bovine serum. Conditioned medium from keloid cultures did not stimulate growth of normal cells in plasma nor did it contain detectable platelet-derived growth factor or epidermal growth factor. Keloid fibroblasts responded differently than normal adult fibroblasts to transforming growth factor ..beta... Whereas transforming growth factor ..beta.. reduced growth stimulation by epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from keloids. Normal and keloid fibroblasts also responded differently to hydrocortisone: growth was stimulated in normal adult cells and unaffected or inhibited in keloid cells. Fetal fibroblasts resembled keloid cells in their ability to grow in plasma and in their response to hydrocortisone. The ability of keloid fibroblasts to grow to higher cell densities in low-serum medium than cells from normal adult skin or from normal early or mature scars suggests that a reduced dependence on serum growth factors may account for their prolonged growth in vivo. Similarities between keloid and fetal cells suggest that keloids may result from the untimely expression of growth-control mechanism that is developmentally regulated.

Russell, S.B.; Trupin, K.M.; Rodriguez-Eaton, S.; Russell, J.D.; Trupin, J.S.

1988-01-01

244

7-Mercaptoheptanoylthreonine phosphate substitutes for heat-stable factor (mobile factor) for growth of Methanomicrobium mobile.  

PubMed

Methanomicrobium mobile requires a heat-stable factor present in ruminal fluid and in boiled cell extract from Methanobacterium thermoautotrophicum for growth. By comparing the growth of M. mobile with boiled cell extract with that observed with various methanogenic cofactors, we found that 7-mercaptoheptanoylthreonine phosphate (HS-HTP) supported sustained growth of M. mobile, at an optimal concentration of 100 microM. No derivatives or possible biosynthetic precursors of HS-HTP could replace HS-HTP as the sole source of growth factor. Results suggest that the growth requirement might be satisfied by 7-mercaptoheptanoic acid plus a second, unidentified heat-stable factor. PMID:1746950

Kuhner, C H; Smith, S S; Noll, K M; Tanner, R S; Wolfe, R S

1991-10-01

245

TGF?1 overexpression by keratinocytes alters skin dendritic cell homeostasis and enhances contact hypersensitivity.  

PubMed

Overexpression of transforming growth factor beta-1 (TGF?1) in mouse epidermis causes cutaneous inflammation and keratinocyte hyperproliferation. Here we examined acute effects of TGF?1 overproduction by keratinocytes on skin dendritic cells (DCs). TGF?1 induction for 2 and 4 days increased the numbers and CD86 expression of B220(+) plasmacytoid DCs (pDCs) and CD207(+)CD103(+), CD207(-)CD103(-)CD11b(+), and CD207(-)CD103(-)CD11b(-) dermal DCs (dDCs) in skin-draining lymph nodes (SDLNs). The dermis of TGF?1-overexpressing mice had significantly more pDCs, CD207(+)CD103(+) dDCs, and CD207(-)CD11b(+) dDCs in the absence of increased dermal proliferation. Application of dye, tetramethyl rhodamine iso-thiocyanate (TRITC), in dibutylpthalate (DBP) solution after TGF?1 induction increased the numbers of TRITC(+)CD207(-) dDCs in SDLNs, and augmented TRITC/DBP-induced Langerhans cell (LC) migration 72 ?hours post TRITC treatment. Consistent with this, LC migration was increased in vitro by TGF?1 overexpression in skin explants and by exogenous TGF?1 in culture media. Transient TGF?1 induction during DNFB sensitization increased contact hypersensitivity responses by 1.5-fold. Thus, elevated epidermal TGF?1 alone is sufficient to alter homeostasis of multiple cutaneous DC subsets, and enhance DC migration and immune responses to contact sensitizers. These results highlight a role for keratinocyte-derived TGF?1 in DC trafficking and in the initiation of skin inflammation. PMID:22832490

Mohammed, Javed; Gunderson, Andrew J; Khong, Hong-Hanh; Koubek, Richard D; Udey, Mark C; Glick, Adam B

2013-01-01

246

A Two-Stage, p16INK4A- and p53Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status  

Microsoft Academic Search

With increasing frequency during serial passage in culture, primary human keratinocytes express p16INK4A (p16) and undergo senescence arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid or greatly reduce p16 expression. We have confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the

James G. Rheinwald; William C. Hahn; Matthew R. Ramsey; Jenny Y. Wu; Zongyou Guo; Hensin Tsao; Michele De Luca; Caterina Catricala; Kathleen M. O'Toole

247

Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth  

Microsoft Academic Search

Endochondral ossification is a major mode of bone formation that occurs as chondrocytes undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. We have identified a role for fibroblast growth factor receptor 3 (FGFR-3) in this process by disrupting the murine Fgfr-3 gene to produce severe and progressive bone dysplasia with enhanced and prolonged endochondral bone growth. This growth is accompanied

Chuxia Deng; Anthony Wynshaw-Boris; Fen Zhou; Ann Kuo; Philip Leder

1996-01-01

248

Modulation of skin cell functions by transforming growth factor-beta1 and ACTH after ultraviolet irradiation  

Microsoft Academic Search

The adaptive responses in skin to ultraviolet (UV) radi- ation include increased cornification of keratinocytes and increased synthesis and distribution of melanin by melanocytes. The possible involvement of paracrine factors in the generation of these responses was studied in a novel two- stage culture model. Human melanocytes or keratino- cytes were first irradiated or sham-irradiated and then the conditioned media

N S Dissanayake; R S Mason

1998-01-01

249

Multiple signaling pathways are responsible for prostaglandin E2-induced murine keratinocyte proliferation  

PubMed Central

Although prostaglandin E2 (PGE2) has been shown by pharmacological and genetic studies to be important in skin cancer, the molecular mechanism(s) by which it contributes to tumor growth is not well understood. In this study we investigated the mechanisms by which PGE2 stimulates murine keratinocyte proliferation using in vitro and in vivo models. In primary mouse keratinocyte (PMK) cultures, PGE2 activated the epidermal growth factor receptor (EGFR) and its downstream signaling pathways as well as increased cyclic AMP (cAMP) production and activated the cAMP response element binding protein (CREB). EGFR activation was not significantly inhibited by pretreatment with a c-src inhibitor (PP2), nor by a protein kinase A inhibitor (H-89). However, PGE2-stimulated extracellularly-regulated kinase1/2 (ERK1/2) activation was completely blocked by EGFR, ERK1/2 and phosphatidylinositol 3-kinase (PI3-K) pathway inhibitors. In addition, these inhibitors attenuated the PGE2-induced proliferation, nuclear factor-?B (NF-?B), activator protein-1 (AP-1) and CREB binding to the promoter regions of the cyclin D1 and vascular endothelial growth factor (VEGF) genes and expression of cyclin D1 and VEGF in PMKs. Similarly, in vivo, we found that wild type (WT) mice treated with PGE2 and untreated COX-2 overexpressing transgenic mice had higher levels of cell proliferation and expression of cyclin D1 and VEGF, as well as higher levels of activated EGFR, NF-?B, AP-1 and CREB, than vehicle-treated WT mice. Our findings provide evidence for a link between COX-2 overexpression and EGFR-, ERK-, PI3-K-, cAMP-mediated cell proliferation, and the tumor promoting activity of PGE2 in mouse skin. PMID:18567804

Ansari, Kausar M.; Rundhaug, Joyce E.; Fischer, Susan M.

2008-01-01

250

Immunoglobulins, growth factors and growth hormone in bovine colostrum and the effects of processing  

Microsoft Academic Search

In colostrum collected 0–80h postpartum the contents of immunoglobulins (Igs), transforming growth factor beta-2 (TGF-?2), insulin-like growth factor-1 (IGF-1) and growth hormone (GH) were analysed. Colostrum initially contained 90mgmL?1 IgG1, 2.8mgmL?1 IgG2, 1.6mgmL?1 IgA, 4.5mgmL?1 IgM, and these concentrations declined by 92%, 87%, 93% and 84%, respectively, in the samples collected later. Of the growth factors, colostrum initially contained 289–310ngmL?1

Lidia Elfstrand; Helena Lindmark-Mĺnsson; Marie Paulsson; Lena Nyberg; Björn Ĺkesson

2002-01-01

251

P-cadherin potentiates ligand-dependent EGFR and IGF-1R signaling in dysplastic and malignant oral keratinocytes.  

PubMed

Oral and oropharyngeal cancer together constitute the sixth most common cancer worldwide, with over 400,000 new cases diagnosed each year. Early detection is paramount, as the 5-year survival rate for these cancers decreases markedly once tumors have become regionally invasive. In many tissues, including oral epithelia, neoplastic progression is accompanied by alterations in expression of the epithelial cell adhesion molecules E-cadherin and P-cadherin. Oral epithelia is one of only a few tissues in which P-cadherin levels have been noted to increase in dysplasia and well-differentiated carcinomas and decrease in advanced malignancies. In the present study, P-cadherin was overexpressed in both dysplastic and malignant oral keratinocytes to characterize the mechanisms by which aberrantly expressed P-cadherin may modulate tumor progression. We found that P-cadherin was able to potentiate ligand-dependent signaling of insulin-like growth factor 1 receptor (IGF-1R) in malignant keratinocytes and epidermal growth factor receptor (EGFR) in dysplastic cells. P-cadherin prolonged activation of the mitogen-activated protein kinase (MAPK) in both cell lines and also increased the magnitude of AKT phosphorylation in dysplastic cells. P-cadherin overexpression alone was sufficient to increase steady-state levels of the mesenchymal transcription factor Snail, increase cell motility and also induce morphological changes in dysplastic keratinocytes. Taken together, these data suggest that the aberrantly elevated levels of P-cadherin which occur in early oral tumor development may play a critical role in the augmentation of neoplastic signaling networks and in the further acquisition of aggressive phenotypes. PMID:25322858

Lysne, Desseree; Johns, James; Walker, Andrew; Ecker, Rachel; Fowler, Christopher; Lawson, Kathryn R

2014-12-01

252

Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization.  

PubMed

Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization. PMID:23803710

Gaál, Emília Ilona; Tammela, Tuomas; Anisimov, Andrey; Marbacher, Serge; Honkanen, Petri; Zarkada, Georgia; Leppänen, Veli-Matti; Tatlisumak, Turgut; Hernesniemi, Juha; Niemelä, Mika; Alitalo, Kari

2013-08-01

253

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation  

PubMed Central

Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. PMID:16618808

Nguyen, Bach-Cuc; Lefort, Karine; Mandinova, Anna; Antonini, Dario; Devgan, Vikram; Della Gatta, Giusy; Koster, Maranke I.; Zhang, Zhuo; Wang, Jian; di Vignano, Alice Tommasi; Kitajewski, Jan; Chiorino, Giovanna; Roop, Dennis R.; Missero, Caterina; Dotto, G. Paolo

2006-01-01

254

Sputa nerve growth factor forms a preferable substitute to mouse 7S-? nerve growth factor  

PubMed Central

The NGF (nerve growth factor) from Naja sputatrix has been purified by gel filtration followed by reversed-phase HPLC. The protein showed a very high ability to induce neurite formation in PC12 cells relative to the mouse NGF. Two cDNAs encoding isoforms of NGF have been cloned and an active recombinant NGF, sputa NGF, has been produced in Escherichia coli as a His-tagged fusion protein. Sputa NGF has been found to be non-toxic under both in vivo and in vitro conditions. The induction of neurite outgrowth by this NGF has been found to involve the high-affinity trkA–p75NTR complex of receptors. The pro-survival mechanism of p75NTR has been mediated by the activation of nuclear factor ?B gene by a corresponding down-regulation of inhibitory ?B gene. Real-time PCR and protein profiling (by surface-enhanced laser-desorption–ionization time-of-flight) have confirmed that sputa NGF up-regulates the expression of the endogenous NGF in PC12 cells. Preliminary microarray analysis has also shown that sputa NGF is capable of promoting additional beneficial effects such as the up-regulation of arginine vasopressin receptor 1A, voltage-dependent T-type calcium channel. Hence, sputa NGF forms a new and useful NGF. PMID:15225125

2004-01-01

255

Endothelin-1 is a transcriptional target of p53 in epidermal keratinocytes and regulates UV induced melanocyte homeostasis  

PubMed Central

Summary Keratinocytes contribute to melanocyte activity by influencing their microenvironment, in part, through secretion of paracrine factors. Here we discovered that p53 directly regulates Edn1 expression in epidermal keratinocytes and controls UV-induced melanocyte homeostasis. Selective ablation of EDN1 in murine epidermis (EDN1ep?/?) does not alter melanocyte homeostasis in newborn skin but decreases dermal melanocytes in adult skin. Results showed that keratinocytic EDN1 in a non-cell autonomous manner controls melanocyte proliferation, migration, DNA damage and apoptosis after UVB irradiation. Expression of other keratinocyte derived paracrine factors did not compensate for the loss of EDN1. Topical treatment with EDN1 receptor (EDNRB) antagonist BQ788 abrogated UV induced melanocyte activation and recapitulated the phenotype seen in EDN1ep?/? mice. Altogether, present studies establish an essential role of EDN1 in epidermal keratinocytes to mediate UV induced melanocyte homeostasis in vivo. PMID:23279852

Hyter, Stephen; Coleman, Daniel J.; Ganguli-Indra, Gitali; Merrill, Gary F.; Ma, Steven; Yanagisawa, Masashi; Indra, Arup K.

2013-01-01

256

Nerve Growth Factor Effects on the Immune System.  

National Technical Information Service (NTIS)

In the present phase of our study, we have investigated the relationship between the nerve growth factor protein (NGF) and the hypothalamus-pituitary-adrenocortical axis (HPAA), a neuroendocrine system active in the response to stress and the immune syste...

J. R. Perez-Polo

1990-01-01

257

Nerve Growth Factor Effects on the Immune System.  

National Technical Information Service (NTIS)

The nerve growth factor protein, NGF, has been shown to play a physiologic role in the development and regeneration of the peripheral nervous system, acting on sensory and sympathetic ganglia. In the central nervous system, NGF induces choline acetyltrans...

J. R. Perez-Polo

1989-01-01

258

Nerve Growth Factor Effects on the Immune System.  

National Technical Information Service (NTIS)

The nerve growth factor protein, NGF, has been shown to play a physiologic role in the development and regeneration of the peripheral nervous system, acting on sensory and sympathetic ganglia. In the central nervous system, NGF induces choline acetyltrans...

J. R. Perez-Polo

1988-01-01

259

Nerve Growth Factor Effects on the Immune System.  

National Technical Information Service (NTIS)

The nerve growth factor protein, NGF, has been shown to play a physiologic role in the development and regeneration of the peripheral nervous system, acting on sensory and sympathetic ganglia. In the central nervous system, NGF induces choline acetyltrans...

J. R. Perez-Polo

1987-01-01

260

Neurobiological Effects of Colchicine: Modulation by Nerve Growth Factor.  

National Technical Information Service (NTIS)

To study the effects of exogenously applied nerve growth factor (NGF) on colchicine-induced neurodegeneration in the dentate gyrus of the rat hippocampal formation, colchicine (COLCH) or artificial cerebrospinal fluid (ACSF) was infused into the dorsal hi...

S. Barone, M. Bonner, P. Tandon, J. F. McGinty, H. A. Tilson

1992-01-01

261

Effects of Biosynthetic Human Epidermal Growth Factor on Wound Healing.  

National Technical Information Service (NTIS)

The authors are investigating the ability of biosynthetic epidermal growth factor (EGF) to accelerating healing of cutaneous injuries including middermal wounds and incisions. In preclinical animal studies, EGF significantly increased the rate of epiderma...

G. S. Schultz

1986-01-01

262

Characterizing and engineering antibodies against the epidermal growth factor receptor  

E-print Network

Epidermal growth factor receptor (EGFR) signaling leads to cellular proliferation and migration, and thus EGFR dysregulation can significantly contribute to the survival of tumor cells. Aberrant EGFR signaling due to ...

Chao, Ginger

2008-01-01

263

Human Keratinocytes Are Vanilloid Resistant  

Microsoft Academic Search

BackgroundUse of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain\\/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca2+-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular

László Pecze; Kornélia Szabó; Márta Széll; Katalin Jósvay; Krisztián Kaszás; Erzsébet Kúsz; Tamás Letoha; János Prorok; István Koncz; András Tóth; Lajos Kemény; Csaba Vizler; Zoltán Oláh; Leslie B. Vosshall

2008-01-01

264

Expression of transforming growth factor-?1 during diabetic renal hypertrophy  

Microsoft Academic Search

Expression of transforming growth factor-?1 during diabetic renal hypertrophy. Experimental type I diabetes mellitus is characterized by an early increase in kidney weight and glomerular volume, but changes in gene expression accompanying diabetic renal growth have not been fully elucidated. In the current study, total RNA was extracted from renal cortex and isolated glomeruli of streptozotocin-induced diabetic rats 24 hours,

Stuart J Shankland; James W Scholey; Hao Ly; Kerri Thai

1994-01-01

265

Epidermal growth factor receptor inhibition strategies in oncology  

Microsoft Academic Search

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in

P M Harari

2004-01-01

266

Vascular Endothelial Growth Factor is a Secreted Angiogenic Mitogen  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic

David W. Leung; George Cachianes; Wun-Jing Kuang; David V. Goeddel; Napoleone Ferrara

1989-01-01

267

Epidermal growth factor receptor (EGFR) signaling in cancer  

Microsoft Academic Search

The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). These trans-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Evidence suggests that the EGFR is involved in the pathogenesis and progression of different carcinoma types. The EGFR and EGF-like peptides are often over-expressed in human carcinomas, and

Nicola Normanno; Antonella De Luca; Caterina Bianco; Luigi Strizzi; Mario Mancino; Monica R. Maiello; Adele Carotenuto; Gianfranco De Feo; Francesco Caponigro; David S. Salomon

2006-01-01

268

Immunohistochemical demonstration of nerve growth factor receptor in bovine testis  

Microsoft Academic Search

Nerve growth factor receptor (low-affinity form) was demonstrated immunohistochemically in bovine testis by using a monoclonal mouse anti-human antibody. In the 7-month-old fetus and in the early postnatal testis, the peritubular and intertubular fibroblast-like mesenchymal cells showed a strong reaction. Following differentiation of these cells into Leydig and myoid peritubular cells, the nerve growth factor receptor was no longer expressed.

Karl-Heinz Wrobel; Daniela Bickel; Margit Schimmel; Richard Kujat

1996-01-01

269

The Role of Angiogenic Growth Factors in Arteriogenesis  

Microsoft Academic Search

Background\\/Aims: Collateral vessels restore only about 40% of the maximum dilatory reserve after femoral artery occlusion, whereas complete normalization is reached by increased fluid shear stress (FSS). We studied the role of known potent angiogenic growth factors (separately or in combination) in arteriogenesis by determining their expression in FSS-stimulated collaterals and close-to-collateral infusion of growth factor peptides in a rabbit

Wilma Schierling; Kerstin Troidl; Christian Troidl; Thomas Schmitz-Rixen; Wolfgang Schaper; Inka K. Eitenmüller

2009-01-01

270

Making a tooth: growth factors, transcription factors, and stem cells  

Microsoft Academic Search

Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of odontogenic tissues. Multiple signaling molecules, including BMPs, FGFs, Shh, and Wnt proteins, have been implicated in mediating these tissue interactions. Transcription factors participate in epithelial-mesenchymal interactions via linking the

Yan Ding ZHANG; Zhi CHEN; Yi Qiang SONG; Chao LIU; Yi Ping CHEN

2005-01-01

271

Multilayered Inorganic Microparticles for Tunable Dual Growth Factor Delivery  

PubMed Central

There is an increasing need to control the type, quantity, and timing of growth factors released during tissue healing. Sophisticated delivery systems offering the ability to deliver multiple growth factors with independently tunable kinetics are highly desirable. Here, a multilayered, mineral coated micro-particle (MCMs) platform that can serve as an adaptable dual growth factor delivery system is developed. Bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) are bound to the mineral coatings with high binding efficiencies of up to 80%. BMP-2 is firstly bound onto a 1st mineral coating layer; then VEGF is bound onto a 2nd mineral coating layer. The release of BMP-2 is sustained over a period of 50 days while the release of VEGF is a typical two-phase release with rapid release in the first 14 days and more sustained release for the following 36 days. Notably, the release behaviors of both growth factors can be independently tailored by changing the intrinsic properties of the mineral coatings. Furthermore, the release of BMP-2 can be tuned by changing the thickness of the 2nd layer. This injectable microparticle based delivery platform with tunable growth factor release has immense potential for applications in tissue engineering and regenerative medicine. PMID:25342948

Yu, Xiaohua; Khalil, Andrew; Dang, Phuong Ngoc; Alsberg, Eben

2014-01-01

272

Changes in Serum Levels of Growth Factors in Healthy Individuals After Living Related Liver Donation  

Microsoft Academic Search

IntroductionTo obtain better insight into the kinetics of hepatic growth factors following partial hepatectomy for living related liver donation, we investigated the postoperative changes in serum levels of hepatocyte growth factor (HGF), epidermal growth factor (EGF), vascular epidermal growth factor (VEGF), and transforming growth factor-alpha (TGF-alpha).

E. A. Efimova; M. Glanemann; A. K. Nussler; G. Schumacher; U. Settmacher; S. Jonas; N. Nussler; P. Neuhaus

2005-01-01

273

Vaccinia virus growth factor stimulates tyrosine protein kinase activity of A431 cell epidermal growth factor receptors.  

PubMed Central

Infection of A431 cells with vaccinia virus, or exposure to a mitogenic polypeptide secreted by vaccinia virus-infected cells, induces tyrosine phosphorylation of epidermal growth factor receptors. Images PMID:2431267

King, C S; Cooper, J A; Moss, B; Twardzik, D R

1986-01-01

274

Identification and Partial Purification of a Basic Fibroblast Growth Factor-Like Growth Factor Derived from Bovine Colostrum  

Microsoft Academic Search

Bovine colostrum that had been collected up to 6 h postpartum was fractionated by ammonium sulfate precipitation, and various fractions were examined for basic fibroblast growth factor activity. Activity that stimulated cell growth was detected in the cream fraction, which was purified by isoelectric focusing and heparin affinity chromatography. Three peaks were eluted from the heparin affinity column at ap-

T. Hironaka; H. Ohishi; T. Masaki

1997-01-01

275

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth  

PubMed Central

Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming. PMID:20921199

Sferruzzi-Perri, A N; Owens, J A; Pringle, K G; Roberts, C T

2011-01-01

276

Induction of nerve growth factor and basic fibroblast growth factor mRNA following clenbuterol: Contrasting anatomical and cellular localization  

Microsoft Academic Search

RNase protection assay and in situ hybridization were used to analyze the temporal and cellular changes in nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) mRNA content evoked by the lipophilic ?-adrenergic receptor agonist clenbuterol in adult rat brain. Clenbuterol elicited a threefold increase in NGF mRNA expression which was limited to the cerebral cortex. This increase was

Valerie Y. Hayes; Paul J. Isackson; Michele Fabrazzo; Paolo Follesa; Italo Mocchetti

1995-01-01

277

Insulin like growth factor-I, insulin like growth factor binding protein-1, and insulin in childhood Crohn's disease  

Microsoft Academic Search

Twenty nine children with Crohn's disease were studied before and after treatment with steroids or an elemental diet to assess the effect of disease activity and treatment on serum insulin like growth factor I (IGF-I), insulin like growth factor binding protein (IGFBP-1), and insulin concentrations. The median serum IGF-I concentration was lower in patients with active disease than in matched

A G Thomas; J M Holly; F Taylor; V Miller

1993-01-01

278

Upregulation of transforming growth factor-?1 and vascular endothelial growth factor in cultured keloid fibroblasts: relevance to angiogenic activity  

Microsoft Academic Search

Keloids are tumor-like lesions that result from excessive scar formation during healing of wounds. Histologically, keloids\\u000a show an increased blood vessel density compared with normal dermis or normal scars. However, the angiogenic activity of keloid\\u000a fibroblasts remains unknown. In this study, we investigated angiogenic activity of keloid fibroblasts. Transforming growth\\u000a factor-?1 (TGF-?1) and vascular endothelial growth factor (VEGF) were investigated

Masao Fujiwara; Yasuteru Muragaki; Akira Ooshima

2005-01-01

279

Connective tissue growth factor mediates transforming growth factor b-induced collagen synthesis: down- regulation by cAMP  

Microsoft Academic Search

Connective tissue growth factor (CTGF) is a cysteine-rich peptide synthesized and secreted by fibroblastic cells after activation with transforming growth factor beta (TGF-b) that acts as a downstream mediator of TGF-b-induced fibroblast proliferation. We performed in vitro and in vivo studies to determine whether CTGF is also essential for TGF-b-induced fibroblast collagen synthesis. In vitro studies with normal rat kidney

MATTHEW R. DUNCAN; KEN S. FRAZIER; SUSAN ABRAMSON; SHAWN WILLIAMS; HELENE KLAPPER; XINFAN HUANG; GARY R. GROTENDORST

280

Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression.  

PubMed

Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a(+) LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-beta1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-beta1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis. PMID:18385519

Herfs, Michael; Hubert, Pascale; Kholod, Natalia; Caberg, Jean Hubert; Gilles, Christine; Berx, Geert; Savagner, Pierre; Boniver, Jacques; Delvenne, Philippe

2008-05-01

281

An Effect of Nerve Growth Factor on Parasympathetic Neurite Outgrowth  

NASA Astrophysics Data System (ADS)

Addition of nerve growth factor (NGF) to dissociated parasympathetic ciliary ganglion neurons resulted, within 60 min of its addition, in a 2-fold increase in average neurite length and an accompanying enlargement and spreading of neuronal growth cones. These effects occurred over a concentration range of NGF of 0.1-10 ng/ml and were blocked by affinity-purified antibody to NGF. Epidermal growth factor, fibroblast growth factor, and angiotensin did not have these effects, although insulin at high concentrations was able to induce a response similar to that of NGF. Dissociated sympathetic chain neurons also responded to NGF with increased neurite lengths, and, in addition, NGF considerably extended the survival time of these neurons in culture. However, the effect of NGF on ciliary ganglion neurons was limited to neurite outgrowth, and NGF did not promote the survival of these parasympathetic neurons.

Collins, Frank; Dawson, Andrea

1983-04-01

282

Confirmatory Factor Analysis of the Posttraumatic Growth Inventory  

Microsoft Academic Search

With a sample of 372 participants who had experienced a range of adverse life events, we conducted a confirmatory factor analysis (CFA) of the Posttraumatic Growth Inventory (Tedeschi & Calhoun, 1996). CFA results support the original five-factor structure, as well as indicating that a single higher-order construct with five first-order latent variables provides an acceptable fit.

P. Alex Linley; Leanne Andrews; Stephen Joseph

2007-01-01

283

Cytokines and Growth Factors Expressed by Human Cutaneous Melanoma  

PubMed Central

Cytokines and growth factors have biologic effects that could stimulate tumor growth, invasion and angiogenesis. The incidence of 24 factors was investigated in 25 cultured human melanoma cell lines and in 62 fixed tissues at different stages of the disease. Over 80% of the human melanoma cell lines expressed TGF-?, IL-8, IL-6, VEGF, PDGF-AA and OPN. Significantly higher TGF-?, IGF-1 and IL-15 were determined in primary lesions compared to distant metastases by immunohistochemistry. Illustrating the complexity of the milieu of the tumor microenvironment, some of these factors may have to be considered in targeted therapy. PMID:24281094

Elias, Elias G.; Hasskamp, Joanne H.; Sharma, Bhuvnesh K.

2010-01-01

284

Nerve Growth Factor Potentiates the Neurotoxicity of ? Amyloid  

NASA Astrophysics Data System (ADS)

The role of growth factors in the pathogenesis of Alzheimer disease is unknown. The ?-amyloid protein accumulates abnormally in the brain in Alzheimer disease and is neurotoxic to differentiated hippocampal neurons in culture. Nerve growth factor (NGF) increased the neurotoxic potency of a ?-amyloid polypeptide by a factor of ?100,000, which resulted in a reduction of the ?-amyloid neurotoxic EC50 from 0.1 ?M to 1 pM. This potentiating effect of NGF was reversed by a monoclonal antibody against NGF and was not observed for a variety of other neurotrophic growth factors. Exposure of hippocampal neurons to very low concentrations of ? amyloid alone resulted in a marked induction of immunoreactive NGF receptors. Addition of NGF with ? amyloid resulted in the appearance of neurodegenerative changes in NGF receptor-positive neurons. The early and profound degeneration of hippocampal and basal forebrain cholinergic neurons that occurs in Alzheimer disease may result from a neurotoxic interaction of ? amyloid with NGF.

Yankner, Bruce A.; Caceres, Alfredo; Duffy, Lawrence K.

1990-11-01

285

Insulin-like 3-induced rat preantral follicular growth is mediated by growth differentiation factor 9.  

PubMed

The communication of somatic cells and oocytes by intrafollicular paracrine factors is essential for follicular growth in the ovary. Insulin-like 3 (INSL3) is a theca cell-secreted paracrine factor. Androgens and growth differentiation factor 9 (GDF9), an oocyte-derived growth factor, are essential for follicular development. Using a rat preantral follicle culture model, we examined in the present study the influence of INSL3 on preantral follicular growth and the molecular mechanisms involved. We have observed that the receptor for INSL3, relaxin/insulin-like family peptide receptor 2 (RXFP2), was exclusively expressed in oocytes. Recombinant INSL3 stimulated Gdf9 expression, preantral follicular growth, and testosterone synthesis in vitro. Inhibition of the cAMP/protein kinase A signaling pathway (with cAMP antagonist, 8-bromoadenosine 3',5'-cyclic monophosphorothioate, Rp-isomer) attenuated INSL3-induced Gdf9 expression and preantral follicular growth. Moreover, knocking down Gdf9 expression (with small interfering RNA) or inhibiting GDF9 signaling (with SB431542, an activin receptor-like kinase receptor 5 inhibitor, or specific inhibitor of mothers against decapentaplegic homolog 3) or androgen action (with flutamide, an androgen receptor antagonist) suppressed INSL3-induced preantral follicular growth. In addition, LH and DHT regulated the expression of Insl3 mRNA in preantral follicles. These observations suggest that INSL3 is a key theca cell-derived growth factor for preantral follicle and that its action is mediated by GDF9. PMID:24169563

Xue, Kai; Kim, Ji Young; Liu, Jia-yin; Tsang, Benjamin K

2014-01-01

286

The Retinoid-Related Orphan Receptor ROR? Promotes Keratinocyte Differentiation via FOXN1  

PubMed Central

ROR? is a retinoid-related orphan nuclear receptor that regulates inflammation, lipid metabolism, and cellular differentiation of several non-epithelial tissues. In spite of its high expression in skin epithelium, its functions in this tissue remain unclear. Using gain- and loss-of-function approaches to alter ROR? gene expression in human keratinocytes (HKCs), we have found that this transcription factor functions as a regulator of epidermal differentiation. Among the 4 ROR? isoforms, ROR?4 is prominently expressed by keratinocytes in a manner that increases with differentiation. In contrast, ROR? levels are significantly lower in skin squamous cell carcinoma tumors (SCCs) and cell lines. Increasing the levels of ROR?4 in HKCs enhanced the expression of structural proteins associated with early and late differentiation, as well as genes involved in lipid barrier formation. Gene silencing of ROR? impaired the ability of keratinocytes to differentiate in an in vivo epidermal cyst model. The pro-differentiation function of ROR? is mediated at least in part by FOXN1, a well-known pro-differentiation transcription factor that we establish as a novel direct target of ROR? in keratinocytes. Our results point to ROR? as a novel node in the keratinocyte differentiation network and further suggest that the identification of ROR? ligands may prove useful for treating skin disorders that are associated with abnormal keratinocyte differentiation, including cancer. PMID:23922987

Dai, Jun; Brooks, Yang; Lefort, Karine; Getsios, Spiro; Dotto, G. Paolo

2013-01-01

287

Markers of squamous cell carcinoma in sarco/endoplasmic reticulum Ca2+ ATPase 2 heterozygote mice keratinocytes.  

PubMed

A mutation of Atp2a2 gene encoding the sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) causes Darier's disease in human and null mutation in one copy of Atp2a2 leads to a high incidence of squamous cell tumor in a mouse model. In SERCA2 heterozygote (SERCA2(+/-)) mice keratinocytes, mechanisms involved in partial depletion of SERCA2 gene and its related tumor induction have not been studied. In this study, we investigated Ca(2+) signaling and differential gene expression in primary cultured keratinocytes from SERCA2(+/-) mice. SERCA2(+/-) keratinocytes showed reduced initial increases in intracellular concentration of calcium in response to ATP, a G-protein coupled receptor agonist, and higher store-operated Ca(2+) entry with the treatment of thapsigargin, an inhibitor of SERCA, compared to wild type kerationcytes. Protein expressions of plasma membrane Ca(2+) ATPases, NFATc1, phosphorylated ERK, JNK, and phospholipase gamma1 were increased in SERCA2(+/-) keratinocytes. Using the gene fishing system, we first found in SERCA2(+/-) keratinocytes that gene level of tumor-associated calcium signal transducer 1, crystalline alphaB, procollagen XVIII alpha1, and nuclear factor I-B were increased. Expression of involucrin, a marker of keratinocyte differentiation, was decreased in SERCA2(+/-) keratinocytes. These results suggest that the alterations of Ca(2+) signaling by SERCA2 haploinsufficiency alternate the gene expression of tumor induction and differentiation in keratinocytes. PMID:19840814

Hong, Jeong Hee; Yang, Yu-Mi; Kim, Hyun Sil; Lee, Syng-Ill; Muallem, Shmuel; Shin, Dong Min

2010-09-01

288

Hypoxia-Mediated Induction of Acidic\\/Basic Fibroblast Growth Factor and Platelet-Derived Growth Factor in Mononuclear Phagocytes Stimulates Growth of Hypoxic Endothelial Cells  

Microsoft Academic Search

Wound repair and tumor vascularization depend upon blood vessel growth into hypoxic tissue. Although hypoxia slows endothelial cell (EC) proliferation and suppresses EC basic fibroblast growth factor (bFGF) expression, we report that macrophages (MPs) exposed to PO_2≈ 12-14 torr (1 torr = 133.3 Pa) synthesize and release in a time-dependent manner platelet-derived growth factor (PDGF) and acidic\\/basic FGFs (a\\/bFGFs), which

Keisuke Kuwabara; Satoshi Ogawa; Masayasu Matsumoto; Shin Koga; Matthias Clauss; David J. Pinsky; Peter Lyn; Jeffrey Leavy; Larry Witte; Jacqueline Joseph-Silverstein; Martha B. Furie; Gabriella Torcia; Federico Cozzolino; Takenobu Kamada; David M. Stern

1995-01-01

289

Cultured keratinocytes as biological wound dressings  

Microsoft Academic Search

Human epidermal keratinocytes now can be grown reliably and reproducibly in vitro to form multilayered epithelium. These sheets of cultured keratinocytes have been used successfully to autograft patients with severe burns, leg ulcers and following excision of extensive congenital naevi. Whilst the technique carries the obvious advantage of huge expansion of the initial skin biopsy, thus removing the need for

Richard J Pye

1988-01-01

290

Cultivation and Transplantation of Epidermal Keratinocytes  

Microsoft Academic Search

Transplantation of autologous cultured keratinocytes is the most advanced area of tissue engineering which has clinical application in restoration of skin lesions.In vitro, disaggregated keratinocytes undergo activation and after adhesion and histogenic aggregation form three-dimensional epithelial sheets suitable for grafting on prepared wounds that provide a reparative environment. Epidermal stem cells survive and proliferate in culture, retaining their potential to

V. V Terskikh; A. V. Vasiliev

1999-01-01

291

Thalidomide Increases Human Keratinocyte Migration and Proliferation  

Microsoft Academic Search

Thalidomide is reported to have therapeutic utility in the treatment of pyoderma gangrenosum, Behçet’s disease, aphthous ulcers, and skin wounds. We investigated the effect of thalidomide on human keratinocyte proliferation and migration, two early and critical events in the re-epithelialization of skin wounds. Thalidomide at concentrations less than 1 ?M did not affect keratinocyte viability. Using a thymidine incorporation assay,

Maria R Nasca; Edel A O’Toole; Prema Palicharla; Dennis P West; David T Woodley

1999-01-01

292

Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer  

Microsoft Academic Search

The epidermal growth factor receptor (EGFR) inhibitor erlotinib is approved for treatment of pancreatic cancer but the overall activity is minimal, and known predictive factors for EGFR inhibitor efficacy are infrequent in this disease.We tested the hypothesis that global activation of the EGFR pathway is predictive of EGFR inhibitor efficacy.Pancreatic cancer tumors directly xenografted at surgery were treated with the

Antonio Jimeno; Aik Choon Tan; Jordy Coffa; N. V. Rajeshkumar; Peter Kulesza; Belen Rubio-Viqueira; Jenna Wheelhouse; Begona Diosdado; Wells A. Messersmith; Christine Iacobuzio-Donahue; Anirban Maitra; Fred R. Hirsch; Gerrit A. Meijer; Manuel Hidalgo

2008-01-01

293

Inhibition of Transcription Factor Specificity Protein 1 Alters the Gene Expression Profile of Keratinocytes Leading to Upregulation of Kallikrein-Related Peptidases and Thymic Stromal Lymphopoietin  

Microsoft Academic Search

Transcription factor specificity protein 1 (Sp1) is involved in diverse cellular functions. We recently found that Sp1 was significantly decreased in skin biopsy samples obtained from patients with atopic dermatitis (AD) and had an even greater reduction in AD patients with a history of eczema herpeticum. In the current study, we sought to better understand the role of Sp1 in

Lianghua Bin; Byung E Kim; Clifton F Hall; Sonia M Leach; Donald Y M Leung

2011-01-01

294

Cytokine and Growth Factor Responses After Radiotherapy for Localized Ependymoma  

SciTech Connect

Purpose: To determine the time course and clinical significance of cytokines and peptide growth factors in pediatric patients with ependymoma treated with postoperative radiotherapy (RT). Methods and Materials: We measured 15 cytokines and growth factors (fibroblast growth factor, epidermal growth factor, vascular endothelial growth factor [VEGF], interleukin [IL]-1{beta}, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon-{gamma}, tumor necrosis factor-{alpha}, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and macrophage inflammatory protein-{alpha}) from 30 patients before RT and 2 and 24 h, weekly for 6 weeks, and at 3, 6, 9, and 12 months after the initiation of RT. Two longitudinal models for the trend of log-transformed measurements were fitted, one during treatment and one through 12 months. Results: During RT, log IL-8 declined at a rate of -0.10389/wk (p = 0.0068). The rate of decline was greater (p = 0.028) for patients with an infratentorial tumor location. The decline in IL-8 after RT was significant when stratified by infratentorial tumor location (p = 0.0345) and more than one surgical procedure (p = 0.0272). During RT, the decline in log VEGF was significant when stratified by the presence of a ventriculoperitoneal shunt. After RT, the log VEGF declined significantly at a rate of -0.06207/mo. The decline was significant for males (p = 0.0222), supratentorial tumors (p = 0.0158), one surgical procedure (p = 0.0222), no ventriculoperitoneal shunt (p = 0.0005), and the absence of treatment failure (p = 0.0028). Conclusion: The pro-inflammatory cytokine IL-8 declined significantly during RT and the decline differed according to tumor location. The angiogenesis factor VEGF declined significantly during the 12 months after RT. The decline was greater in males, those without a ventriculoperitoneal shunt, and in those with favorable disease factors, including one surgical procedure, supratentorial tumor location, and tumor control.

Merchant, Thomas E. [Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN (United States)], E-mail: thomas.merchant@stjude.org; Li Chenghong; Xiong Xiaoping [Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN (United States); Gaber, M. Waleed [Department of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN (United States)

2009-05-01

295

Pituitary gland: neuropeptides, neurotransmitters and growth factors.  

PubMed

The hypothalamus receives neuronal afferents from numerous sources including inputs from limbic structures, such as the amygdala and hippocampus, and from brainstem regions involved in the regulation of the cardiovascular system and other autonomic functions. These afferents using a vast array of neurotransmitters and neuropeptides influence the activity of the hypothalamic neurons which synthesize and secrete the hypothalamic releasing and release-inhibiting factors into the hypophyseal portal circulatory system. The afferents can modulate the activity of the hypothalamic neurons by forming synapses on the neuronal cell body, on the nerve terminals in the median eminence or both. The chemicals most frequently used as neurotransmitters are the biogenic amines, including the catecholamines (norepinephrine, dopamine and epinephrine), serotonin, acetylcholine and gamma-aminobutyric acid (GABA). The stimulatory influence of norepinephrine, serotonin, and acetylcholine on the secretion of corticotropin (ACTH) in rodents and man will be discussed, whereas GABA exerts an inhibitory effect on the secretion of ACTH in both man and rodents. These effects appear to be mediated by changes in the secretion of the corticotropin-releasing hormone (CRH) and vasopressin into the hypophyseal portal circulation. Numerous neuropeptides appear to alter the secretion of ACTH in the rat. We will discuss the stimulatory actions of neuropeptide Y (NPY), angiotensin II, and peptides of immune cell origin on the secretion of ACTH and CRH. The opioid peptides inhibit the secretion of CRH into the portal blood, however, they exert a potent stimulatory effect on prolactin secretion in the rat and man.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2571183

Koenig, J I

1989-01-01

296

Molecular characteristics of fibroblast growth factor-fibroblast growth factor receptor-heparin-like glycosaminoglycan complex  

PubMed Central

Fibroblast growth factor (FGF) family plays key roles in development, wound healing, and angiogenesis. Understanding of the molecular nature of interactions of FGFs with their receptors (FGFRs) has been seriously limited by the absence of structural information on FGFR or FGF–FGFR complex. In this study, based on an exhaustive analysis of the primary sequences of the FGF family, we determined that the residues that constitute the primary receptor-binding site of FGF-2 are conserved throughout the FGF family, whereas those of the secondary receptor binding site of FGF-2 are not. We propose that the FGF–FGFR interaction mediated by the ‘conserved’ primary site interactions is likely to be similar if not identical for the entire FGF family, whereas the ‘variable’ secondary sites, on both FGF as well as FGFR mediates specificity of a given FGF to a given FGFR isoform. Furthermore, as the pro-inflammatory cytokine interleukin 1 (IL-1) and FGF-2 share the same structural scaffold, we find that the spatial orientation of the primary receptor-binding site of FGF-2 coincides structurally with the IL-1? receptor-binding site when the two molecules are superimposed. The structural similarities between the IL-1 and the FGF system provided a framework to elucidate molecular principles of FGF–FGFR interactions. In the FGF–FGFR model proposed here, the two domains of a single FGFR wrap around a single FGF-2 molecule such that one domain of FGFR binds to the primary receptor-binding site of the FGF molecule, while the second domain of the same FGFR binds to the secondary receptor-binding site of the same FGF molecule. Finally, the proposed model is able to accommodate not only heparin-like glycosaminoglycan (HLGAG) interactions with FGF and FGFR but also FGF dimerization or oligomerization mediated by HLGAG. PMID:10097093

Venkataraman, Ganesh; Raman, Rahul; Sasisekharan, V.; Sasisekharan, Ram

1999-01-01

297

The role of connective tissue growth factor in skeletal growth and development  

E-print Network

­ extracellular matrix production; IB domain ­ insulin growth factor-binding protein; VWC domain ­ Von Willebrand production, and it is involved in many bio- logical and pathological processes. CTGF has special importance

298

Newly discovered olfactory receptors in epidermal keratinocytes are associated with proliferation, migration, and re-epithelialization of keratinocytes.  

PubMed

Skin contains receptors for various environmental factors. In this issue of the Journal, Busse et al. cloned a new olfactory receptor, OR2AT4, in keratinocytes. They show that the activation of OR2AT4 induces phosphorylation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinases, and that it accelerates wound healing. OR2AT4 may be a promising candidate as a target in clinical drug development. PMID:25318430

Denda, Mitsuhiro

2014-11-01

299

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo  

Microsoft Academic Search

THE development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation1,2. Blood vessel neoformation is also important in the pathogenesis of many disorders1-5, particularly rapid growth and metastasis of solid tumours3-5. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-alpha and

K. Jin Kim; Bing Li; Jane Winer; Mark Armanini; Nancy Gillett; Heidi S. Phillips; Napoleone Ferrara

1993-01-01

300

Differential expression of the angiogenesis growth factors in psoriasis vulgaris  

PubMed Central

Background Angiogenesis has been reported to be one of the contributory factors to the pathogenesis of psoriasis vulgaris. This study aims to compare the expression of different angiogenesis growth factors namely (1) the vascular endothelial growth factor (VEGF) subfamily: A, B, C, D and placenta growth factor (PlGF); (2) nerve growth factor (NGF) and (3) von Willebrand factor (vWFr) in the skins of patients with psoriasis vulgaris and non-psoriatic volunteers. Results Comparative immunohistochemistry study was performed on the paraffin-sectioned psoriatic and healthy skins with the abovementioned markers. VEGF-C (p = 0.016) and NGF (p = 0.027) were expressed intensely in the cases when compared with the controls. The NGF was the only marker that was solely expressed in the cases and absent in all the controls. Conclusion The NGF (angiogenesis) and VEGF-C (lymphangiogenesis) might play a crucial role in the pathogenesis of psoriasis vulgaris and could be researched further as potential new targeted therapies for psoriasis vulgaris. PMID:22537619

2012-01-01

301

Fibroblast growth factor 2 isoforms and cardiac hypertrophy  

Microsoft Academic Search

Fibroblast growth factor 2 (FGF-2), a multifunctional polypeptide that affects cell growth and differentiation and becomes upregulated by stress, is expressed as AUG-initiated 18 kDa FGF-2 or CUG-initiated 21-34 kDa (hi-FGF-2) isoforms. Animal models have provided strong evidence that FGF-2 is essential for the manifestation of overload- and angiotensin-induced cardiac hypertrophy. Nevertheless, studies to-date have not discriminated between the activities

Elissavet Kardami; Zhi-Sheng Jiang; Sarah K. Jimenez; Cheryl J. Hirst; Farah Sheikh; Peter Zahradka; Peter A. Cattini

2004-01-01

302

Insulin-Like Growth Factor I Levels in Healthy Adults  

Microsoft Academic Search

Insulin-like growth factor I (IGF-I) levels mainly reflect secretion of growth hormone (GH) in the body. The aims of this study were to compare different IGF-I assay methods in healthy individuals, test the reliability of the methods and discuss the utility of IGF-I measurement in adults. The Nichols Institute Diagnostics radioimmunoassay was used to evaluate IGF-I in two random population

Kerstin Landin-Wilhelmsen; Per-Arne Lundberg; Georg Lappas; Lars Wilhelmsen

2004-01-01

303

Growth factors with heparin binding affinity in human synovial fluid  

SciTech Connect

Synovial effusions were obtained from the knees of 15 subjects with joint trauma, menisceal or ligamentous injury, or osteoarthritis. Heparin-Sepharose affinity chromatography of these synovial fluids revealed, in general, three major peaks of mitogenic activity as measured by incorporation of /sup 3/H-thymidine into 3T3 cells. Gradient elution patterns showed activities at 0.5M NaCl, which is characteristic of platelet derived growth factor, and at 1.1 M NaCl and 1.6M NaCl, indicative of acidic and basic fibroblast growth factors, respectively. The identities of these mitogenic fractions were confirmed by specific immunologic and receptor-binding assays. The presence of platelet derived, acidic and basic fibroblast growth factors in the synovial fluid may contribute to wound healing in the arthritic joint.

Hamerman, D.; Taylor, S.; Kirschenbaum, I.; Klagsbrun, M.; Raines, E.W.; Ross, R.; Thomas, K.A.

1987-12-01

304

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis.  

PubMed

Cells generate new organelles when stimulated by extracellular factors to grow and divide; however, little is known about how growth and mitogenic signalling pathways regulate organelle biogenesis. Using mitochondria as a model organelle, we have investigated this problem in primary Schwann cells, for which distinct factors act solely as mitogens (neuregulin) or as promoters of cell growth (insulin-like growth factor 1; IGF1). We find that neuregulin and IGF1 act synergistically to increase mitochondrial biogenesis and mitochondrial DNA replication, resulting in increased mitochondrial density in these cells. Moreover, constitutive oncogenic Ras signalling results in a further increase in mitochondrial density. This synergistic effect is seen at the global transcriptional level, requires both the ERK and phosphoinositide 3-kinase (PI3K) signalling pathways and is mediated by the transcription factor ERRalpha. Interestingly, the effect is independent of Akt-TOR signalling, a major regulator of cell growth in these cells. This separation of the pathways that drive mitochondrial biogenesis and cell growth provides a mechanism for the modulation of mitochondrial density according to the metabolic requirements of the cell. PMID:19920079

Echave, Pedro; Machado-da-Silva, Gisela; Arkell, Rebecca S; Duchen, Michael R; Jacobson, Jake; Mitter, Richard; Lloyd, Alison C

2009-12-15

305

Paronychia induced by the epidermal growth factor receptor inhibitor cetuximab.  

PubMed

While the development of epidermal growth factor receptor inhibitors has been hailed as a remarkable triumph in the field of oncology, it has inherited with it a host of cutaneous side-effects that have been increasingly observed in a substantial number of patients in the recent years. One cutaneous manifestation that may inflict significant pain and affect activities of daily living among some of the patients receiving epidermal growth factor receptor inhibitors is paronychia. A case of paronychia associated with the use of cetuximab in the management of KRAS wild-type midrectal adenocarcinoma along with its management has been described. PMID:23161875

Lee, Soo Lin; Tan, Boon Seang; Chan, Lee Chin

2013-09-01

306

Signaling By Fibroblast Growth Factors: The Inside Story  

NSDL National Science Digital Library

Polypeptide growth factors bind to the extracellular domains of cell surface receptors, triggering activation of receptor-intrinsic or receptor-associated protein kinases. Although this central thesis is widely accepted, one family of proteins, the fibroblast growth factors (FGFs), have for more than a decade attracted a research "counterculture" looking for direct FGF actions inside cells. Goldfarb discusses how the search for alternative signaling pathways is moving mainstream with the help of two recent publications reporting specific intracellular targets for FGF and FGF-like proteins.

Mitchell Goldfarb (Mount Sinai School of Medicine;Department of Biochemistry and Molecular Biology REV)

2001-10-30

307

Growth factor receptors signaling in glioblastoma cells: therapeutic implications  

Microsoft Academic Search

In this study, we investigated the protein expression of platelet-derived growth factor receptor (PDGFR), insulin like growth\\u000a factor-1 receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1\\/2) in five\\u000a primary glioblastoma (GB), with a view to their possible use as therapeutic targets. Our results demonstrated that appreciable\\u000a levels of these proteins could be detected in the analysed GB cell

Mia Carapancea; Oana Alexandru; Ani S. Fetea; Laura Dragutescu; Juan Castro; Ada Georgescu; A. Popa-Wagner; Magnus L. Bäcklund; Rolf Lewensohn; Anica Dricu

2009-01-01

308

Transcriptional profiling in human HaCaT keratinocytes in response to kaempferol and identification of potential transcription factors for regulating differential gene expression  

PubMed Central

Kaempferol is the major flavonol in green tea and exhibits many biomedically useful properties such as antioxidative, cytoprotective and anti-apoptotic activities. To elucidate its effects on the skin, we investigated the transcriptional profiles of kaempferol-treated HaCaT cells using cDNA microarray analysis and identified 147 transcripts that exhibited significant changes in expression. Of these, 18 were up-regulated and 129 were down-regulated. These transcripts were then classified into 12 categories according to their functional roles: cell adhesion/cytoskeleton, cell cycle, redox homeostasis, immune/defense responses, metabolism, protein biosynthesis/modification, intracellular transport, RNA processing, DNA modification/ replication, regulation of transcription, signal transduction and transport. We then analyzed the promoter sequences of differentially-regulated genes and identified over-represented regulatory sites and candidate transcription factors (TFs) for gene regulation by kaempferol. These included c-REL, SAP-1, Ahr-ARNT, Nrf-2, Elk-1, SPI-B, NF-?B and p65. In addition, we validated the microarray results and promoter analyses using conventional methods such as real-time PCR and ELISA-based transcription factor assay. Our microarray analysis has provided useful information for determining the genetic regulatory network affected by kaempferol, and this approach will be useful for elucidating gene-phytochemical interactions. PMID:18446059

Kang, Byung Young; Lee, Ki-Hwan; Lee, Yong Sung; Hong, Il; Lee, Mi-Ock; Min, Daejin; Chang, Ihseop; Hwang, Jae Sung; Park, Jun Seong; Kim, Duck Hee

2008-01-01

309

The Antimicrobial Protein REG3A Regulates Keratinocyte Proliferation and Differentiation after Skin Injury  

PubMed Central

Summary Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by kerati-nocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis. PMID:22727489

Lai, Yuping; Li, Dongqing; Li, Changwei; Muehleisen, Beda; Radek, Katherine A.; Park, Hyun Jeong; Jiang, Ziwei; Li, Zhiheng; Lei, Hu; Quan, Yanchun; Zhang, Tian; Wu, Yelin; Kotol, Paul; Morizane, Shin; Hata, Tissa R.; Iwatsuki, Keiji; Tang, Ce; Gallo, Richard L.

2013-01-01

310

Erk5 Controls Slug Expression and Keratinocyte Activation during Wound Healing  

PubMed Central

Reepithelialization during cutaneous wound healing involves numerous signals that result in basal keratinocyte activation, spreading, and migration, all linked to a loosening of cell–cell adhesion structures. The transcription factor Slug is required for this process, and EGF treatment of human keratinocytes induced activating phosphorylation of Erk5 that coincides with slug transcription. Accordingly, ectopic activation of Erk5 led to increased Slug mRNA levels and faster wound healing, whereas keratinocyte migration was totally blocked by Erk5 pathway inhibition. Expression of a shRNA specific for Erk5 strongly diminished Erk5 levels in keratinocytes and significantly decreased their motility response to EGF, along with induction of Slug expression. These Erk5-deprived keratinocytes showed an altered, more compact morphology, along with disruption of desmosome organization. Accordingly, they displayed an altered ability to form cell aggregates. These results implicate a novel EGFR/Erk5/Slug pathway in the control of cytoskeleton organization and cell motility in keratinocytes treated with EGF. PMID:18716062

Arnoux, Valerie; Nassour, Mayssaa; L'Helgoualc'h, Annie; Hipskind, Robert A.

2008-01-01

311

Erk5 controls Slug expression and keratinocyte activation during wound healing.  

PubMed

Reepithelialization during cutaneous wound healing involves numerous signals that result in basal keratinocyte activation, spreading, and migration, all linked to a loosening of cell-cell adhesion structures. The transcription factor Slug is required for this process, and EGF treatment of human keratinocytes induced activating phosphorylation of Erk5 that coincides with slug transcription. Accordingly, ectopic activation of Erk5 led to increased Slug mRNA levels and faster wound healing, whereas keratinocyte migration was totally blocked by Erk5 pathway inhibition. Expression of a shRNA specific for Erk5 strongly diminished Erk5 levels in keratinocytes and significantly decreased their motility response to EGF, along with induction of Slug expression. These Erk5-deprived keratinocytes showed an altered, more compact morphology, along with disruption of desmosome organization. Accordingly, they displayed an altered ability to form cell aggregates. These results implicate a novel EGFR/Erk5/Slug pathway in the control of cytoskeleton organization and cell motility in keratinocytes treated with EGF. PMID:18716062

Arnoux, Valerie; Nassour, Mayssaa; L'Helgoualc'h, Annie; Hipskind, Robert A; Savagner, Pierre

2008-11-01

312

Cytokines and growth factors which regulate bone cell function  

NASA Astrophysics Data System (ADS)

Everybody knows that growth factors are most important in making bone. Hormones enhance bone formation from a long distance. Growth factors promote bone formation as an autocrine or paracrine factor in nearby bone. BMP-2 through BMP-8 are in the TGF-? family. BMP makes bone by enchondral ossification. In bone, IGF-II is most abundant, second, TGF-?, and third IGF-I. TGF-? enhances bone formation mainly by intramembranous ossification in vivo. TGF-? affects both cell proliferation and differentiation, however, TGF-? mainly enhances bone formation by intramembranous ossification. Interestingly, TGF-? is increased by estrogen(E 2), androgen, vitamin D, TGF-? and FGF. IGF-I and IGF-II also enhance bone formation. At present it remains unclear why IGF-I is more active in bone formation than IGF-II, although IGF-II is more abundant in bone compared to IGF-I. However, if only type I receptor signal transduction promotes bone formation, the strong activity of IGF-I in bone formation is understandable. GH, PTH and E 2 promotes IGF-I production. Recent data suggest that hormones containing vitamin D or E 2 enhance bone formation through growth factors. Therefore, growth factors are the key to clarifying the mechanism of bone formation.

Seino, Yoshiki

313

Potentiated Angiogenic Effect of Scatter Factor\\/Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor The Case for Paracrine Amplification of Angiogenesis  

Microsoft Academic Search

Background—Scatter factor\\/hepatocyte growth factor (SF\\/HGF) is a pleiotropic growth factor that stimulates proliferation and migration of endothelial cells (ECs) via the c-Met receptor, present on ECs as well as other cell types, including smooth muscle cells (SMCs). We studied the effects of recombinant human (rh) SF\\/HGF in vitro and in vivo in a rabbit model of hindlimb ischemia. We further

Eric Van Belle; Bernhard Witzenbichler; Donghui Chen; Marcy Silver; Ling Chang; Ralph Schwall; Jeffrey M. Isner

314

Relation of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels to growth retardation in extrahepatic portal vein obstruction  

Microsoft Academic Search

Background  Growth retardation has been described in patients with extrahepatic portal vein obstruction (EHPVO). An abnormal growth hormone\\u000a (GH)–insulin-like growth factor (IGF) axis has been postulated as a possible etiology. We compared anthropometric parameters\\u000a and IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels in patients with EHPVO with their siblings as\\u000a controls.\\u000a \\u000a \\u000a \\u000a Methods and patients  Consecutive patients diagnosed with EHPVO who

Lalit Nihal; Mukta R. Bapat; Pravin Rathi; Nalini S. Shah; Anjana Karvat; Philip Abraham; Shobna J. Bhatia

2009-01-01

315

Human carcinoid cell production of paracrine growth factors that can stimulate fibroblast and endothelial cell growth.  

PubMed

A serotonin-secreting human pancreatic carcinoid cell line (BON) is demonstrated to express transcripts for all three mammalian types of transforming growth factor beta (TGF beta 1, 2, and 3). Similarly, freshly excised carcinoid tumors from six patients were also found to express mRNA for all three of the type-beta TGFs. Medium conditioned by BON cells had detectable TGF beta activity, although most of the activity was latent as determined by radioreceptor assay with and without prior acid treatment. However, nonactivated BON-conditioned medium stimulated DNA synthesis, soft agar growth, and an increase in TGF beta 1 and fibronectin mRNA expression in AKR-2B fibroblasts. In addition, BON-conditioned medium had a potent endothelial cell growth-stimulatory activity. Since the TGF beta s inhibit growth of endothelial cells, the presence of other growth factors was suspected. TGF alpha, c-sis, and basic fibroblast growth factor transcripts were also found to be expressed by the BON carcinoid cells. These data indicate that multiple peptide growth factors may have a paracrine role in the desmoplastic reaction accompanying carcinoid tumors. PMID:1913648

Beauchamp, R D; Coffey, R J; Lyons, R M; Perkett, E A; Townsend, C M; Moses, H L

1991-10-01

316

Differential effect of ethanol and hydrogen peroxide on barrier function and prostaglandin E2 release in differentiated Caco-2 cells: selective prevention by growth factors.  

PubMed

The present study investigates the effects of ethanol and hydrogen peroxide (H(2)O(2)) on the barrier function and prostaglandin E(2) (PGE(2)) release in differentiated Caco-2 cells. Epithelial barrier integrity was estimated by measuring transepithelial electrical resistance (TEER), the transport of reference compounds and lactate dehydrogenase leakage, the PGE(2) release by enzyme immunoassay. Ethanol and H(2)O(2) decreased TEER and increased the transport of lucifer yellow without affecting that of propranolol and phenylalanine. Only the effects of ethanol were accompanied by PGE(2) production and were reversible without causing long-term cytotoxicity. The cyclooxygenase-2 inhibitor, NS-398, prevented the effect of ethanol on both PGE(2) release and TEER, while inhibition of both cyclooxygenase-2 and tyrosine kinase drastically compromised cell viability and TEER recovery. Hepatocyte growth factor, keratinocyte growth factor or insulin prevented the effect of ethanol on cell permeability, but not on PGE(2) release. Their combination prevented the effect of H(2)O(2). In conclusion, ethanol and H(2)O(2) increased paracellular permeability in differentiated Caco-2 cells without affecting transcellular and active transport. Cyclooxygenase-2 stimulated PGE(2) release mediated the reversible effect of ethanol on tight junctions and, meanwhile, contributed to cell survival. Growth factors, normally present in the intestine, exerted a selective protective effect toward paracellular permeability increase induced by irritants. PMID:18481313

Catalioto, Rose-Marie; Festa, Carla; Triolo, Antonio; Altamura, Maria; Maggi, Carlo Alberto; Giuliani, Sandro

2009-02-01

317

Lactobacillus rhamnosus GG inhibits the toxic effects of Staphylococcus aureus on epidermal keratinocytes.  

PubMed

Few studies have evaluated the potential benefits of the topical application of probiotic bacteria or material derived from them. We have investigated whether a probiotic bacterium, Lactobacillus rhamnosus GG, can inhibit Staphylococcus aureus infection of human primary keratinocytes in culture. When primary human keratinocytes were exposed to S. aureus, only 25% of the keratinocytes remained viable following 24 h of incubation. However, in the presence of 10(8) CFU/ml of live L. rhamnosus GG, the viability of the infected keratinocytes increased to 57% (P = 0.01). L. rhamnosus GG lysates and spent culture fluid also provided significant protection to keratinocytes, with 65% (P = 0.006) and 57% (P = 0.01) of cells, respectively, being viable following 24 h of incubation. Keratinocyte survival was significantly enhanced regardless of whether the probiotic was applied in the viable form or as cell lysates 2 h before or simultaneously with (P = 0.005) or 12 h after (P = 0.01) S. aureus infection. However, spent culture fluid was protective only if added before or simultaneously with S. aureus. With respect to mechanism, both L. rhamnosus GG lysate and spent culture fluid apparently inhibited adherence of S. aureus to keratinocytes by competitive exclusion, but only viable bacteria or the lysate could displace S. aureus (P = 0.04 and 0.01, respectively). Furthermore, growth of S. aureus was inhibited by either live bacteria or lysate but not spent culture fluid. Together, these data suggest at least two separate activities involved in the protective effects of L. rhamnosus GG against S. aureus, growth inhibition and reduction of bacterial adhesion. PMID:25015889

Mohammedsaeed, Walaa; McBain, Andrew J; Cruickshank, Sheena M; O'Neill, Catherine A

2014-09-01

318

The biology of stem cell factor, a new hematopietic growth factor involved in stem cell regulation  

Microsoft Academic Search

Summary  Recently, a new hematopoietic growth factor, stem cell factor, the ligand for the c-kit-proto-oncogene, has been cloned. The\\u000a gene for this factor or for its receptor are deleted in two well know series of mice mutants which display pleiotropic stem\\u000a cell defects. Therefore, this factor supposedly plays an important role in stem cell biology. This paper reviews some of the

Maria Cristina Galli; Patricia-Jane V. Giardina; Anna Rita Migliaccio; Giovanni Migliaccio

1993-01-01

319

Modulation of NFAT-5, an outlying member of the NFAT family, in human keratinocytes and skin  

PubMed Central

Background Cyclosporin A (CsA) and tacrolimus block T cell activation by inhibiting the phosphatase calcineurin and preventing translocation from the cytoplasm to the nucleus of the transcription factor Nuclear Factor of Activated T cells (NFAT). NFAT compose a family of transcription factors that are turned on during T cell activation. Aims To study the expression of NFAT-5 mRNA and protein in normal human keratinocytes and to investigate the cellular and subcellular pattern of expression of NFAT-5 in normal human skin and psoriasis, and analyze effects of different agonists and ultraviolet radiation on NFAT-5 in normal human skin. Methods Tissue cultures, Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), Western analysis, immunostaining, confocal microscopy. Results Sequencing of RT-PCR products confirmed the identity of the product that showed 100 % homology with the predicted NFAT-5 sequence. anti-NFAT-5 mainly detected a single band in cultured keratinocytes and dermal fibroblasts using Western analysis. Immunohistochemistry showed that epidermal keratinocytes and dermal fibroblasts in normal human and psoriatic skin express NFAT-5. NFAT-5 showed predominantly nuclear localization in epidermal keratinocytes and dermal fibroblasts within five normal adult skin biopsies. Our data also suggest that UV irradiation reduces NFAT-5 nuclear localization within the epidermis. Unlike NFAT 1-4, NFAT-5/TonEBP was localized to both nucleus and cytoplasm of cultured keratinocytes. Cyclosporin A induces nuclear membrane translocation of NFAT-5 in cultured keratinocytes and raffinose (a hypertonicity inducing agent) induces more nuclear localization of NFAT-5 compared to untreated cells. In addition, differentiation-promoting agonists that induce sustained rise in intracellular calcium did not result in changes in NFAT-5 localization in cultured keratinocytes. Conclusion These studies provide the first observation of expression of NFAT-5/TonEBP mRNA protein in cultured keratinocytes and dermal fibroblasts and possible functional regulation in cultured keratinocytes. CsA and raffinose effects on NFAT-5/TonEBP in cultured keratinocytes suggest diverse intracellular signaling pathways for NFAT-5/TonEBP in these cells, and that NFAT-5/TonEBP might function to translate different extracellular stimuli into appropriate functional responses. PMID:19956430

Al-Daraji, Wael I; Afolayan, John; Zelger, Bettina G; Abdellaoui, Adel; Zelger, Bernhard

2009-01-01

320

Controlling factors for crack growth under creep conditions  

SciTech Connect

The creep crack growth behavior of a class I solid solution alloy, Cu-2.7 at.% Sn, has been investigated. The characteristics of creep crack growth of this class I solid solution alloy are found to be the same as those of pure metals and class II solid solution alloys. Crack growth involves a transient stage and a constant growth rate stage. The crack growth behavior in the transient stage can be characterized by the line integral C/sub 1/, while at steady state neither the path independent line integral C/sub 1/ nor the stress intensity factor applies. However, steady state crack growth can be characterized by the power release rate C/sub rho/ measured using a technique developed by Landes and Begley. The results suggest that the HRR stress field does not exist when extensive damage occurs and that steady state creep crack growth is not due to a stress singularity. Rather, crack growth appears to occur in a progressive manner because of a damage gradient which develops during the transient stage.

Wang, J.S.; Kim, Y.S.; Nix, W.D.

1987-10-01

321

Functional upregulation of system xc- by fibroblast growth factor-2.  

PubMed

The cystine/glutamate antiporter (system xc-) is a Na(+)-independent amino acid transport system. Disruption of this system may lead to multiple effects in the CNS including decreased cellular glutathione. Since multiple neurological diseases involve glutathione depletion, and disruption of growth factor signaling has also been implicated in these diseases, it is possible that some growth factors effects are mediated by regulation of system xc-. We tested the growth factors fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG), neurotrophin-4 (NT-4), and brain derived neurotrophic factor (BDNF) on system xc- mediated 14C-cystine uptake in mixed neuronal and glial cortical cultures. Only FGF-2 significantly increased cystine uptake. The effect was observed in astrocyte-enriched cultures, but not in cultures of neurons or microglia. The increase was blocked by the system xc- inhibitor (s)-4-carboxyphenylglycine, required at least 12 h FGF-2 treatment, and was prevented by the protein synthesis inhibitor cycloheximide. Kinetic analysis indicated FGF-2 treatment increased the V(max) for cystine uptake while the K(m) remained the same. Quantitative PCR showed an increase in mRNA for xCT, the functional subunit of system xc-, beginning at 3 h of FGF-2 treatment, with a dramatic increase after 12 h. Blocking FGFR1 with PD 166866 blocked the FGF-2 effect. Treatment with a PI3-kinase inhibitor (LY-294002) or a MEK/ERK inhibitor (U0126) for 1 h prior to and during the FGF-2 treatment, each partially blocked the increased cystine uptake. The upregulation of system xc- by FGF-2 may be responsible for some of the known physiological actions of FGF-2. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID:21967732

Liu, Xiaoqian; Resch, Jon; Rush, Travis; Lobner, Doug

2012-02-01

322

Factors affecting growth and pigmentation of Penicillium caseifulvum.  

PubMed

Color formation, metabolite production and growth of Penicillium caseifulvum were studied in order to elucidate factors contributing to yellow discoloration of Blue Cheese caused by the mold. A screening experiment was set up to study the effect of pH, concentration of salt (NaCl), P, K, N, S, Mg and the trace metals Fe, Cu, Zn, Mn on yellow color formation, metabolite production and mold growth. Multivariate statistical analysis showed that the most important factor affecting yellow color formation was pH. The most pronounced formation of yellow color, supported by highest amount of colored metabolites, appeared at low pH (pH 4). Mold growth was not correlated to the yellow color formation. Salt concentration was the most important factor affecting mold growth and length of lag phase. Production of secondary metabolites was strongly influenced by both pH and salt concentration. The screening results were used to divide the metabolites into the following three groups: 1) correlated to growth, 2) correlated to color formation, and 3) formed at high pH. Subsequently, a full factorial experiment with factors P, Mg and Cu, showed that low P concentrations (2,000 mg/kg) induced yellow color formation. Among the factors contributing to yellow color formation, pH and salt concentration are easy to control for the cheesemaker, while the third factor, P-concentration, is not. Naturally occurring variations in the P-concentration in milk delivered to Blue Cheese plants, could be responsible for the yellow discoloration phenomenon observed in the dairy industry. PMID:12487445

Suhr, K I; Haasum, I; Steenstrup, L D; Larsen, T O

2002-11-01

323

Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth Factor - A Splice Variant of IGF-1 within the Growth Plate  

PubMed Central

Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation. PMID:24146828

Schlegel, Werner; Raimann, Adalbert; Halbauer, Daniel; Scharmer, Daniela; Sagmeister, Susanne; Wessner, Barbara; Helmreich, Magdalena; Haeusler, Gabriele; Egerbacher, Monika

2013-01-01

324

Herpes simplex virus type-I and pyogenic granuloma: a vascular endothelial growth factor-mediated association?  

PubMed

Pyogenic granuloma (PG) is a vascular endothelial growth factor (VEGF)-related neoangiogenic process. Minor trauma, chronic irritation, certain drugs and pregnancy may favor PG. Viral triggers have not been reported up to date. A 52-year-old woman with hairy-cell leukemia presented because of a 3-month history of a giant pseudotumoral lesion on her left cheek. All prior antibacterial, antifungal and anti-inflammatory treatments had failed. Histology revealed PG with sparse and isolated epithelial cell aggregates. Immunohistochemistry (IHC) identified herpes simplex virus type-I (HSV-I) antigens in the nuclei and cytoplasm of normal-appearing as well as cytopathic epithelial cells, suggesting a chronic, low-productive HSV infection. No HSV-I signal was evidenced in the endothelial cells of the PG. Furthermore, IHC revealed VEGF in the HSV-I infected epithelial cells as well as within the PG endothelial cells. These results incited oral treatment with valaciclovir, and the PG promptly resolved after 2 weeks. These findings suggest that a chronic HSV-I infection might play an indirect, partial role in neoangiogenesis, presumably via HSV-I infection-related stimulation of keratinocytic VEGF production. PMID:24019777

El Hayderi, L; Paurobally, D; Fassotte, M F; André, J; Arrese, J E; Sadzot-Delvaux, C; Ruebben, A; Nikkels, A F

2013-01-01

325

Hyperglycemia to nephropathy via transforming growth factor beta.  

PubMed

Nephropathy is one of the major complications of diabetes which further directs to end stage renal disease. Extensive work has been done to find out the mechanisms involved in pathogenesis of the DN. Now, many researchers have been convinced that almost all of the molecular mediators and intracellular signaling pathways involved in progression of diabetic nephropathy have involvement in transforming growth factor beta (TGF- ?) at some stage. In DN, hyperglycemia causes increase in the expression of TGF- ? genes, TGF- ? proteins and their receptors. Increased glucose level mediates these effects through activation of polyol pathway, protein kinase C pathway, hexosamine pathway, increases advanced glycation end products (AGE) and increases oxidative stress. Hyperglycemia also activates the TGF- ? via activation of glucose transporters (GLUT), angiotensine II and platelet derived growth factor (PDGF). Activated TGF-? further leads to glomerular basement membrane (GBM) thickening and glomerulosclerosis through activation of connective tissue growth factor (CDGF) and vascular endothelial growth factor (VEGF). We have discussed the progression of hyperglycemia to DN via TGF- ?, whose schematic presentation may serve as an effective way to understand the mechanisms and to find out an effective way for the management of diabetic nephropathy. PMID:24919657

Garud, Mayuresh Sudamrao; Kulkarni, Yogesh Anant

2014-05-01

326

Genealogy, expression, and cellular function of transforming growth factor-?  

Microsoft Academic Search

The transforming growth factor-? (TGF-?) gene superfamily expresses a large set of structurally and functionally related polypeptides. Three TGF-? isoforms are regulated by specific genes and have been identified in mammals (TGF-?1, -?2, and -?3). All three-protein isoforms are observed abundantly during development and display overlapping and distinct spatial and temporal patterns of expressions. Each isoform plays a distinct role,

R. Govinden; K. D. Bhoola

2003-01-01

327

NEUROBIOLOGICAL EFFECTS OF COLCHICINE: MODULATION BY NERVE GROWTH FACTOR  

EPA Science Inventory

To study the effects of exogenously applied nerve growth factor (NGF) on colchicine-induced neurodegeneration in the dentate gyrus of the rat hippocampal formation, male Fischer 344 rats (n=75) weighing 275-325 grams received colchicine [COLCH; 2.5 ug/site in 0.5 ul of artificial...

328

Total Factor Productivity Growth in Chinese Industry: 1952–2005  

Microsoft Academic Search

This paper presents new estimates of total factor productivity (TFP) growth in Chinese industry over the past half century that seek to improve on earlier estimates in several respects: better data series are developed for capital and labour; the production function is estimated with fewer restrictive assumptions and corrected for serial correlation; and the TFP estimates are adjusted for cyclical

Selin Ozyurt

2009-01-01

329

Mechanisms of Disease: radiosensitization by epidermal growth factor receptor inhibitors  

Microsoft Academic Search

The epidermal growth factor receptor (EGFR) inhibitors are among the most intensely studied new molecular therapeutic agents. Although response rates have been somewhat disappointing when EGFR inhibitors are used as single-agent therapy for advanced disease, these inhibitors may be more effective as chemo- and radiosensitizers. The first phase III randomized trial evaluating EGFR inhibitors as radiosensitizers in patients with locally

Carolyn I Sartor

2004-01-01

330

Neurotrophic actions of a novel molluscan epidermal growth factor  

Microsoft Academic Search

The mammalian epidermal growth factor (EGF) is expressed in the developing and adult CNS, and it has been implicated in the control of cell proliferation, differentiation, and neurotrophic events. Despite extensive evolutionary conservation of the EGF motif in a range of different types of proteins, secreted EGF homologs with neurotrophic actions have not been reported in invertebrates. In this study,

Petra M. Hermann; Kesteren van R. E; Willem C. Wildering; Sherry D. Painter; John M. Reno; John S. Smith; Santosh B. Kumar; Wijnand P. M. Geraerts; Lowell H. Ericsson; August B. Smit; Andrew G. M. Bulloch; Gregg T. Nagle

2000-01-01

331

Factors Affecting Growth and Pigmentation of Penicillium caseifulvum  

Microsoft Academic Search

Color formation, metabolite production and growth of Penicillium caseifulvum were studied in order to elu- cidate factors contributing to yellow discoloration of Blue Cheese caused by the mold. A screening experi- ment was set up to study the effect of pH, concentration of salt (NaCl), P, K, N, S, Mg and the trace metals Fe, Cu, Zn, Mn on yellow

K. I. Suhr; I. Haasum; L. D. Steenstrup; T. O. Larsen

2002-01-01

332

ARTICLE IN PRESS Platelet-derived growth factor regulates oligodendrocyte  

E-print Network

ARTICLE IN PRESS Platelet-derived growth factor regulates oligodendrocyte progenitor numbers such as multiple sclerosis, it will be important to understand the mechanisms that control oligodendrocyte­xxx sclerosis (MS) (Franklin, 2002; Ludwin, 1987). A major source of remyelinating oligodendrocytes is thought

Richardson, William D.

333

Platelet-derived growth factor in chemotactic for fibroblasts  

Microsoft Academic Search

Chemotaxis assays in modified Boyden chambers were used to detect fibroblast chemoat- tractants in materials released from early-stage inflammatory cells, namely, mast cells, platelets, and neutrophils . Strong attractant activity was found in substances released from platelets . This activity was accounted for mainly by the platelet-derived growth factor (PDGF), which is released from the platelets and which was active

HEIKKI SEPPA; GARY GROTENDORST; SILJA SEPPA; ELLIOTT SCHIFFMANN; GEORGE R. MARTIN

1982-01-01

334

Mast Cells Synthesize, Store, and Release Nerve Growth Factor  

Microsoft Academic Search

Mast cells and nerve growth factor (NGF) have both been reported to be involved in neuroimmune interactions and tissue inflammation. In many peripheral tissues, mast cells interact with the innervating fibers. Changes in the behaviors of both of these elements occur after tissue injury\\/inflammation. As such conditions are typically associated with rapid mast cell activation and NGF accumulation in inflammatory

A. Leon; A. Buriani; R. dal Toso; M. Fabris; S. Romanello; L. Aloe; R. Levi-Montalcini

1994-01-01

335

Inhibition of Myofibroblast Apoptosis by Transforming Growth Factor b 1  

Microsoft Academic Search

Fibroblast differentiation to the myofibroblast phenotype is associated with a -smooth-muscle actin ( a -SMA) expression and regulated by cytokines. Among these, transforming growth factor (TGF)- b 1 and interleukin (IL)-1 b can stimulate and inhibit myofibroblast differentiation, respectively. IL-1 b inhibits a -SMA expres- sion by inducing apoptosis selectively in myofibroblasts via induction of nitric oxide synthase (inducible nitric

Hong-Yu Zhang; Sem H. Phan

336

Vascular endothelial growth factor - basic science and its clinical implications  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is the most important signaling molecule involved in the regulation of the formation of new vessels. Results of recent studies have provided new insights into the molecular mechanisms of the VEGF signaling pathways. VEGF local or systemic application represents a new approach in the therapy of ischemic diseases, especially of the coronary artery disease. Inhibition

Peter Celec; Yoshikazu Yonemitsu

2004-01-01

337

Nerve growth factor alleviates a painful peripheral neuropathy in rats  

Microsoft Academic Search

Nerve growth factor (NGF) reverses some effects of axotomy and prevents toxic neuropathy in adult rodents. We tested the effect of NGF on behavioral hyperalgesia resulting from a chronic constriction injury (CCI) of the sciatic nerve in the rat [5]. CCI rats exhibit thermal hyperalgesia as demonstrated by a reduction of paw withdrawal latency to a noxious thermal stimulus applied

K. Ren; D. A. Thomas; R. Dubner

1995-01-01

338

Discovering Small Molecule Ligands of Vascular Endothelial Growth Factor  

E-print Network

Discovering Small Molecule Ligands of Vascular Endothelial Growth Factor That Block VEGF detection and small molecule microarrays (SMM), this platform consists of three assays: (1) the first assay strategies in drug development.2­13 So far, small molecule compounds have been explored almost exclusively

Zhu, Xiangdong

339

Sulodexide induces hepatocyte growth factor release in humans.  

PubMed

Heparin influences numerous pleiotropic growth factors, including hepatocyte growth factor (HGF), partially by their release from endothelial and extracellular matrix stores. The effects of sulodexide, a heparin-like glycosaminoglycan medication of growing importance in medicine, on HGF liberation are not known. We performed a 2-week open-label sulodexide trial in healthy male volunteers. The drug was initially administered intravenously (i.v.) in a single dose of 1200 Lipoprotein Lipase Releasing Units (LRU), then -- orally for 12 days (500 LRU twice a day), and -- again by i.v. route (1200 LRU) on day 14. Intravenous sulodexide injections were repeatedly found to induce marked and reproducible increases in immunoreactive plasma HGF levels (more than 3500% vs baseline after 10 min, and more than 1200% after 120 min), and remained unchanged when measured 120 min following oral sulodexide administration. The percentage increments in plasma HGF evoked by i.v. sulodexide at both time points and on both days inversely correlated with baseline levels of the growth factor. On day 14, the HGF levels after 120 min and their percentage increase vs baseline were strongly and directly dependent on i.v. sulodexide dose per kg of body weight. This study shows that sulodexide has a novel, remarkable and plausibly biologically important stimulating effect on the release of pleiotropic hepatocyte growth factor in humans. PMID:17258198

Borawski, Jacek; Dubowski, Miroslaw; Pawlak, Krystyna; Mysliwiec, Michal

2007-03-01

340

Fibroblast Growth Factor-2 Alters the Nature of Extinction  

ERIC Educational Resources Information Center

These experiments examined the effects of the NMDA-receptor (NMDAr) antagonist MK801 on reacquisition and re-extinction of a conditioned fear that had been previously extinguished before injection of fibroblast growth factor-2 (FGF2) or vehicle. Recent findings have shown that relearning and re-extinction, unlike initial learning and extinction,…

Graham, Bronwyn M.; Richardson, Rick

2011-01-01

341

Total Chemical Synthesis of Biologically Active Vascular Endothelial Growth Factor  

SciTech Connect

The 204-residue covalent-dimer vascular endothelial growth factor (VEGF, see picture) with full mitogenic activity was prepared from three unprotected peptide segments by one-pot native chemical ligations. The covalent structure of the synthetic VEGF was confirmed by precise mass measurement, and the three-dimensional structure of the synthetic protein was determined by high-resolution X-ray crystallography.

Mandal, Kalyaneswar; Kent, Stephen B.H. (UC)

2011-09-15

342

A micro sustained release system for epidermal growth factor  

Microsoft Academic Search

Summary A technique for ensuring the controlled release of microgram and smaller amounts of biologically active epidermal growth factor (EGF) from polymeric delivery systems is described. We show that albumin in milligram quantities can facilitate the sustained release of picogram amounts of EGF for at least 3 wk. The EGF-containing polymer matrix can be placed directly into cell culture and

Joanne B. Murray; Larry Brown; Robert S. Langer; Michael Klagsburn

1983-01-01

343

Transforming growth factor ? as a therapeutic target in systemic sclerosis  

Microsoft Academic Search

Transforming growth factor ? (TGF-?) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-? expression is implicated in the pathogenesis of fibrosis in systemic sclerosis (SSc); thus, TGF-? represents a molecular therapeutic target in this disease. Anti-TGF-? monoclonal antibody has been evaluated in a small trial of early SSc, with disappointing results. Antibodies against the ?v?6 integrin that prevent

Boris Pasche; John Varga

2009-01-01

344

Fibroblast growth factor signalling: from development to cancer  

Microsoft Academic Search

Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents

Nicholas Turner; Richard Grose

2010-01-01

345

Nerve growth factor regulates nociception in human health and disease  

Microsoft Academic Search

In this review, evidence is marshalled for the hypothesis that nerve growth factor (NGF) regulates nociception in human health and disease. The data from humans complement the studies of NGF in animal inflammatory pain models described else- where in this issue. An attempt is made to unify the role of NGF in inflammatory and neuropathic hyperalgesia. Although largely speculative at

P. ANAND

1995-01-01

346

Carbachol stimulates a different phospholipid metabolism than nerve growth factor and basic fibroblast growth factor in PC12 cells.  

PubMed Central

We have examined 1,2-diglycerides (DGs) generated in PC12 cells in response to the muscarinic agonist carbachol and compared them with those generated in response to the differentiation factors nerve growth factor and basic fibroblast growth factor. Whereas carbachol stimulates a greater release of inositol phosphates, all three agonists generate similar levels of DGs. In this report, we have analyzed the molecular species of PC12 DGs generated in response to these three agonists. Additionally, we have analyzed the molecular species of PC12 phospholipids. The data indicate that 1) after 1 min of either nerve growth factor or basic fibroblast growth factor stimulation, DGs arise primarily from phosphoinositide hydrolysis; 2) in contrast, after 1 min of carbachol stimulation, DG are generated equally by both phosphoinositide and phosphatidylcholine hydrolysis; and 3) after 15 min of stimulation by any of these agonists, DGs are generated largely by phosphatidylcholine hydrolysis, with a smaller component arising from the phosphoinositides. These results suggest that at least part of the mechanism by which PC12 cells distinguish between different agonists is via alterations in phospholipid sources and kinetics of DG generation. PMID:1892912

Pessin, M S; Altin, J G; Jarpe, M; Tansley, F; Bradshaw, R A; Raben, D M

1991-01-01

347

Neurodevelopmental effects of insulin-like growth factor signaling  

PubMed Central

Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development. PMID:22710100

O'Kusky, John; Ye, Ping

2012-01-01

348

[Study on the osteoblast and the growth factors of bone tissue engineering].  

PubMed

To build artificial bone with osteoblast and growth factors is one of popular studies on current bone tissue engineering. This paper has reviewed current studies on the function of the growth factors and the resource, isolation and culture of the osteoblast. It also introduces the interaction of the growth factors, and the development in the transgenosis of the relative growth factors. PMID:12901113

Zhang, L H; Zhang, Q Q

2001-12-01

349

Induction of nerve growth factor receptors on cultured human melanocytes.  

PubMed Central

Normal differentiation and malignant transformation of human melanocytes involve a complex series of interactions during which both genetic and environmental factors play roles. At present, the regulation of these processes is poorly understood. We have induced the expression of nerve growth factor (NGF) receptors on cultured human melanocytes with phorbol 12-tetradecanoate 13-acetate and have correlated this event with the appearance of a more differentiated, dendritic morphology. Criteria for NGF receptor expression included protein accumulation and cell-surface immunofluorescent staining with a monoclonal antibody directed against the human receptor and induction of the messenger RNA species as determined by blot-hybridization studies. The presence of the receptor could also be induced by UV irradiation or growth factor deprivation. The NGF receptor is inducible in cultured human melanocytes, and we suggest that NGF may modulate the behavior of this neural crest-derived cell in the skin. Images PMID:2839841

Peacocke, M; Yaar, M; Mansur, C P; Chao, M V; Gilchrest, B A

1988-01-01

350

Fibroblast Growth Factor 21 (FGF21) Inhibits Chondrocyte Function and Growth Hormone Action Directly at the Growth Plate  

PubMed Central

Fibroblast growth factor 21 (FGF21) modulates glucose and lipid metabolism during fasting. In addition, previous evidence indicates that increased expression of FGF21 during chronic food restriction is associated with reduced bone growth and growth hormone (GH) insensitivity. In light of the inhibitory effects on growth plate chondrogenesis mediated by other FGFs, we hypothesized that FGF21 causes growth inhibition by acting directly at the long bones' growth plate. We first demonstrated the expression of FGF21, FGFR1 and FGFR3 (two receptors known to be activated by FGF21) and ?-klotho (a co-receptor required for the FGF21-mediated receptor binding and activation) in fetal and 3-week-old mouse growth plate chondrocytes. We then cultured mouse growth plate chondrocytes in the presence of graded concentrations of rhFGF21 (0.01–10 ?g/ml). Higher concentrations of FGF21 (5 and 10 ?g/ml) inhibited chondrocyte thymidine incorporation and collagen X mRNA expression. 10 ng/ml GH stimulated chondrocyte thymidine incorporation and collagen X mRNA expression, with both effects prevented by the addition in the culture medium of FGF21 in a concentration-dependent manner. In addition, FGF21 reduced GH binding in cultured chondrocytes. In cells transfected with FGFR1 siRNA or ERK 1 siRNA, the antagonistic effects of FGF21 on GH action were all prevented, supporting a specific effect of this growth factor in chondrocytes. Our findings suggest that increased expression of FGF21 during food restriction causes growth attenuation by antagonizing the GH stimulatory effects on chondrogenesis directly at the growth plate. In addition, high concentrations of FGF21 may directly suppress growth plate chondrocyte proliferation and differentiation. PMID:22696219

Wu, Shufang; Levenson, Amy; Kharitonenkov, Alexei; De Luca, Francesco

2012-01-01

351

Growth of Factor Inputs and Total Factor Productivity in Public Sector Enterprises in India  

Microsoft Academic Search

This study makes an attempt to examine the trend in Total Factor Productivity in the public sector enterprises by estimating and analyzing the contributions made by major factor inputs to the growth rate of not product originating in the public enterprises. It is divided into six sectors. After introducing the problem in the first section, the next three sections deal

Dholakia Bakul H

352

Overexpression of Vascular Permeability Factor\\/Vascular Endothelial Growth Factor and its Receptors in Psoriasis  

Microsoft Academic Search

Summary Psoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and fit-l, are overexpressed by papillary dermal

Michael Detmar; Lawrence F. Brown; Kevin P. Claffey; Kiang-Teck Yeo; Olivier Kocher; Robert W. Jackman; Brygida Berse; Harold F. Dvorak

1994-01-01

353

C/EBP? Gene Targets in Human Keratinocytes  

PubMed Central

C/EBPs are a family of B-Zip transcription factors -TFs- involved in the regulation of differentiation in several tissues. The two most studied members -C/EBP? and C/EBP?- play important roles in skin homeostasis and their ablation reveals cells with stem cells signatures. Much less is known about C/EBP? which is highly expressed in the granular layer of interfollicular epidermis and is a direct target of p63, the master regular of multilayered epithelia. We identified C/EBP? target genes in human primary keratinocytes by ChIP on chip and profiling of cells functionally inactivated with siRNA. Categorization suggests a role in differentiation and control of cell-cycle, particularly of G2/M genes. Among positively controlled targets are numerous genes involved in barrier function. Functional inactivation of C/EBP? as well as overexpressions of two TF targets -MafB and SOX2- affect expression of markers of keratinocyte differentiation. We performed IHC on skin tumor tissue arrays: expression of C/EBP? is lost in Basal Cell Carcinomas, but a majority of Squamous Cell Carcinomas showed elevated levels of the protein. Our data indicate that C/EBP? plays a role in late stages of keratinocyte differentiation. PMID:21072181

Borrelli, Serena; Fanoni, Daniele; Dolfini, Diletta; Alotto, Daniela; Ravo, Maria; Grober, Oli Maria Victoria; Weisz, Alessandro; Castagnoli, Carlotta; Berti, Emilio; Vigano, M. Alessandra; Mantovani, Roberto

2010-01-01

354

Cell-Mediated Delivery of Fibroblast Growth Factor2 and Vascular Endothelial Growth Factor onto the Chick Chorioallantoic Membrane: Endothelial Fenestration and Angiogenesis  

Microsoft Academic Search

Fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF) exert their angiogenic activity by interacting with endothelial cells in a distinct manner. In this study, we investigated the morphological features of endothelial cells of the chick embryo chorioallantoic membrane (CAM) microvasculature after stimulation with FGF2 or VEGF. In order to provide a continuous delivery of the growth factor, we

Domenico Ribatti; Beatrice Nico; Lucia Morbidelli; Sandra Donnini; Marina Ziche; Angelo Vacca; Luisa Roncali; Marco Presta

2001-01-01

355

Basic fibroblast growth factor and vascular endothelial growth factor serum levels in breast cancer patients and healthy women: useful as diagnostic tools?  

Microsoft Academic Search

INTRODUCTION: The aim of the present study was to analyze the relationship between the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in breast cancer cells and the corresponding serum levels in individual patients. The study also evaluated the potential of serum levels of the two growth factors as diagnostic markers in a case–control study.

Anna Maria Granato; Oriana Nanni; Fabio Falcini; Secondo Folli; Gabriella Mosconi; Franca De Paola; Laura Medri; Dino Amadori; Annalisa Volpi

2004-01-01

356

Reciprocal functions of hepatocyte growth factor and transforming growth factor-?1 in the progression of renal diseases: A role for CD44?  

Microsoft Academic Search

Reciprocal functions of hepatocyte growth factor and transforming growth factor-?1 in the progression of renal diseases: A role for CD44? Progressive renal fibrosis occurs via common pathophysiologic mechanisms, regardless of the primary underlying disease. This cascade includes release of cytokines\\/chemokines and toxic molecules, interstitial inflammation, tubular cell damage, accumulation of myofibroblasts, and finally, fibrosis. Hepatocyte growth factor (HGF) and transforming

Sandrine Florquin; Kasper M. A. Rouschop

2003-01-01

357

Transforming growth factor-?-independent role of connective tissue growth factor in the development of liver fibrosis.  

PubMed

We previously identified transforming growth factor (TGF)-? signaling as a fibronectin-independent mechanism of type I collagen fibrillogenesis following adult liver injury. To address the contribution of TGF-? signaling during the development of liver fibrosis, we generated adult mice lacking TGF-? type II receptor (TGF-?IIR) from the liver. TGF-?IIR knockout livers indeed showed a dominant effect in reducing fibrosis, but fibrosis still remained approximately 45% compared with control and fibronectin knockout livers. Unexpectedly, this was accompanied by significant up-regulation of connective tissue growth factor mRNA levels. Organized type I collagen networks in TGF-?IIR knockout livers colocalized well with fibronectin. We provide evidence that elimination of TGF-?IIR is not sufficient to completely prevent liver fibrosis. Our results indicate a TGF-?-independent mechanism of type I collagen production and suggest connective tissue growth factor as its potent mediator. We advocate combined elimination of TGF-? signaling and connective tissue growth factor as a potential therapeutic target by which to attenuate liver fibrosis. PMID:25108224

Sakai, Keiko; Jawaid, Safdar; Sasaki, Takako; Bou-Gharios, George; Sakai, Takao

2014-10-01

358

Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor)  

Microsoft Academic Search

The control of vascular endothelial and muscle cell proliferation is important in such processes as tumor angiogenesis, wound healing, and the pathogenesis of atherosclerosis. Class I heparin-binding growth factor (HBGF-I) is a potent mitogen and chemoattractant for human endothelial cells in vitro and will induce angiogenesis in vivo. RNA gel blot hybridization experiments demonstrate that cultured human vascular smooth muscle

J. A. Winkles; R. Friesel; W. H. Burgess; R. Howk; T. Mehlman; R. Weinstein; T. Maciag

1987-01-01

359

Extrinsic Factors Influencing Fetal Deformations and Intrauterine Growth Restriction  

PubMed Central

The causes of intrauterine growth restriction (IUGR) are multifactorial with both intrinsic and extrinsic influences. While many studies focus on the intrinsic pathological causes, the possible long-term consequences resulting from extrinsic intrauterine physiological constraints merit additional consideration and further investigation. Infants with IUGR can exhibit early symmetric or late asymmetric growth abnormality patterns depending on the fetal stage of development, of which the latter is most common occurring in 70–80% of growth-restricted infants. Deformation is the consequence of extrinsic biomechanical factors interfering with normal growth, functioning, or positioning of the fetus in utero, typically arising during late gestation. Biomechanical forces play a critical role in the normal morphogenesis of most tissues. The magnitude and direction of force impact the form of the developing fetus, with a specific tissue response depending on its pliability and stage of development. Major uterine constraining factors include primigravida, small maternal size, uterine malformation, uterine fibromata, early pelvic engagement of the fetal head, aberrant fetal position, oligohydramnios, and multifetal gestation. Corrective mechanical forces similar to those that gave rise to the deformation to reshape the deformed structures are often used and should take advantage of the rapid postnatal growth to correct form. PMID:22888434

Moh, Wendy; Graham, John M.; Wadhawan, Isha; Sanchez-Lara, Pedro A.

2012-01-01

360

Transforming growth factor (TGF)-. alpha. in human milk  

SciTech Connect

Transforming growth factor (TGF)-{alpha} and epidermal growth factor (EGF) were measured in human milk by means of homologous radioimmunoassay. As previously reported, EGF concentration in the colostrum was approximately 200 ng/ml and decreased to 50 ng/ml by day 7 postpartum. The value of immunoreactive (IR)-TGF-{alpha} was 2.2-7.2 ng/ml, much lower than that of EGF. In contrast to EGF, the concentration of IR-TGF-{alpha} was fairly stable during the 7 postpartum days. There was no relationship between the concentrations of IR-TGF-{alpha} and IR-EGF, suggesting that the regulatory mechanism in the release of the two growth factors is different. On gel-chromatography using a Sephadex G-50 column, IR-EGF appeared in the fraction corresponding to that of authentic human EGF, while 70%-80% of the IR-TGF-{alpha} was eluted as a species with a molecular weight greater than that of authentic human TGF-{alpha}. Although the physiological role of TGF-{alpha} in milk is not known, it is possible that it is involved in the development of the mammary gland and/or the growth of newborn infants.

Okada, Masaki; Wakai, Kae; Shizume, Kazuo (Research Institute for Growth Sciences, Tokyo (Japan)); Iwashita, Mitsutoshi (Tokyo Women's Medical College (Japan)); Ohmura, Eiji; Kamiya, Yoshinobu; Murakami, Hitomi; Onoda, Noritaka; Tsushima, Toshio

1991-01-01

361

Epidermal growth factor, but not cortisol, suppresses fibre growth in cultured follicles  

Microsoft Academic Search

This experiment was conducted to examine the role of cortisol and epidermal growth factor (EGF) in the growth of cultured follicles. Intact Tukidale and Romney anagen hair follicles (n=12\\/dose) were isolated from skin strips and maintained in Williams E medium supplemented with 1 mM L-glutamine, Fungizone and antibiotics. Measurement of the changes in length of the follicles was made using

H. R Ansari-Renani; P. I Hynd

2004-01-01

362

Polysomnographic Sleep, Growth Hormone Insulin-like Growth Factor-I Axis, Leptin, and Weight Loss  

Microsoft Academic Search

Short sleep appears to be strongly associated with obesity and altered metabolic function, and sleep and growth hormone (GH) secretion seems interlinked. In obesity, both the GH-insulin-like-growth-factor-I (GH-IGF-I) axis and sleep have been reported to be abnormal, however, no studies have investigated sleep in relation to the GH-IGF-I axis and weight loss in obese subjects. In this study polygraphic sleep

Michael H. Rasmussen; Gordon Wildschiřdtz; Anders Juul; Jannik Hilsted

2008-01-01

363

Vascular Endothelial Growth Factor C Promotes Tumor Lymphangiogenesis and Intralymphatic Tumor Growth1  

Microsoft Academic Search

Many solid tumors produce vascular endothelial growth factor C (VEGF-C), and its receptor, VEGFR-3, is expressed in tumor blood vessels. To study the role of VEGF-C in tumorigenesis, we implanted MCF-7 human breast carcinoma cells overexpressing recombinant VEGF-C orthotopically into severe combined immunodeficient mice. VEGF-C increased tumor growth, but unlike VEGF, it had little effect on tumor angiogenesis. Instead, VEGF-C

Terhi Karpanen; Mikala Egeblad; Marika J. Karkkainen; Hajime Kubo; Kari Alitalo

2001-01-01

364

Regulation of GM-CSF and IL-3 production from the murine keratinocyte cell line PAM 212 following exposure to ultraviolet radiation  

SciTech Connect

Ultraviolet radiation (UVR) exposure induces profound changes in the synthesis and secretion of various cytokines both in vivo and in vitro. Little is known regarding the mechanism of these responses. This investigation evaluated the effects of UVR on the ability of a murine keratinocyte line (PAM 212) to produce interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF). Subconfluent rapidly dividing PAM 212 cells were shown by RNA slot-blot hybridization studies to have increased levels of mRNA for both IL-3 and GM-CSF within 1 h of UVR exposure. However, only GM-CSF-specific bioactivity, as determined by antibody neutralization studies, was shown to increase above baseline in cell supernatants. Cells grown to confluence responded differently to UVR. Under these culture conditions an apparent decrease in bioactivity was detected after UVR exposure for both growth factors, and no change in mRNA levels was detected. In addition to culture density, removal of extracellular calcium or sodium during irradiation, treatment with amiloride, or inhibition of new mRNA synthesis with cordycepin was shown to influence the UVR-induced alteration in release of IL-3 or GM-CSF bioactivity from both confluent and subconfluent PAM 212 cells. These results demonstrate that UVR influences the release of the colony stimulating factors GM-CSF and IL-3 from keratinocyte, and suggests that the state of cell growth and conditions of membrane ion transport influence the mechanisms regulating secretion of those factors.

Gallo, R.L.; Staszewski, R.; Sauder, D.N.; Knisely, T.L.; Granstein, R.D. (Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Boston (USA))

1991-08-01

365

Key nutrients and growth factors for the neonatal gastrointestinal tract.  

PubMed

The nutritional support of gastrointestinal growth and function is an important consideration in the clinical care of neonatal infants. In most health infants, the provision of either breast milk or formula seems to support normal intestinal mucosal growth, but the most significant advantages of breast milk may be for host defense or gut barrier-related functions that are involved in reducing infection. The specific effects of various milk-borne growth factors on key mucosal immune and barrier functions are likely to provide valuable new clues to the advantages of human milk. A substantial number of preterm, low-birth weight babies or those suffering from compromised intestinal function, however, often cannot tolerate oral feedings and instead receive TPN. The consequences of TPN on gastrointestinal function and how this contributes to morbidity of these infants warrants further study, with respect to both clinical and basic research questions. Although enteral nutrition seems to be a critical stimulus for intestinal function, the minimal amounts and composition of nutrients necessary to maintain specific intestinal functions remain to be established. The experimental tools exist to start defining the specific nutrient requirements for the infant gut and some of these nutrients are known (e.g., glutamate, glutamine, and threonine). Peptide growth factors and gut hormones clearly play a role in gut growth and in several ways mediate the trophic actions of enteral nutrition. Although a number of these growth factors are good candidates for therapeutic use, their clinical application in the management of gastrointestinal insufficiency and disease has been slow. The emergence of GLP-2 as a trophic peptide that seems to target the gut is a promising candidate on the horizon. PMID:11917740

Burrin, Douglas G; Stoll, Barbara

2002-03-01

366

Repression of Vascular Endothelial Growth Factor A in Glioblastoma Cells Using Engineered Zinc Finger Transcription Factors  

Microsoft Academic Search

Angiogenic factors are necessary for tumor proliferation and thus are attractive therapeutic targets. In this study, we have used engineered zinc finger protein (ZFP) transcription factors (TFs) to repress expression of vascular endothelial growth factor (VEGF)-A in human cancer cell lines. We create potent transcriptional repressors by fusing a designed ZFP targeted to the VEGF-A promoter with either the ligand-binding

Andrew W. Snowden; Lei Zhang; Fyodor Urnov; Carolyn Dent; Yann Jouvenot; Xiaohong Zhong; Edward J. Rebar; Andrew C. Jamieson; H. Steven Zhang; Siyuan Tan; Casey C. Case; Carl O. Pabo; Alan P. Wolffe; Philip D. Gregory

2003-01-01

367

Regulation of Vascular Endothelial Growth Factor Production and Angiogenesis by the Cytoplasmic Tail of Tissue Factor  

Microsoft Academic Search

Tissue factor (TF), a transmembrane receptor for coagulation factor VII\\/VIIa, is aberrantly expressed in human cancers. We demonstrated a significant correlation between TF and vascular endothelial growth factor (VEGF) production in 13 human malignant melanoma cell lines (r2 = 0.869, P<0.0001). Two of these cell lines, RPMI-7951, a high TF and VEGF producer, and WM-115, a low TF and VEGF

Keisuke Abe; Mamoru Shoji; Jiang Chen; Angelika Bierhaus; Indrani Danave; Cornelia Micko; Katherine Casper; Dirck L. Dillehay; Peter P. Nawroth; Frederick R. Rickles

1999-01-01

368

Temporins A and B Stimulate Migration of HaCaT Keratinocytes and Kill Intracellular Staphylococcus aureus  

PubMed Central

The growing number of microbial pathogens resistant to available antibiotics is a serious threat to human life. Among them is the bacterium Staphylococcus aureus, which colonizes keratinocytes, the most abundant cell type in the epidermis. Its intracellular accumulation complicates treatments against resulting infections, mainly due to the limited diffusion of conventional drugs into the cells. Temporins A (Ta) and B (Tb) are short frog skin antimicrobial peptides (AMPs). Despite extensive studies regarding their antimicrobial activity, very little is known about their activity on infected cells or involvement in various immunomodulatory functions. Here we show that Tb kills both ATCC-derived and multidrug-resistant clinical isolates of S. aureus within infected HaCaT keratinocytes (80% and 40% bacterial mortality, respectively) at a nontoxic concentration, i.e., 16 ?M, whereas a weaker effect is displayed by Ta. Furthermore, the peptides prevent killing of keratinocytes by the invading bacteria. Further studies revealed that both temporins promote wound healing in a monolayer of HaCaT cells, with front speed migrations of 19 ?m/h and 12 ?m/h for Ta and Tb, respectively. Migration is inhibited by mitomycin C and involves the epidermal growth factor receptor (EGFR) signaling pathway. Finally, confocal fluorescence microscopy indicated that the peptides diffuse into the cells. By combining antibacterial and wound-healing activities, Ta and Tb may act as multifunctional mediators of innate immunity in humans. Particularly, their nonendogenous origin may reduce microbial resistance to them as well as the risk of autoimmune diseases in mammals. PMID:24514087

Di Grazia, Antonio; Luca, Vincenzo; Segev-Zarko, Li-av T.; Shai, Yechiel

2014-01-01

369

Temporins A and B stimulate migration of HaCaT keratinocytes and kill intracellular Staphylococcus aureus.  

PubMed

The growing number of microbial pathogens resistant to available antibiotics is a serious threat to human life. Among them is the bacterium Staphylococcus aureus, which colonizes keratinocytes, the most abundant cell type in the epidermis. Its intracellular accumulation complicates treatments against resulting infections, mainly due to the limited diffusion of conventional drugs into the cells. Temporins A (Ta) and B (Tb) are short frog skin antimicrobial peptides (AMPs). Despite extensive studies regarding their antimicrobial activity, very little is known about their activity on infected cells or involvement in various immunomodulatory functions. Here we show that Tb kills both ATCC-derived and multidrug-resistant clinical isolates of S. aureus within infected HaCaT keratinocytes (80% and 40% bacterial mortality, respectively) at a nontoxic concentration, i.e., 16 ?M, whereas a weaker effect is displayed by Ta. Furthermore, the peptides prevent killing of keratinocytes by the invading bacteria. Further studies revealed that both temporins promote wound healing in a monolayer of HaCaT cells, with front speed migrations of 19 ?m/h and 12 ?m/h for Ta and Tb, respectively. Migration is inhibited by mitomycin C and involves the epidermal growth factor receptor (EGFR) signaling pathway. Finally, confocal fluorescence microscopy indicated that the peptides diffuse into the cells. By combining antibacterial and wound-healing activities, Ta and Tb may act as multifunctional mediators of innate immunity in humans. Particularly, their nonendogenous origin may reduce microbial resistance to them as well as the risk of autoimmune diseases in mammals. PMID:24514087

Di Grazia, Antonio; Luca, Vincenzo; Segev-Zarko, Li-Av T; Shai, Yechiel; Mangoni, Maria Luisa

2014-05-01

370

Effects of Growth Hormone and Insulin-Like Growth Factor I on Muscle in Mouse Models of Human Growth Disorders  

Microsoft Academic Search

The precise effects of growth hormone (GH) and insulin-like growth factor I (IGF-I) on muscle development and physiology are relatively unknown. Furthermore, there have been conflicting reports on the effects of GH\\/IGF-I on muscle. Distinguishing the direct effects of GH versus those of IGF-I is problematic, but animal models with altered GH\\/IGF-I action could help to alleviate some of the

Ryan P. Clark; Mark Schuenke; Stephanie M. Keeton; Robert S. Staron; John J. Kopchick

2006-01-01

371

Keratinocyte-Targeted Overexpression of the Glucocorticoid Receptor Delays Cutaneous Wound Healing  

PubMed Central

Delayed wound healing is one of the most common secondary adverse effects associated to the therapeutic use of glucocorticoid (GC) analogs, which act through the ligand-dependent transcription factor GC-receptor (GR). GR function is exerted through DNA-binding-dependent and –independent mechanisms, classically referred to as transactivation (TA) and transrepression (TR). Currently both TA and TR are thought to contribute to the therapeutical effects mediated by GR; however their relative contribution to unwanted side effects such as delayed wound healing is unknown. We evaluated skin wound healing in transgenic mice with keratinocyte-restricted expression of either wild type GR or a mutant GR that is TA-defective but efficient in TR (K5-GR and K5-GR-TR mice, respectively). Our data show that at days (d) 4 and 8 following wounding, healing in K5-GR mice was delayed relative to WT, with reduced recruitment of granulocytes and macrophages and diminished TNF-? and IL-1? expression. TGF-?1 and Kgf expression was repressed in K5-GR skin whereas TGF-?3 was up-regulated. The re-epithelialization rate was reduced in K5-GR relative to WT, as was formation of granulation tissue. In contrast, K5-GR-TR mice showed delays in healing at d4 but re-established the skin breach at d8 concomitant with decreased repression of pro-inflammatory cytokines and growth factors relative to K5-GR mice. Keratinocytes from both transgenic mice closed in vitro wounds slower relative to WT, consistent with the in vivo defects in cell migration. Overall, the delay in the early stages of wound healing in both transgenic models is similar to that elicited by systemic treatment with dexamethasone. Wound responses in the transgenic keratinocytes correlated with reduced ERK activity both in vivo and in vitro. We conclude that the TR function of GR is sufficient for negatively regulating early stages of wound closure, while TA by GR is required for delaying later stages of healing. PMID:22235328

Sanchis, Ana; Alba, Lorena; Latorre, Victor; Sevilla, Lisa M.; Perez, Paloma

2012-01-01

372

Regulation of in vitro growth of preantral follicles by growth factors in goats.  

PubMed

Goat preantral follicles were cultured to investigate the effects of insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on the in vitro growth and viability of oocytes. Preantral follicles were isolated mechanically and enzymatically (using collagenase and DNase) from prepuberal goat ovaries. The working medium was composed of Defined Eagle's Minimum Essential Medium (DMEM) supplemented with HEPES (20 mM), 10% fetal calf serum (FCS), hypoxanthine (2 mM), dibutyryl cyclic adenosine 3',5'-monophosphate (dbcAMP) (2 mM), penicillin (75 ng/ml) and streptomycin (50 ng/ml). The culture medium consisted of the working medium with follicle stimulating hormone (FSH) (100 ng/ml) and hydrocortisone (40 ng/ml) added. In the experiment, goat preantral follicles were cultured for 9 days in the culture medium and in the culture medium supplemented with either IGF-I (100 ng/ml), EGF (50 ng/ml), bFGF (50 ng/ml) or IGF-I (100 ng/ml)+EGF (50 ng/ml). The results indicated that IGF-I (100 ng/ml) effectively maintained the survival of oocytes and promoted their growth; EGF (50 ng/ml) enhanced the survival rate of oocytes but had a negative effect on oocyte growth; bFGF (50 ng/ml) stimulated oocyte survival but had no obvious effect on their growth while IGF-I (100 ng/ml) and EGF (50 ng/ml) in combination had a greater effect on both survival and growth rate of oocytes than IGF-I or EGF alone. The supplementation of IGF-1 and EGF to the culture medium is recommended in the culture of goat preantral follicles. PMID:15760665

Zhou, Huanmin; Zhang, Yong

2005-04-01

373

A high molecular arabinogalactan from Ribes nigrum L.: influence on cell physiology of human skin fibroblasts and keratinocytes and internalization into cells via endosomal transport.  

PubMed

An arabinogalactan protein (F2) was isolated in 1.5% yield from the seeds of Ribes nigrum L. (Grossulariaceae) by aqueous extraction and a one-step anion exchange chromatography on DEAE-Sephacel with 24% galactose, 43% arabinose, and 20% xylose as main carbohydrate residues. Methylation analysis revealed the presence of a 1,3-/1,3,6-galactose backbone, side chains from arabinose in different linkages, and terminal xylose residues. The polysaccharide which turned out to be an arabinogalactan protein had a molecular weight of >10(6) Da and deaggregated under chaotropic conditions. The cellular dehydrogenase activities (MTT and WST-1 tests) of human skin cells (fibroblasts, keratinocytes) as well as the proliferation rate of keratinocytes (BrdU incorporation ELISA) were significantly stimulated by the polymer at 10 and 100 microg/mL. F2 had no influence on differentiation status of keratinocytes and did not exhibit any cytotoxic potential (LDH test). The biological activity of F2 was not dependent on the high molecular weight. Influence of the polysaccharide on the gene expression of specific growth factors, growth factor receptors, signal proteins and marker proteins for skin cell proliferation, and differentiation by RT-PCR could not be shown. Gene array investigations indicated an increased expression of various genes encoding for catabolic enzymes, DNA repair, extracellular matrix proteins, and signal transduction factors. Removal of terminal arabinose residues by alpha-L-arabinofuranosidase did not influence the activity toward skin cells, while the treatment with beta-D-galactosidase yielded an inactive polysaccharide. The FITC-labeled polysaccharide was incorporated in a time-dependent manner into human fibroblasts (laser scanning microscopy) via endosomal transport. This internalization of the polysaccharide was inhibited by Cytochalasin B. PMID:19368904

Zippel, Janina; Deters, Alexandra; Pappai, Dirk; Hensel, Andreas

2009-05-26

374

Comparisons of norcantharidin cytotoxic effects on oral cancer cells and normal buccal keratinocytes  

Microsoft Academic Search

Norcantharidin (NCTD) is the demethylated analogue of cantharidin. In this study, multi-parameter assessments of morphological alterations, clonogenic efficiency, cell growth curves, DNA synthesis, and DNA strand break were employed to determine and compare the cytotoxic effects of NCTD on oral cancer KB cell line and normal buccal keratinocytes. The results showed NCTD induced significant cytotoxicity in KB cells after 24

S. H Kok; C. Y Hong; M. Y. P Kuo; C. H. K Lee; J. J Lee; I. U Lou; M. S Lee; M Hsiao; S. K Lin

2003-01-01

375

Modulation of Keratinocyte Gene Expression and Differentiation by PPAR-Selective Ligands and Tetradecylthioacetic Acid  

Microsoft Academic Search

Peroxisome proliferator-activated receptors (PPARs) are pleiotropic regulators of growth and differentiation of many cell types. We have performed a comprehensive analysis of the expression of PPARs, transcriptional cofactors, and marker genes during differentiation of normal human keratinocytes using a combination of reverse transcriptase polymerase chain reaction, Northern and Western blotting, and immunohistochemistry. PPAR? was the predominant PPAR subtype in human

Majken Westergaard; Jeanette Henningsen; Morten Lyne Svendsen; Claus Johansen; Uffe Birk Jensen; Henrik Daa Schrřder; Irina Kratchmarova; Rolf Kristian Berge; Lars Iversen; Lars Bolund; Knud Kragballe; Karsten Kristiansen

2001-01-01

376

Expression of a Secreted Fibroblast Growth Factor Binding Protein-1 (FGFBP1) in Angioproliferative Kaposi Sarcoma  

PubMed Central

Objective Kaposi’s sarcoma (KS) is an angioproliferative disease frequently seen in patients with the acquired immunodeficiency syndrome (AIDS). Previous studies suggest that the HIV-1 protein Tat and Fibroblast Growth Factor 2 (FGF-2) have synergistic angiogenic effects in AIDS-KS tumors. However, the mechanisms by which FGF-2 is released and activated in KS tumors are not clearly defined. We carried out this study to determine whether an FGF-binding protein (FGFBP1 or BP1) that enhances the angiogenic activity of FGF-2 is expressed in AIDS-KS tumors, and to define whether BP1, FGF-2, and HIV-Tat protein-protein interactions could play a potential clinically role in the pathogenesis of AIDS-KS. Methods BP1 was localized in AIDS-KS lesions by immunohistochemistry and in situ hybridization studies. The binding of radiolabeled FGF-2 to His-tagged BP1 or the FGF-receptor 1 was assessed in the presence and absence of HIV-Tat and other viral proteins. Mice carrying tetracycline-regulated BP1 transgene mice were used to determine whether activation of BP1 during wound healing induces KS-like lesions. Results BP1 expression was detected in AIDS-KS tumor keratinocytes, spindle cells, and infiltrating mononuclear cells. In addition, HIV-Tat competed for the binding of FGF-2 to immobilized BP1, but does not affect the interactions of FGF-2 with its high affinity receptor (FGFR-1). In contrast, two other HIV-proteins, Nef and gp120, did not affect the binding of FGF-2 to BP1 or to FGFR-1. Finally, up-regulation of BP1 expression in tetracycline-regulated –conditional BP1 transgenic mice subjected to skin wounds, induced KS-like skin lesions. Conclusion Taking into consideration the results of previous studies showing that both HIV-Tat and BP1 enhance the mitogenic and angiogenic activity of locally-stored FGF-2, both in vitro and in vivo, our findings suggest a novel mechanism by which the release and activity of FGFs can be modulated in AIDS-KS tumors by HIV-Tat as well as BP1.

Ray, Patricio E; Al-Attar, Ali; Liu, Xue-Hui; Das, Jharna R; Tassi, Elena; Wellstein, Anton

2014-01-01

377

Growth Factors and Gene Expression: Fresh Insights from Arrays  

NSDL National Science Digital Library

Gene array technology allows researchers to evaluate patterns of gene expression at a genome-wide level. Two recent papers have applied this powerful technique to characterize how gene expression is changed in response to growth factors and mitogens. The studies focus on two important questions concerning specificity in signal transduction. First, are the multiple signaling pathways activated by a single growth factor receptor used to activate gene expression, and if so, do these pathways act combinatorially? Second, how does the initial genetic response of a cell to a signal stimulus relate to the patterns of gene expression that determine that cell's ultimate biological response to the stimulus? Hill and Treisman take a critical look at what these array technology studies tell us concerning these questions and discuss technical issues arising from them.

Caroline S. Hill (Developmental Signalling Laboratory; REV); Richard Treisman (London;Imperial Cancer Research Fund REV)

1999-10-12

378

Self-inactivating MLV vectors have a reduced genotoxic profile in human epidermal keratinocytes.  

PubMed

Transplantation of epithelia derived from keratinocyte stem cells transduced by retroviral vectors is a potential therapy for epidermolysis bullosa (EB), a family of inherited skin adhesion defects. The biosafety characteristics of retroviral vectors in keratinocytes are, however, poorly defined. We developed self-inactivating (SIN) vectors derived from the Moloney murine leukemia (MLV) and the human immunodeficiency (HIV) viruses expressing therapeutic levels of LAMB3, a transgene defective in junctional EB, and tested their integration profile in human primary keratinocytes. The SIN-HIV vector showed the expected preference for transcribed genes while the SIN-MLV vector integrated preferentially in regulatory elements, but showed a significantly lower tendency to target cell growth-related genes, transcription start sites and epigenetically defined promoters compared with a wild-type MLV vector in an epithelial cell context. A quantitative gene expression assay in individual keratinocyte clones showed that MLV-derived vectors deregulate expression of targeted genes at a lower frequency than in hematopoietic cells, and that the SIN-MLV design has the lowest activity compared to both MLV and SIN-HIV vectors. This study indicates that SIN-MLV vectors may have a better safety profile in keratinocyte than in hematopoietic cells, and be a reasonable alternative to lentiviral vectors for gene therapy of inherited skin disorders. PMID:23615186

Cavazza, A; Cocchiarella, F; Bartholomae, C; Schmidt, M; Pincelli, C; Larcher, F; Mavilio, F

2013-09-01

379

KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased proliferation and apoptosis. Black-Right-Pointing-Pointer KLF10{sup -/-} MEFs yielded more colonies than wild-type one with H-Ras transfection. Black-Right-Pointing-Pointer KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription. Black-Right-Pointing-Pointer KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription. -- Abstract: Krueppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription, which was independent of p53 and Sp1 binding sites in p21{sup WAF1/CIP1} promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription.

Song, Ki-Duk [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of) [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Kim, Duk-Jung [The Institute of Hankook Life Science, 7-9 Myungryun-dong, Jongno-gu, Seoul 110-521 (Korea, Republic of)] [The Institute of Hankook Life Science, 7-9 Myungryun-dong, Jongno-gu, Seoul 110-521 (Korea, Republic of); Lee, Jong Eun [Department of Anatomy, College of Medicine, Yonsei University, Seoul 120-752 (Korea, Republic of)] [Department of Anatomy, College of Medicine, Yonsei University, Seoul 120-752 (Korea, Republic of); Yun, Cheol-Heui [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of) [Center for Agricultural Biomaterials, Seoul National University, Seoul 151-921 (Korea, Republic of); Laboratory of Protein Engineering and Comparative Immunology, School of Agricultural Biotechnology, Seoul National University, Seoul 151-921 (Korea, Republic of); Lee, Woon Kyu, E-mail: wklee@inha.ac.kr [Laboratory of Developmental Genetics, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of); Brain Korea 21 Center for Advanced Medical Education, School of Medicine, Inha University, Incheon 400-712 (Korea, Republic of)

2012-03-09

380

Extract of Coptidis rhizoma induces cytochrome-c dependent apoptosis in immortalized and malignant human oral keratinocytes.  

PubMed

Coptidis rhizoma (C. rhizoma) had been demonstrated as an antioxidant and anticancer agent, however, its antioral cancer mechanism still remains unclear. Using water extracts of C. rhizoma, growth and apoptosis-related experiments for the treatment of multi-stage of oral cancer were carried out on immortalized human oral keratinocytes (IHOK), primary oral cancer cells (HN4), metastatic oral cancer cells (HN12) and human skin keratinocytes (HaCaT) by MTT assay, three-dimensional (3-D) raft cultures, western blotting, cell cycle analysis, nuclear staining and cytochrome c expression related to the apoptosis signaling pathway. C. rhizoma inhibited the proliferation of immortalized and malignant oral keratinocytes in a dose- and time-dependent manner. In 3-D organotypic culture, C. rhizoma-treated cells showed less maturation than the control cells, displaying low surface keratinization and decreased epithelial thickness. The major mechanism of growth inhibition by C. rhizoma appears to be the induction of apoptosis, which is supported by the results of the cell cycle analysis, FITC-annexin V staining, DNA fragmentation assay and DAPI staining. The induction of apoptosis by C. rhizoma was more prominent in immortalized keratinocytes than in malignant oral keratinocytes. Cytochrome-c release from mitochondria, accompanied by the activation of caspase-3, was observed in C. rhizoma-treated IHOK and oral cancer cells. These results suggest that C. rhizoma has apoptotic effects in immortalized and malignant oral keratinocytes via the mitochondrial signaling pathway. PMID:16807885

Lee, Hwa-Jeong; Son, Dae-Hyung; Lee, Sun-Kyung; Lee, Jun; Jun, Chang-Duk; Jeon, Byung-Hun; Lee, Suk-Keun; Kim, Eun-Cheol

2006-09-01

381

Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.  

PubMed

Prostate cancer is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that fibroblast growth factor (FGF) receptors are important in prostate cancer initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21, and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require ?-Klotho (KL) and/or ?-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as coreceptors along with classic FGF receptors (FGFR) to mediate potent biologic activity. Here we show that FGF19 is expressed in primary and metastatic prostate cancer tissues, where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion, and colony formation of prostate cancer cells at low ligand concentrations. FGF19 silencing in prostate cancer cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in prostate cancer cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biologic effects in prostate cancer. Our findings support the concept that therapies targeting FGFR signaling may have efficacy in prostate cancer and highlight FGF19 as a relevant endocrine FGF in this setting. PMID:23440425

Feng, Shu; Dakhova, Olga; Creighton, Chad J; Ittmann, Michael

2013-04-15

382

Fetal and infant growth and cardiovascular risk factors in women  

Microsoft Academic Search

AbstractObjective: To examine whether cardiovascular risk factors in women are related to fetal and infant growth.Design: Follow up study of women born 1923-30 whose birth weights and weights at one year were recorded.Setting: Hertfordshire.Subjects: 297 women born and still living in East Hertfordshire.Main outcome measures: Plasma glucose and insulin concentrations during a standard oral glucose tolerance test; fasting plasma proinsulin

C H D Fall; C Osmond; D J P Barker; P M S Clark; C N Hales; Y Stirling; T W Meade

1995-01-01

383

Roles of Fibroblast Growth Factors in the Inner Ear  

Microsoft Academic Search

The basic biology of the fibroblast growth factor (FGF) receptors and their splice variants is first reviewed, followed by a review of the known roles of FGFs in the inner ear. They include induction of the otocyst by FGF19, followed by FGF3 in further development of the otocyst. In later development, FGF3 or FGF10 acting on FGF receptor 2b is

James O. Pickles; Brian Chir

2002-01-01

384

Hormone-like fibroblast growth factors and metabolic regulation  

Microsoft Academic Search

The family of fibroblast growth factors (FGFs) consisting now of 22 members is generally considered to control a wide range of biological functions such as development, differentiation and survival. However, research during the past decade provided substantial evidence that a so called “hormone-like” subgroup of FGFs, comprised of FGF19, FGF21 and FGF23, is involved in the regulation of diverse metabolic

Yun Chau Long; Alexei Kharitonenkov

2011-01-01

385

Fibroblast growth factor-hedgehog interdependence during retina regeneration  

Microsoft Academic Search

The embryonic chick is able to regenerate the retina after it has been removed. We have previously shown that proliferating stem\\/progenitor cells present in the ciliary body\\/ciliary marginal zone (CB\\/CMZ) of the chick eye are responsible for regeneration, which can be induced by ectopic fibroblast growth factor-2 (FGF2) or Sonic hedgehog (Shh). Here, we reveal the mechanisms showing how FGF2

Jason R. Spence; Juan-Carlos Aycinena; Katia Del Rio-Tsonis

2007-01-01

386

Skin toxicities associated with epidermal growth factor receptor inhibitors  

Microsoft Academic Search

The use of epidermal growth factor receptor (EGFR) inhibitors in several epithelial tumors has increased considerably in recent\\u000a years. Currently, they are approved in non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer and head and\\u000a neck cancer. Skin toxicity is a class-specific side effect that is typically manifested as a papulopustular rash in the majority\\u000a (45–100%) of patients receiving

Tianhong Li; Roman Perez-Soler

2009-01-01

387

Identification of a new fibroblast growth factor receptor, FGFR5  

Microsoft Academic Search

A novel fibroblast growth factor receptor (FGFR), designated FGFR5, was identified from an EST database of a murine lymph node stromal cell cDNA library. The EST has approximately 32% identity to the extracellular domain of FGFR1–4. Library screening with this EST identified two full-length alternative transcripts which we designated as FGFR5? and FGFR5?. The main difference between these transcripts is

Matthew Sleeman; Jonathan Fraser; Megan McDonald; Shining Yuan; Damian White; Prudence Grandison; Krishnanand Kumble; James D. Watson; J. Greg Murison

2001-01-01

388

Expression of transforming growth factor-? isoforms in human glomerular diseases  

Microsoft Academic Search

Expression of transforming growth factor-? isoforms in human glomerular diseases. Protein and mRNA expression of TGF-? isoforms, TGF-?1, -?2 and -?3, and deposition of fibronectin containing extra domain A (fibronectin EDA+) and plasminogen activator inhibitor-1 (PAI-1) were studied in human chronic glomerulonephritis and diabetic nephropathy. Normal kidneys showed similar, weak immunostaining for all three TGF-? isoforms. TGF-? mRNA expression was

Tatsuo Yamamoto; Nancy A Noble; Arthur H Cohen; Cynthia C Nast; Akira Hishida; Leslie I Gold; Wayne A Border

1996-01-01

389

Nerve growth factor regulates gene expression by several distinct mechanisms.  

PubMed Central

To help elucidate the mechanisms by which nerve growth factor (NGF) regulates gene expression, we have identified and studied four genes (a-2, d-2, d-4, and d-5) that are positively regulated by NGF in PC12 cells, including one (d-2) which has previously been identified as a putative transcription factor (NGF I-A). Three of these genes, including d-2, were induced very rapidly at the transcriptional level, but the relative time courses of transcription and mRNA accumulation of each of these three genes were distinct. The fourth gene (d-4) displayed no apparent increase in transcription that corresponded to the increase in its mRNA, suggesting that NGF may regulate its expression at a posttranscriptional level. Thus, NGF positively regulates gene expression by more than one mechanism. These genes could also be distinguished on the basis of their response to cyclic AMP. The expression of d-2 and a-2 was increased by cholera toxin and further augmented by NGF; however, cholera toxin not only failed to increase the levels of d-5 and d-4 mRNA but also actually inhibited the NGF-dependent increase. The expression of each of these genes, including d-2 (NGF I-A), was also increased by fibroblast growth factor, epidermal growth factor (EGF), phorbol myristate acetate, and in some cases insulin, showing that the regulation of these genes is not unique to NGF. Because each of these genes was expressed in response to phorbol myristate acetate and EGF, their expression may be necessary but is certainly not sufficient for neurite formation. The protein kinase inhibitor K-252a prevented the NGF-associated, but not the acidic FGF-associated, induction of d-2 and d-5 gene expression, suggesting that these two growth factors