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1

Aberrant Homeobox Gene Expression in Mammary Tumorigenesis.  

National Technical Information Service (NTIS)

We hypothesized that aberrant expression of Hox genes in mammary epithelial cells results in the inappropriate regulation of a wide variety of Hox target genes; this could lead to a change from a normal to a preneoplastic, or from a preneoplastic to a neo...

L. J. Gudas

2001-01-01

2

Aberrant GAP-43 gene expression in Alzheimer's disease.  

PubMed Central

GAP-43 is a growth-associated phosphoprotein expressed at high levels in neurons during development, axonal regeneration, and neuritic sprouting. GAP-43 gene expression in mature neurons is probably functionally important for the structural remodeling of synapses as required for learning and establishing new memory. The widespread aberrant neuritic growth accompanied by impaired synaptic plasticity in Alzheimer's disease (AD) suggests that abnormal GAP-43 gene expression may contribute to the cascade of neurodegeneration. In the present study, end-stage AD brains exhibited reduced neuronal expression but increased glial cell levels of GAP-43 mRNA and protein. Glial cell localization of GAP-43 gene expression was confirmed by in situ hybridization of cerebral tissue, Northern blot analysis of microdissected cerebral white matter, and independent analysis of astrocytoma cell lines and primary malignant astrocytomas. In addition, in AD, GAP-43 immunoreactivity was translocated from the cytosol to membranes of swollen neuritic (dendritic) and glial cell processes throughout cerebral cortex and white matter. Downregulated and aberrant neuronal GAP-43 gene expression appears to reflect an important molecular lesion that precedes and progresses with the widespread synaptic disconnection and dementia in AD. At the same time, the presence of similar neuronal abnormalities in Pick's disease, diffuse Lewy body disease, Parkinson's disease, and Down syndrome suggests common mechanisms in the respective cascades of neurodegeneration. Finally, the finding of aberrantly increased glial cell GAP-43 gene expression in AD exposes a previously unrecognized neurodegenerative change that may account for the axonal loss and white matter atrophy detected early in the course of disease. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

de la Monte, S. M.; Ng, S. C.; Hsu, D. W.

1995-01-01

3

Aberrant expression of the PRAC gene in prostate cancer.  

PubMed

Identification of aberrant expression patterns of genes in prostate cancer (PCa) is a key step towards the development of effective therapies. Prostate-specific antigen (PSA) levels are commonly measured for the early detection of PCa, but which itself is still not an ideal biomarker. We analysed the expression patterns of prostate cancer susceptibility candidate (PRAC) in prostate cancer. The PRAC gene is known to be commonly expressed in prostate tissue, rectum and colon. To provide clear insights into the expression patterns of PRAC in PCa, we examined the gene expression by quantitative real-time PCR (qRT-PCR), western blot analysis and immunohistochemistry (IHC). The results showed that PRAC expression levels in androgen?insensitive cells (DU145 and PC3) are lower than those in androgen-sensitive cell lines (LNCaP, LNCaP-R and CW22R). However, treatment of the LNCaP cell line with androgen and anti-androgen demonstrated that PRAC is expressed in an androgen-independent manner. Further, PRAC expression was restored upon treatment of DU145 and PC3 cells with the methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza-CdR), which indicates the effect of methylation in the control of PRAC expression. In addition, IHC analysis revealed a significantly decreased immunoreactivity of PRAC protein in PCa tissues compared to benign prostatic hyperplasia (BPH) (p<0.0001). Thus, our findings suggest that the pathogenesis of PCa may be due to the expression levels of PRAC protein, and this protein can serve as a potential biomarker for the management of PCa. PMID:24100630

Lenka, Govinda; Weng, Wen-Hui; Chuang, Cheng-Keng; Ng, Kwai-Fong; Pang, See-Tong

2013-10-02

4

Deciphering causal and statistical relations of molecular aberrations and gene expressions in NCI-60 cell lines  

PubMed Central

Background Cancer cells harbor a large number of molecular alterations such as mutations, amplifications and deletions on DNA sequences and epigenetic changes on DNA methylations. These aberrations may dysregulate gene expressions, which in turn drive the malignancy of tumors. Deciphering the causal and statistical relations of molecular aberrations and gene expressions is critical for understanding the molecular mechanisms of clinical phenotypes. Results In this work, we proposed a computational method to reconstruct association modules containing driver aberrations, passenger mRNA or microRNA expressions, and putative regulators that mediate the effects from drivers to passengers. By applying the module-finding algorithm to the integrated datasets of NCI-60 cancer cell lines, we found that gene expressions were driven by diverse molecular aberrations including chromosomal segments' copy number variations, gene mutations and DNA methylations, microRNA expressions, and the expressions of transcription factors. In-silico validation indicated that passenger genes were enriched with the regulator binding motifs, functional categories or pathways where the drivers were involved, and co-citations with the driver/regulator genes. Moreover, 6 of 11 predicted MYB targets were down-regulated in an MYB-siRNA treated leukemia cell line. In addition, microRNA expressions were driven by distinct mechanisms from mRNA expressions. Conclusions The results provide rich mechanistic information regarding molecular aberrations and gene expressions in cancer genomes. This kind of integrative analysis will become an important tool for the diagnosis and treatment of cancer in the era of personalized medicine.

2011-01-01

5

Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas.  

PubMed

HOX genes are known as master regulator genes which give cells positional information in embryogenesis. In this study, we compared the expression patterns of 39 HOX genes among human colorectal carcinomas from the right large intestine (cecum, ascending and transverse colon), those from the left large intestine (discending and sigmoid colon, and rectum) and hepatocellular carcinoma. The expression levels of each HOX gene were quantified by analysis based on the real-time RT-PCR. The expression patterns of HOX genes in colorectal and hepatocellular carcinoma tissues differed from those in their normal or non-cancerous tissues. Between the tumor tissues in the right-side large intestine and those in the left-side, different HOX genes were expressed in association with cancer. Further, the expression levels of HOXD8 in liver-metastatic tissues of colorectal carcinomas were as low as in non-cancerous liver tissues, and were significantly lower than those in the primary tissues. These results suggest that dysregulated expressions of HOX genes play an important role in carcinogenesis and malignant progression of colorectal and hepatocellular carcinomas. PMID:20127028

Kanai, Motoshi; Hamada, Jun-Ichi; Takada, Minoru; Asano, Toshimichi; Murakawa, Katsuhiko; Takahashi, Yoko; Murai, Taichi; Tada, Mitsuhiro; Miyamoto, Masaki; Kondo, Satoshi; Moriuchi, Tetsuya

2010-03-01

6

Aberrant Gene Expression in NF1-Mediated Oncogenesis.  

National Technical Information Service (NTIS)

Recent genetic understanding has identified the gene NFl to be disrupted or mutated in patients affected with NFl resulting in reduced expression of the protein neurofibromin. One function if NFl has shown that it acts to negatively regulate, or turn off ...

J. M. Shields

2002-01-01

7

Activation-induced cytidine deaminase auto-activates and triggers aberrant gene expression.  

PubMed

DNA methylation is a well-characterized epigenetic landmark involved in transcriptional regulation; however, mechanisms underlying its regulation remain poorly characterized. Recent studies demonstrate that activation-induced cytidine deaminase (AID) is involved in active DNA demethylation. AID is aberrantly expressed in inflammation-associated cancers and generates point mutations; however, cellular disorders attributed to its demethylation function are largely unexplored. Here we demonstrate that ectopic AID expression perturbs tumor-related gene expression. AID (with Gadd45) activated a methylated paired box gene 5 (Pax5) reporter construct, and induced expression and association of endogenous Pax5 with the AID promoter, suggesting that aberrant AID expression triggers an auto-activation circuit to consolidate self-expression. PMID:23820005

Isobe, Tomoyasu; Song, Soken-Nakazawa J; Tiwari, Prabha; Ito, Hiroki; Yamaguchi, Yuki; Yoshizaki, Kazuyuki

2013-06-29

8

Aberrant Epigenetic Silencing Is Triggered by a Transient Reduction in Gene Expression  

PubMed Central

Background Aberrant epigenetic silencing plays a major role in cancer formation by inactivating tumor suppressor genes. While the endpoints of aberrant silencing are known, i.e., promoter region DNA methylation and altered histone modifications, the triggers of silencing are not known. We used the tet-off system to test the hypothesis that a transient reduction in gene expression will sensitize a promoter to undergo epigenetic silencing. Methodology/Principal Findings The tet responsive promoter (PTRE) was used to drive expression of the selectable human HPRT cDNA in independent transfectants of an Hprt deficient mouse cell line. In this system, high basal HPRT expression is greatly reduced when doxycycline (Dox) is added to the culture medium. Exposure of the PTRE-HPRT transfectants to Dox induced HPRT deficient clones in a time dependent manner. A molecular analysis demonstrated promoter region DNA methylation, loss of histone modifications associated with expression (i.e., H3 lysine 9 and 14 acetylation and lysine 4 methylation), and acquisition of the repressive histone modification H3 lysine 9 methylation. These changes, which are consistent with aberrant epigenetic silencing, were not present in the Dox-treated cultures, with the exception of reduced H3 lysine 14 acetylation. Silenced alleles readily reactivated spontaneously or after treatment of cells with inhibitors of histone deacetylation and/or DNA methylation, but re-silencing of reactivated alleles did not require a new round of Dox exposure. Inhibition of histone deacetylation inhibited both the induction of silencing and re-silencing, whereas inhibition of DNA methylation had no such effect. Conclusions/Significance This study demonstrates that a transient reduction in gene expression triggers a pathway for aberrant silencing in mammalian cells and identifies histone deacetylation as a critical early step in this process. DNA methylation, in contrast, is a secondary step in the silencing pathway under study. A model to explain these observations is offered.

Oyer, Jon A.; Chu, Adrian; Brar, Sukhmani; Turker, Mitchell S.

2009-01-01

9

Aberrant expression of the PHF14 gene in biliary tract cancer cells  

PubMed Central

DNA copy number aberrations in human biliary tract cancer (BTC) cell lines were investigated using a high-density oligonucleotide microarray. A novel homozygous deletion was detected at chromosomal region 7p21.3 in the OZ cell line. Further validation experiments using genomic PCR revealed a homozygous deletion of a single gene, plant homeodomain (PHD) finger protein 14 (PHF14). No PHF14 mRNA or protein expression was detected, thus demonstrating the absence of PHF14 expression in the OZ cell line. Although the PHD finger protein is considered to be involved in chromatin-mediated transcriptional regulation, little is known about the function of PHF14 in cancer. The present study observed that the knock down of PHF14 using small interfering RNA (siRNA) enhanced the growth of the BTC cells. These observations suggest that aberrant PHF14 expression may have a role in the tumorigenesis of BTC.

AKAZAWA, TAKAKO; YASUI, KOHICHIROH; GEN, YASUYUKI; YAMADA, NOBUHISA; TOMIE, AKIRA; DOHI, OSAMU; MITSUYOSHI, HIRONORI; YAGI, NOBUAKI; ITOH, YOSHITO; NAITO, YUJI; YOSHIKAWA, TOSHIKAZU

2013-01-01

10

Aberrant gene expression patterns in extraembryonic tissue from cloned porcine embryos.  

PubMed

The abnormal development of embryos reconstructed by somatic cell nuclear transfer (SCNT) is considered to be associated with consequent changes in gene expression following errors in epigenetic reprogramming. In this study, we carried out SCNT using donor fibroblast cells derived from 3-way hybrids (Landrace×Duroc×Yorkshire). A total of 655 SCNT embryos were transferred, and 6.97±2.3 cloned fetuses were successfully recovered from three surrogates at gestational day 30. An analysis of the 6.97±2.3 cloned embryos revealed that most had severe extraembryonic defects. The extraembryonic tissue from the SCNT embryos was abnormally small compared with that of the control. To investigate the differentially expressed genes between the SCNT and control extraembryonic tissues, we compared the gene expression profiles of the extraembryonic tissues from gestational day 30 cloned pig embryos with those from the control using an annealing control primer-based GeneFishing polymerase chain reaction. As a result, we found that a total of 50 genes were differentially expressed by utilizing 120 ACPs, 38 genes of which were known. Among them, 26 genes were up-regulated, whereas 12 genes were down-regulated. Real-time RT-PCR showed that apoptosis-related genes were expressed significantly higher in SCNT extraembryonic tissue than in the control, whereas metabolism-related genes were expressed at significantly lower levels in the SCNT extraembryonic tissue. These observations strongly indicate that early gestational death of SCNT embryo is caused, at least in part, by the disruption of developing extraembryonic tissues as a result of aberrant gene expression, which results in abnormal apoptosis and metabolism. PMID:23146142

Park, Mi-Ryung; Im, Gi-Sun; Kim, Sung Woo; Hwang, Seongsoo; Park, Jae-Hong; Kim, Hyun; Do, Yoon Jung; Park, Soo Bon; Yang, Bo-Suck; Song, Young Min; Cho, Jae-Hyeon; Ko, Yeoung-Gyu

2012-11-10

11

Aberrant Expression of ID2, a Suppressor of B-Cell-Specific Gene Expression, in Hodgkin's Lymphoma  

PubMed Central

The global loss of B-cell-specific gene expression is a distinctive feature of the Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin’s lymphoma (HL). The reasons for this loss remained largely unknown as transcription factors with pleiotropic effects on B-cell-specific gene expression, namely E2A, EBF, and PAX5, are present in primary HRS cells. We show here that ID2, which can inactivate E2A and perhaps PAX5, is not detectable in normal B cells but is strongly and uniformly expressed in HRS cells of all cases of classical HL. Recurrent chromosomal gains of the ID2 gene might contribute to this aberrant expression. Co-immunoprecipitation of E2A with ID2 from HRS-derived cell lines together with the high amount of ID2 relative to the B-cell transcription factors E2A and PAX5 in HRS-derived cell lines and primary HRS cells indicated that aberrant ID2 expression contributes significantly to the loss of the B-cell-specific gene expression in HRS cells. ID2 was also expressed in lymphocyte-predominance HL, mediastinal large B-cell, diffuse large B-cell, and Burkitt’s lymphoma, where lower amounts of ID2 relative to E2A and PAX5 compared with HRS cells might prevent a global down-regulation of B-cell-specific genes and ID2 may contribute to lymphomagenesis in other ways.

Renne, Christoph; Martin-Subero, Jose Ignacio; Eickernjager, Maren; Hansmann, Martin-Leo; Kuppers, Ralf; Siebert, Reiner; Brauninger, Andreas

2006-01-01

12

Disrupted redox homeostasis and aberrant redox gene expression in porcine oocytes contribute to decreased developmental competence.  

PubMed

The objective of this study was to identify specific redox-related genes whose function contributes to oocyte quality and to characterize the role of redox homeostasis in oocyte development. We determined the redox genes glutaredoxin 2 (GLRX2), protein disulfide isomerase family A, members 4 and 6 (PDIA4, PDIA6), and thioredoxin reductase 1 (TXNRD1) were differentially expressed between adult (more competent) and prepubertal (less competent) porcine in vitro-matured (IVM) oocytes. The association between these genes and oocyte quality was further validated by comparing transcript abundance in IVM with that in in vivo-matured (VVM) prepubertal and adult oocytes. By maturing oocytes in variable redox environments, we demonstrated that a balanced redox environment is important for oocyte quality, and over-reduction of the environment is as detrimental as excess oxidation. Critical levels of reactive oxygen species (ROS) and glutathione (GSH) are required for oocyte competence. Elevated GSH and lower ROS in prepubertal oocytes suggest disrupted redox homeostasis exists in these cells. By further comparing GLRX2, PDIA4, PDIA6, and TXNRD1 expression levels in oocytes matured under these different redox environments, we found aberrant expression patterns in prepubertal oocytes but not in adult oocytes when the maturation medium contained high concentrations of antioxidants. These results suggest that prepubertal oocytes are less competent in regulating redox balance than adult oocytes, contributing to lower oocyte quality. In conclusion, aberrant redox gene expression patterns and disrupted redox homeostasis contribute to decreased developmental competence in prepubertal and IVM porcine oocytes. The balance between ROS and GSH plays an important role in oocyte quality. PMID:22811572

Yuan, Ye; Wheeler, Matthew B; Krisher, Rebecca L

2012-10-04

13

Arsenic-induced aberrant gene expression in fetal mouse primary liver-cell cultures.  

PubMed

Exposure of maternal mice to inorganic arsenic through the drinking water induces liver tumors and aberrant gene expression in offspring when they reach adulthood. To help define if these are direct fetal effects of arsenic, fetal liver cells were isolated from untreated mice at gestation day 13.5 by mechanical dissection and centrifugation. Two hours after seeding the cells on collagen1-coated plates in William E media containing 10% fetal bovine serum, 1x ITS (insulin, transferrin, and selenium) and antibiotics, inorganic arsenite (0, 0.1, 0.3, and 1.0 microM) was added to the fresh media for 72 h. Cell morphology and viability were not significantly altered by these arsenic concentrations. At the end of arsenic exposure, cells were harvested into Trizol, and total RNA was extracted, purified, and subjected to real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Arsenite exposure produced a concentration-dependent induction of heme oxygenase-1 (up to eight-fold) and metallothionein-1 (up to five-fold), indicative of stress response to adapt to arsenic insult. Expression of genes related to steroid metabolism, such as 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7) and Cyp2a4, were increased approximately two-fold, together with increases in estrogen receptor-alpha (ER-alpha) and ER-alpha-linked genes, such as anterior gradient-2, keratin 1-19, and trefoil factor-3. Arsenic in vitro induced a three-fold increase in the expression of alpha-fetoprotein (AFP), a biomarker associated with transplacental arsenic-induced mouse liver tumors. Thus, exposure of mouse fetal liver cells to arsenic induces adaptive responses and aberrant gene expression, which could alter genetic programming at a very early life stage, potentially contributing to tumor formation much later in life. PMID:18991936

Liu, Jie; Yu, Limei; Tokar, Erik J; Bortner, Carl; Sifre, Maria I; Sun, Yang; Waalkes, Michael P

2008-10-01

14

Aberrant gene expression profiles in pluripotent stem cells induced from fibroblasts of a Klinefelter syndrome patient.  

PubMed

Klinefelter syndrome (KS) is the most common male chromosome aneuploidy. Its pathophysiology is largely unexplained due to the lack of adequate models. Here, we report the derivation of induced pluripotent stem cell (iPSCs) lines from a KS patient with a karyotype of 47, XXY. Derived KS-iPSCs meet all criteria of normal iPSCs with the potential for germ cell differentiation. Although X chromosome inactivation occurs in all KS-iPSCs, genome-wide transcriptome analysis identifies aberrantly expressed genes associated with the clinical features of KS. Our KS-iPSCs can serve as a cellular model for KS research. Identified genes may become biomarkers for early diagnosis or potential therapeutic targets for KS and significantly accelerate the understanding, diagnosis, and treatment of Klinefelter syndrome. PMID:23019320

Ma, Yu; Li, Chunliang; Gu, Junjie; Tang, Fan; Li, Chun; Li, Peng; Ping, Ping; Yang, Shi; Li, Zheng; Jin, Ying

2012-09-27

15

Aberrant host immune response induced by highly virulent PRRSV identified by digital gene expression tag profiling  

PubMed Central

Background There was a large scale outbreak of the highly pathogenic porcine reproductive and respiratory syndrome (PRRS) in China and Vietnam during 2006 and 2007 that resulted in unusually high morbidity and mortality among pigs of all ages. The mechanisms underlying the molecular pathogenesis of the highly virulent PRRS virus (H-PRRSV) remains unknown. Therefore, the relationship between pulmonary gene expression profiles after H-PRRSV infection and infection pathology were analyzed in this study using high-throughput deep sequencing and histopathology. Results H-PRRSV infection resulted in severe lung pathology. The results indicate that aberrant host innate immune responses to H-PRRSV and induction of an anti-apoptotic state could be responsible for the aggressive replication and dissemination of H-PRRSV. Prolific rapid replication of H-PRRSV could have triggered aberrant sustained expression of pro-inflammatory cytokines and chemokines leading to a markedly robust inflammatory response compounded by significant cell death and increased oxidative damage. The end result was severe tissue damage and high pathogenicity. Conclusions The systems analysis utilized in this study provides a comprehensive basis for better understanding the pathogenesis of H-PRRSV. Furthermore, it allows the genetic components involved in H-PRRSV resistance/susceptibility in swine populations to be identified.

2010-01-01

16

Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes  

PubMed Central

Objective To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) oncogene. Methods After 7.3 years of follow-up of the Netherlands Cohort Study (n = 120,852), adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed, based on 401 colon and 130 rectal cancer patients. Results Total, saturated and monounsaturated fat were not associated with the risk of colon or rectal cancer, or different molecular subgroups. There was also no association between polyunsaturated fat and the risk of overall or subgroups of rectal cancer. Linoleic acid, the most abundant polyunsaturated fatty acid in the diet, was associated with increased risk of colon tumors with only a KRAS mutation and no additional truncating APC mutation or lack of MLH1 expression (RR = 1.41, 95% CI 1.18–1.69 for one standard deviation (i.e., 7.5 g/day) increase in intake, p-trend over the quartiles of intake <0.001). Linoleic acid intake was not associated with risk of colon tumors without any of the gene defects, or with tumors harboring aberrations in either MLH1 or APC. Conclusion Linoleic acid intake is associated with colon tumors with an aberrant KRAS gene, but an intact APC gene and MLH1 expression, suggesting a unique etiology of tumors with specific genetic aberrations.

Luchtenborg, Margreet; de Goeij, Anton F. P. M.; Brink, Mirian; van Muijen, Goos N. P.; de Bruine, Adriaan P.; Goldbohm, R. Alexandra; van den Brandt, Piet A.

2007-01-01

17

Integrating chromosomal aberrations and gene expression profiles to dissect rectal tumorigenesis  

PubMed Central

Background Accurate staging of rectal tumors is essential for making the correct treatment choice. In a previous study, we found that loss of 17p, 18q and gain of 8q, 13q and 20q could distinguish adenoma from carcinoma tissue and that gain of 1q was related to lymph node metastasis. In order to find markers for tumor staging, we searched for candidate genes on these specific chromosomes. Methods We performed gene expression microarray analysis on 79 rectal tumors and integrated these data with genomic data from the same sample series. We performed supervised analysis to find candidate genes on affected chromosomes and validated the results with qRT-PCR and immunohistochemistry. Results Integration of gene expression and chromosomal instability data revealed similarity between these two data types. Supervised analysis identified up-regulation of EFNA1 in cases with 1q gain, and EFNA1 expression was correlated with the expression of a target gene (VEGF). The BOP1 gene, involved in ribosome biogenesis and related to chromosomal instability, was over-expressed in cases with 8q gain. SMAD2 was the most down-regulated gene on 18q, and on 20q, STMN3 and TGIF2 were highly up-regulated. Immunohistochemistry for SMAD4 correlated with SMAD2 gene expression and 18q loss. Conclusion On basis of integrative analysis this study identified one well known CRC gene (SMAD2) and several other genes (EFNA1, BOP1, TGIF2 and STMN3) that possibly could be used for rectal cancer characterization.

Lips, Esther H; van Eijk, Ronald; de Graaf, Eelco JR; Oosting, Jan; de Miranda, Noel FCC; Karsten, Tom; van de Velde, Cornelis J; Eilers, Paul HC; Tollenaar, Rob AEM; van Wezel, Tom; Morreau, Hans

2008-01-01

18

Fetal Onset of Aberrant Gene Expression Relevant to Pulmonary Carcinogenesis in Lung Adenocarcinoma Development Induced by In Utero Arsenic Exposure  

PubMed Central

Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-? (ER-?) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-?-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. in utero arsenic exposure also induced overexpression of ?-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-? expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-? expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-? activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood.

Shen, Jun; Liu, Jie; Xie, Yaxiong; Diwan, Bhalchandra A.; Waalkes, Michael P.

2009-01-01

19

Tumoral Environment Triggers Transcript Anomalies in Established Tumors: Induction of Altered Gene Expression and of Aberrant, Truncated and B2 Repeat-Containing Gene Transcripts1  

PubMed Central

Abstract In addition to eugenetic changes, cancerous cells exhibit extensive modifications in the expression levels of a variety of genes. The phenotypic switch observed after inoculation of T lymphoma cells into syngenic mice illustrates the active participation of tumoral environment in the induction of an aberrant gene expression pattern. To further substantiate this contribution, we performed polymerase chain reaction (PCR)-based subtraction suppression hybridization (SSH) to identify genes that are differentially expressed in tumor-derived EL4/13.3 cells compared to the same cells isolated from cultures. Besides a number of unknown genes, the subtracted library contained several known genes that have been reported to be expressed at increased levels in tumors and/or to contribute to carcinogenesis. Apart from clones representing translated transcripts, the subtracted library also contained a high number of clones representing B2 repeat elements, viz. short interspersed repetitive elements that are transcribed by RNA polymerase III. Northern blotting confirmed the induction of B2 transcripts in tumor tissue and also revealed induction of chimeric, B2 repeat-containing mRNA. The appearance of chimeric transcripts was accompanied by aberrant, shorter-than-full-length transcripts, specifically from upregulated genes. Accordingly, in addition to altered gene expression, tumoral environmental triggers constitute a potent mechanism to create an epigenetic diversity in cancers by inducing extensive transcript anomalies.

Rottiers, Pieter; Desmedt, Marjory; Dooms, Hans; Contreras, Roland; Grooten, Johan

1999-01-01

20

Aberrant regulation of human intestinal proglucagon gene expression in the NCI-H716 cell line.  

PubMed

Despite interest in understanding glucagon-like peptide-1 (GLP-1) production, the factors important for GLP-1 biosynthesis remain poorly understood. We examined control of human proglucagon gene expression in NCI-H716 cells, a cell line that secretes GLP-1 in a regulated manner. Insulin, phorbol myristate acetate, or forskolin, known regulators of rodent proglucagon gene expression, had no effect, whereas sodium butyrate decreased levels of NCI-H716 proglucagon mRNA transcripts. The inhibitory effect of sodium butyrate was mimicked by trichostatin A but was not detected with sodium acetate or isobutyrate. The actions of butyrate were not diminished by the ERK1/2 inhibitor PD98059, p38 inhibitor SB203580, or soluble guanylate cyclase inhibitor LY83583 or following treatment of cells with KT5823, a selective inhibitor of cGMP-dependent protein kinase. NCI-H716 cells expressed multiple proglucagon gene transcription factors including isl-1, pax-6, pax-2, cdx-2/3, pax-4, hepatocyte nuclear factor (HNF)-3 alpha, HNF-3beta, HNF-3 gamma, and Nkx2.2. Nevertheless, the butyrate-dependent inhibition of proglucagon gene expression was not associated with coordinate changes in transcription factor expression and both the human and rat transfected proglucagon promoters were transcriptionally inactive in NCI-H716 cells. Hence, NCI-H716 cells may not be a physiologically optimal model for studies of human enteroendocrine proglucagon gene transcription. PMID:12697711

Cao, Xiemin; Flock, Grace; Choi, Caroline; Irwin, David M; Drucker, Daniel J

2003-05-01

21

Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy  

PubMed Central

Myotonic dystrophy (DM1) is associated with expression of expanded CTG DNA repeats as RNA (CUGexp RNA). To test whether CUGexp RNA creates a global splicing defect, we compared skeletal muscle of two mouse DM1 models, one expressing a CTGexp transgene, and another homozygous for a defective Mbnl1 gene. Strong correlation in splicing changes for ~100 new Mbnl1-regulated exons indicates loss of Mbnl1 explains >80% of the splicing pathology due to CUGexp RNA. In contrast, only about half of mRNA level changes can be attributed to loss of Mbnl1, indicating CUGexp RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix (ECM) proteins. We propose that CUGexp RNA causes two separate effects: loss of Mbnl1 function, disrupting splicing, and loss of another function that disrupts ECM mRNA regulation, possibly mediated by MBNL2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies.

Du, Hongqing; Cline, Melissa S.; Osborne, Robert J.; Tuttle, Daniel L.; Clark, Tyson A.; Donohue, John Paul; Hall, Megan P.; Shiue, Lily; Swanson, Maurice S.; Thornton, Charles A.; Ares, Manuel

2009-01-01

22

Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms  

Microsoft Academic Search

Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9

K L Rice; X Lin; K Wolniak; B L Ebert; W Berkofsky-Fessler; M Buzzai; Y Sun; C Xi; P Elkin; R Levine; T Golub; D G Gilliland; J D Crispino; J D Licht; W Zhang

2011-01-01

23

Identification of frequent cytogenetic aberrations in hepatocellular carcinoma using gene-expression microarray data  

Microsoft Academic Search

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Frequent cytogenetic abnormalities that occur in HCC suggest that tumor-modifying genes (oncogenes or tumor suppressors) may be driving selection for amplification or deletion of these particular genetic regions. In many cases, however, the gene(s) that drive the selection are unknown. Although techniques such as comparative genomic hybridization (CGH) have

Joseph J Crawley; Kyle A Furge

2002-01-01

24

Elucidation of the Molecular Mechanisms for Aberrant Expression of Breast Cancer Specific Gene 1 in Invasive and Metastatic Breast Carcinomas.  

National Technical Information Service (NTIS)

Breast cancer specific gene 1 (BCSG1) is not expressed in normal breast tissue but is highly expressed in the vast majority of invasive and metastatic breast carcinomas. When over expressed, BCSG1 significantly stimulates the proliferation and invasion of...

J. Liu

2003-01-01

25

1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma.  

PubMed

Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours--those targeting 1q12 satellite DNA--can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range 'pairing' between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms. PMID:20432501

Fournier, Alexandra; McLeer-Florin, Anne; Lefebvre, Christine; Duley, Samuel; Barki, Leila; Ribeyron, Juliana; Alboukadel, Kassambara; Hamaidia, Sieme; Granjon, Aurélie; Gressin, Rémy; Lajmanovich, Alicia; Bonnefoix, Thierry; Chauvelier, Stéphanie; Debernardi, Alexandra; Rousseaux, Sophie; de Fraipont, Florence; Figeac, Martin; Kerckaert, Jean-Pierre; De Vos, John; Usson, Yves; Delaval, Katia; Grichine, Alexei; Vourc'h, Claire; Khochbin, Saadi; Feil, Robert; Leroux, Dominique; Callanan, Mary B

2010-05-01

26

1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma  

PubMed Central

Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours—those targeting 1q12 satellite DNA—can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range ‘pairing’ between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms.

Fournier, Alexandra; McLeer-Florin, Anne; Lefebvre, Christine; Duley, Samuel; Barki, Leila; Ribeyron, Juliana; Kassambara, Alboukadel; Hamaidia, Sieme; Granjon, Aurelie; Gressin, Remy; Lajmanovich, Alicia; Bonnefoix, Thierry; Chauvelier, Stephanie; Debernardi, Alexandra; Rousseaux, Sophie; de Fraipont, Florence; Figeac, Martin; Kerckaert, Jean-Pierre; De Vos, John; Usson, Yves; Delaval, Katia; Grichine, Alexei; Vourc'h, Claire; Khochbin, Saadi; Feil, Robert; Leroux, Dominique; Callanan, Mary B

2010-01-01

27

Inhibition of Aberrant Androgen Receptor Induction of Prostate Specific Antigen Gene Expression, Cell Proliferation and Tumor Growth by 17?-Estradiol in Prostate Cancer  

PubMed Central

Purpose Androgen independent prostate cancer growth and metastasis are a major cause of prostate cancer death. Aberrant androgen receptor activation due to androgen receptor mutation is an important mechanism of androgen independence. We determined the effectiveness and mechanism of 17?-estradiol (Sigma®) in blocking aberrant androgen receptor activation due to androgen receptor mutation. Materials and Methods We used LNCaP and MDA Pca-2b prostatic tumor cells (ATCC®) containing a mutated androgen receptor and WT estrogen receptor ? to test 17?-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression and cell growth. Cotransfection analysis was used to further elucidate the mechanism of 17?-estradiol action. Xenograft animals with an LNCaP prostate tumor were prepared to study the in vivo effect of 17?-estradiol on tumor growth inhibition. Results In LNCaP cells 17?-estradiol produced a dose dependent inhibition of cyproterone acetate (Sigma) or dihydrotestosterone induced prostate specific antigen gene expression. In MDA Pca-2b cells 17?-estradiol inhibited cortisol (Sigma) induced prostate specific antigen expression and blocked dihydrotestosterone and cortisol induced cell proliferation in LNCaP and MDA Pca-2b cells, respectively. Cotransfection analysis showed that 17?-estradiol inhibition of aberrant androgen receptor activation of prostate specific antigen gene expression was medicated via estrogen receptors. In xenograft mice with LNCaP prostate cancer 17?-estradiol but not 17?-estradiol (Sigma) significantly inhibited tumor growth, although each estrogen tended to decrease tumor growth. Conclusions Results suggest that 17?-estradiol with less classic estrogenic activity is a potential therapeutic agent for androgen independent prostate cancer due to androgen receptor mutation.

Qiao, Yaming; Wang, Lu; Cai, Li-Qun; Tan, Chen; Imperato-McGinley, Julianne; Zhu, Yuan-Shan

2011-01-01

28

Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism  

SciTech Connect

Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17{beta}-hydroxysteroid dehydrogenase-7 (HSD17{beta}7; involved in estradiol production) and decreased expression of HSD17{beta}5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.

Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States)]. E-mail: Liu6@niehs.nih.gov; Xie Yaxiong [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States); Cooper, Ryan [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States); Ducharme, Danica M.K. [National Center For Toxicogenomics, NIEHS, Research Triangle Park, NC (United States); Tennant, Raymond [National Center For Toxicogenomics, NIEHS, Research Triangle Park, NC (United States); Diwan, Bhalchandra A. [Basic Research Program, SAIC-Frederick, Inc., NCI Frederick, MD (United States); Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709 (United States)

2007-05-01

29

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications  

PubMed Central

Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies.

Nagel, Stefan; Ehrentraut, Stefan; Tomasch, Jurgen; Quentmeier, Hilmar; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G.; MacLeod, Roderick A. F.

2013-01-01

30

Over-expression of a flower-specific transcription factor gene AtMYB24 causes aberrant anther development  

Microsoft Academic Search

In plants, MYB transcription factors play important roles in many developmental processes and various defense responses. AtMYB24, as a member of R2R3-MYB gene family in Arabidopsis, was found mainly expressed in flowers, especially in microspores and ovules using Northern blots and in situ hybridization. It was further found that the expression of AtMYB24 was tightly regulated during anther development. Over-expression

X. Y. Yang; J. G. Li; M. Pei; H. Gu; Z. L. Chen; L.-J. Qu

2007-01-01

31

Rex1 (Zfp42) Null Mice Show Impaired Testicular Function, Abnormal Testis Morphology, and Aberrant Gene Expression  

PubMed Central

Rex1(Zfp42), GeneID 132625, is a gene whose expression is closely associated with pluripotency/multipotency in both mouse and human embryonic stem cells. To study the function of the murine Rex1 gene in vivo, we have used cre/lox technology to create Rex1(floxed) mice and mice deficient in Rex1 gene function. Rex1-/- males are characterized by an age-associated decrease in sperm counts, abnormal sperm morphology, and mild testicular atrophy. We characterized global patterns of gene expression in primary germ cells by microarray and identified the growth hormone responsive gene, GRTP1, as a transcript present at a 4.5 fold higher level in wild type (WT) compared to Rex1-/- mice. We analyzed immature germ cell (Dazl), proliferating (PCNA), and Sertoli cell populations, and quantitated levels of apoptosis in Rex1-/- as compared to WT testes. We evaluated the expression of proteins previously reported to correlate with Rex1 expression, such as STAT3, phospho-STAT3, p38, and phospho-p38 in the testis. We report a distinct cellular localization of total STAT3 protein in Rex1-/- affected testes. Our data suggest that loss of Rex1 leads to impaired testicular function.

Rezende, Naira; Lee, Mi-Young; Monette, Sebastien; Mark, Willie; Lu, Ailan; Gudas, Lorraine J.

2011-01-01

32

Aberrant Expression of Critical Genes during Secondary Cell Wall Biogenesis in a Cotton Mutant, Ligon Lintless-1 (Li-1)  

PubMed Central

Over ninety percent of the value of cotton comes from its fiber; however, the genetic mechanisms governing fiber development are poorly understood. Due to their biochemical and morphological diversity in fiber cells cotton fiber mutants have been useful in examining fiber development; therefore, using the Ligon Lintless (Li-1) mutant, a monogenic dominant cotton mutant with very short fibers, we employed the high throughput approaches of microarray technology and real time PCR to gain insights into what genes were critical during the secondary cell wall synthesis stage. Comparative transcriptome analysis of the normal TM-1 genotype and the near isogenic Li-1 revealed that over 100 transcripts were differentially expressed at least 2-fold during secondary wall biogenesis, although the genetic profile of the expansion phase showed no significant differences in the isolines. Of particular note, we identified three candidate gene families-expansin, sucrose synthase, and tubulin—whose expression in Li-1 deviates from normal expression patterns of its parent, TM-1. These genes may contribute to retarded growth of fibers in Li-1 since they are fiber-expressed structural and metabolic genes. This work provides more details into the mechanisms of fiber development, and suggests the Li gene is active during the later stages of fiber development.

Bolton, James J.; Soliman, Khairy M.; Wilkins, Thea A.; Jenkins, Johnie N.

2009-01-01

33

Further studies on aberrant gene expression associated with arsenic-induced malignant transformation in rat liver TRL1215 cells.  

PubMed

Chronic arsenic exposure of rat liver epithelial TRL1215 cells induced malignant transformation in a concentration-dependent manner. To further define the molecular events of these arsenic-transformed cells (termed CAsE cells), gene expressions associated with arsenic carcinogenesis or influenced by methylation were examined. Real-time RT-PCR showed that at carcinogenic concentrations (500 nM, and to a less extent 250 nM of arsenite), the expressions of alpha-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), c-jun, c-myc, H-ras, c-met and hepatocyte growth factor, heme oxygenase-1, superoxide dismutase-1, glutathione-S-transferase-pi and metallothionein-1 (MT) were increased between 3 to 12-fold, while expressions of insulin-like growth factor II (IGF-II) and fibroblast growth factor receptor (FGFR1) were essentially abolished. These changes were not significant at the non-carcinogenic concentration (125 nM), except for IGF-II. The positive cell-cycle regulators cyclin D1 and PCNA were overexpressed in CAsE cells, while the negative regulators p21 and p16 were suppressed. Western-blot confirmed increases in AFP, WT-1, cyclin D1 and decreases in p16 and p21 protein in CAsE cells. The CAsE cells over-expressed MT but the demethylating agent 5-aza-deoxycytidine (5-aza-dC, 2.5 microM, 72 h) stimulated further MT expression. 5-Aza-deoxycytidine restored the loss of expression of p21 in CAsE cells to control levels, but did not restore the expression of p16, IGF-II, or FGFR1, indicating the loss of expression of these genes is due to factors other than DNA methylation changes. Overall, an intricate variety of gene expression changes occur in arsenic-induced malignant transformation of liver cells including oncogene activation and alterations in expression of genes critical to growth regulation. PMID:16876216

Liu, Jie; Benbrahim-Tallaa, Lamia; Qian, Xun; Yu, Limei; Xie, Yaxiong; Boos, Jennifer; Qu, Wei; Waalkes, Michael P

2006-06-20

34

Further studies on aberrant gene expression associated with arsenic-induced malignant transformation in rat liver TRL1215 cells  

SciTech Connect

Chronic arsenic exposure of rat liver epithelial TRL1215 cells induced malignant transformation in a concentration-dependent manner. To further define the molecular events of these arsenic-transformed cells (termed CAsE cells), gene expressions associated with arsenic carcinogenesis or influenced by methylation were examined. Real-time RT-PCR showed that at carcinogenic concentrations (500 nM, and to a less extent 250 nM of arsenite), the expressions of {alpha}-fetoprotein (AFP), Wilm's tumor protein-1 (WT-1), c-jun, c-myc, H-ras, c-met and hepatocyte growth factor, heme oxygenase-1, superoxide dismutase-1, glutathione-S-transferase-{pi} and metallothionein-1 (MT) were increased between 3 to 12-fold, while expressions of insulin-like growth factor II (IGF-II) and fibroblast growth factor receptor (FGFR1) were essentially abolished. These changes were not significant at the non-carcinogenic concentration (125 nM), except for IGF-II. The positive cell-cycle regulators cyclin D1 and PCNA were overexpressed in CAsE cells, while the negative regulators p21 and p16 were suppressed. Western-blot confirmed increases in AFP, WT-1, cyclin D1 and decreases in p16 and p21 protein in CAsE cells. The CAsE cells over-expressed MT but the demethylating agent 5-aza-deoxycytidine (5-aza-dC, 2.5 {mu}M, 72 h) stimulated further MT expression. 5-Aza-deoxycytidine restored the loss of expression of p21 in CAsE cells to control levels, but did not restore the expression of p16, IGF-II, or FGFR1, indicating the loss of expression of these genes is due to factors other than DNA methylation changes. Overall, an intricate variety of gene expression changes occur in arsenic-induced malignant transformation of liver cells including oncogene activation and alterations in expression of genes critical to growth regulation.

Liu Jie [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States)]. E-mail: Liu6@niehs.nih.gov; Benbrahim-Tallaa, Lamia [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Qian Xun [Laboratory of Signal Transduction, NIEHS (United States); Yu, Limei [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Zunyi Medical College, Zunyi (China); Xie Yaxiong [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Boos, Jennifer [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Qu Wei [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States); Waalkes, Michael P. [Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Mail Drop F-09, Research Triangle Park, NC 27709 (United States)

2006-11-01

35

WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors.  

PubMed

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis. PMID:9843955

Pennica, D; Swanson, T A; Welsh, J W; Roy, M A; Lawrence, D A; Lee, J; Brush, J; Taneyhill, L A; Deuel, B; Lew, M; Watanabe, C; Cohen, R L; Melhem, M F; Finley, G G; Quirke, P; Goddard, A D; Hillan, K J; Gurney, A L; Botstein, D; Levine, A J

1998-12-01

36

Comparison of gene expression profiles reveals aberrant expression of FOXO1, Aurora A/B and EZH2 in lesional psoriatic skins.  

PubMed

Psoriasis is a chronic, non-infectious skin disease affects 2-3% of the population worldwide. In order to find genes possibly cause this skin disease, we re-analyzed the gene expression data-sets from three published studies. We compared the gene expression profiles between lesional psoriatic skin (PP), uninvolved psoriatic skin (PN) and normal skin (NN) tissues. We found that compared with in PN and NN tissues, the expression of FOXO1 is significantly repressed and the expression of AURKA, AURKB and EZH2 is significantly up-regulated in PP tissues (P < 0.001). During the treatment of psoriasis patients with TNF-? antagonist Etanercept, the expression of FOXO1 was re-activated and the expression of AURKA and EZH2 was repressed. These results suggest loss of FOXO1 expression and elevated AURKA/B and EZH2 expression in lesional psoriatic tissues have potential contribution to the development of psoriasis. It is worthwhile to test whether the combination of Aurora kinases or EZH2 inhibitors can enhance the therapeutic effects of Etanercept in psoriasis management. PMID:21116854

Liu, Yayan; Luo, Wenhui; Chen, Shuai

2010-11-30

37

Aberrant Expression of the Tyrosine Kinase Receptor EphA4 and the Transcription Factor Twist in Sezary Syndrome Identified by Gene Expression Analysis  

Microsoft Academic Search

Sezary syndrome (Sz) is a malignancy of CD4 memory skin-homing T cells and presents with erythroderma, lymphadenopathy, and peripheral blood involvement. To gain more insight into the molecular features of Sz, oligonucleotide array analysis was performed comparing gene expression patterns of CD4 T cells from peripheral blood of patients with Sz with those of patients with erythroderma secondary to dermatitis

Remco van Doorn; Remco Dijkman; Maarten H. Vermeer; Rein Willemze; Cornelis P. Tensen

2004-01-01

38

Ectopic expression of a maize pollen specific gene, zm401 , results in aberrant anther development in tobacco  

Microsoft Academic Search

Our previous study shows that the maize zm401 cDNA is specifically expressed in maize pollens. This evidence suggests that zm401 likely functions in pollen growth and\\/or development. To confirm its possible involvement in pollen development, the full length cDNA of zm40l was ectopically expressed in tobacco plants under the control of a pollen specific promoter ZM13 (from maize). RT-PCR amplification

Jinxia Ma; Qian Zhao; Jingjuan Yu; Guangming Ao

2005-01-01

39

Elucidation of the Molecular Mechanisms for Aberrant Expression of Breast Cancer Specific Gene 1 in Invasive and Metastatic Breast Carcinomas.  

National Technical Information Service (NTIS)

We demonstrate that synuclein-gamma (SNCG) also named BCSG1 is abnormally expressed in a high percentage (67.5%) of tumor tissues of diversified cancer types including liver, esophagus, colon, gastric, lung, prostate, cervical, and breast cancer but rarel...

J. Liu

2005-01-01

40

The transglutaminase 2 gene is aberrantly hypermethylated in glioma  

PubMed Central

Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein/protein crosslinking. Because extracellular TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type. Because tumor invasiveness is a primary determinant of brain tumor aggressiveness, we sought to determine if TGM2 is targeted for epigenetic silencing in glioma. Analysis of TGM2 gene methylation in a panel of cultured human glioma cells indicated that the 5? flanking region of the TGM2 gene is hypermethylated and that this feature is associated with reduced TG2 expression as judged by immunoblotting. Further, culturing glioma cells in the presence of the global DNA demethylating agent 5-aza-2?-deoxycytidine and the histone deacetylase inhibitor Trichostatin A resulted in re-expression of TG2 in these lines. In primary brain tumors we observed that the TGM2 promoter is commonly hypermethylated and that this feature is a cancer-associated phenomenon. Using publically available databases, TG2 expression in gliomas was found to vary widely, with many tumors showing overexpression or underexpression of this gene. Since overexpression of TG2 leads to resistance to doxorubicin through the ectopic activation of NF?B, we sought to examine the effects of recombinant TG2 expression in glioma cells treated with commonly used brain tumor therapeutics. We observed that in addition to doxorubicin, TG2 expression drove resistance to CCNU; however, TG2 expression did not alter sensitivity to other drugs tested. Finally, a catalytically null mutant of TG2 was also able to support doxorubicin resistance in glioma cells indicating that transglutaminase activity is not necessary for the resistance phenotype.

Dyer, Lisa M.; Schooler, Kevin P.; Ai, Lingbao; Klop, Corinne; Qiu, Jingxin; Robertson, Keith D.

2010-01-01

41

Aberrantly Methylated Genes as Markers of Breast Malignancy.  

National Technical Information Service (NTIS)

The invention is directed to a method of diagnosing a cell proliferative disorder of breast tissue by determining the methylation status of nucleic acids obtained from a subject. Aberrant methylation of several genes including TWIST, HOXA5, NES-1, retinoi...

E. Evron N. Davidson N. Sacchi S. Sukumar W. C. Dooley

2005-01-01

42

Krüppel-Like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen  

Technology Transfer Automated Retrieval System (TEKTRAN)

Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like Factor 9 (KLF9), a member of the evolutionarily conserved Sp-family of transcription factors, is expressed in uterine stroma and glandular epithelium where it affects cellular proliferation, differenti...

43

Aberrant Expression of Hormone Receptors in Adrenal Cushing's Syndrome  

Microsoft Academic Search

In recent years, a novel understanding of the pathophysiology of adrenal Cushing's syndrome has emerged. The ectopic or aberrant\\u000a expression of G-protein-coupled hormone receptors in the adrenal cortex was found to play a central role in the regulation\\u000a of cortisol secretion in ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some unilateral adrenal adenomas.\\u000a Various aberrant receptors, functionally coupled to steroidogenesis,

Stavroula Christopoulos; Isabelle Bourdeau; André Lacroix

2004-01-01

44

DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function.  

PubMed

Genome-wide DNA methylation patterns are established and maintained by the coordinated action of three DNA methyltransferases (DNMTs), DNMT1, DNMT3A and DNMT3B. DNMT3B hypomorphic germline mutations are responsible for two-thirds of immunodeficiency, centromere instability, facial anomalies (ICF) syndrome cases, a rare recessive disease characterized by immune defects, instability of pericentromeric satellite 2-containing heterochromatin, facial abnormalities and mental retardation. The molecular defects in transcription, DNA methylation and chromatin structure in ICF cells remain relatively uncharacterized. In the present study, we used global expression profiling to elucidate the role of DNMT3B in these processes using cell lines derived from ICF syndrome and normal individuals. We show that there are significant changes in the expression of genes critical for immune function, development and neurogenesis that are highly relevant to the ICF phenotype. Approximately half the upregulated genes we analyzed were marked with low-level DNA methylation in normal cells that was lost in ICF cells, concomitant with loss of repressive histone modifications, particularly H3K27 trimethylation, and gains in transcriptionally active H3K9 acetylation and H3K4 trimethylation marks. In addition, we consistently observed loss of binding of the SUZ12 component of the PRC2 polycomb repression complex and DNMT3B to derepressed genes, including a number of homeobox genes critical for immune system, brain and craniofacial development. We also observed altered global levels of certain histone modifications in ICF cells, particularly ubiquitinated H2AK119. Therefore, this study provides important new insights into the role of DNMT3B in modulating gene expression and chromatin structure and reveals new connections between DNMT3B and polycomb-mediated repression. PMID:18029387

Jin, Bilian; Tao, Qian; Peng, Jinrong; Soo, Hui Meng; Wu, Wei; Ying, Jianming; Fields, C Robert; Delmas, Amber L; Liu, Xuefeng; Qiu, Jingxin; Robertson, Keith D

2007-11-20

45

Aberrant expression of the pluripotency marker SOX-2 in endometriosis.  

PubMed

Expression of the pluripotency factors SOX-2, OCT-4, KLF-4, and NANOG was analyzed by quantitative real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence microscopy in the endometrium, myometrium, and endometriotic tissue of 36 patients. Aberrant expression of SOX-2 may indicate a stem cell origin of endometriosis, whereas the presence of all progenitor markers in endometrial tissue marks the endometrium as a potential source for induced pluripotent stem cell generation. PMID:20850729

Götte, Martin; Wolf, Maria; Staebler, Annette; Buchweitz, Olaf; Kiesel, Ludwig; Schüring, Andreas N

2010-09-20

46

A mutation in the Arabidopsis thaliana cell wall biosynthesis gene pectin methylesterase 3 as well as its aberrant expression cause hypersensitivity specifically to Zn.  

PubMed

Defects in metal homeostasis factors are often accompanied by the loss of metal tolerance. Therefore, we screened for mutants with compromised growth in the presence of excess Zn(2+) in order to identify factors involved in Zn biology in plants. Here we report the isolation of six ozs (overly Zn sensitive) ethyl methanesulfonate Arabidopsis thaliana mutants with contrasting patterns of metal sensitivity, and the molecular characterization of two mutants hypersensitive specifically to Zn(2+) . Mutant ozs1 represents a non-functional allele of the vacuolar Zn transporter AtMTP1, providing additional genetic evidence for its major role in Zn(2+) tolerance in seedlings. Mutant ozs2 carries a semi-dominant mutation in the gene encoding pectin methylesterase 3 (AtPME3), an enzyme catalyzing demethylesterification of pectin. The mutation results in impaired proteolytic processing of AtPME3. Ectopic expression of AtPME3 causes strong Zn(2+) hypersensitivity that is tightly correlated with transcript abundance. Together these observations suggest detrimental effects on Golgi-localized processes. The ozs2 but not the ozs1 phenotype can be suppressed by extra Ca(2+) , indicating changes in apoplastic cation-binding capacity. However, we did not detect any changes in bulk metal-binding capacity, overall pectin methylesterification status or cell wall ultrastructure in ozs2, leading us to hypothesize that the ozs2 mutation causes hypersensitivity towards the specific interference of Zn ions with cell wall-controlled growth processes. PMID:23826687

Weber, Michael; Deinlein, Ulrich; Fischer, Sina; Rogowski, Michaela; Geimer, Stefan; Tenhaken, Raimund; Clemens, Stephan

2013-08-05

47

Specific depletion of the B-cell population induced by aberrant expression of human interferon regulatory factor 1 gene in transgenic mice.  

PubMed Central

Interferons (IFNs) are well known both as antiviral proteins and as potent regulators of cell growth and differentiation. In fact, IFNs inhibit growth of various normal and transformed cell types. Previously, a nuclear factor, IRF-1 (interferon regulatory factor 1), which binds to type I IFN and some IFN-inducible gene promoters, was identified and cloned. Since the IRF-1 gene is both virus and IFN inducible, an intriguing issue is raised as to whether the IRF-1 gene is functioning in IFN-mediated regulation of cell growth and differentiation. In this study, we generated transgenic mice carrying the human IRF-1 gene linked to the human immunoglobulin heavy-chain enhancer. In the transgenic mice, all the lymphoid tissues examined showed a dramatic reduction in the number of B lymphocytes (B cells). Preparation and analysis of bone marrow cells from the chimeric mice indicated that the bone marrow is the effective site for specific depletion of the B-cell population. In fact, transgenic bone marrow cells cocultured with a bone marrow-derived stromal cell line revealed an altered B-cell maturation pattern. Images

Yamada, G; Ogawa, M; Akagi, K; Miyamoto, H; Nakano, N; Itoh, S; Miyazaki, J; Nishikawa, S; Yamamura, K; Taniguchi, T

1991-01-01

48

Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinoma  

PubMed Central

METHODS—Cellular localisation of the cyclooxygenase (COX) isozymes COX-1 and COX-2 was analysed in 24 cholangiocarcinomas, including 17 matched tissues originating from non-tumorous liver tissue adjacent to tumours and seven biopsies of normal human liver, by immunohistochemistry using isozyme selective antibodies.?RESULTS—In normal liver, constitutive expression of COX-2 protein was a characteristic feature of hepatocytes whereas no COX-2 immunosignal was detectable in normal bile duct epithelium, Kupffer, and endothelial cells. In cholangiocarcinoma cells, COX-2 protein was strongly expressed at high frequency. The intensity, percentage of positive cells, and pattern of COX-2 expression were found to be independent of the stage of tumour differentiation. In hepatocytes of matched non-tumorous tissue, COX-2 expression was unaltered. In contrast, strong COX-1 expression was frequently localised to Kupffer cells, endothelial cells, and occasionally to hepatocytes, but not to bile duct epithelial cells. In approximately half of moderately and poorly differentiated but not well differentiated cholangiocarcinomas, weak to moderate COX-1 staining was found in tumour cells while COX-1 expression in Kupffer cells was much more pronounced.?CONCLUSION—Aberrant COX-2 expression occurs during the early stage while COX-1 over expression seems to be related to later stages of cholangiocarcinogenesis.???Keywords: cyclooxygenase; immunohistochemistry; cholangiocarcinoma; bile duct; hepatocyte; Kupffer cell

Chariyalertsak, S; Sirikulchayanonta, V; Mayer, D; Kopp-Schneider, A; Furstenberger, G; Marks, F; Muller-Decker, K

2001-01-01

49

Discovering causes and cures for cancer from gene expression analysis  

Microsoft Academic Search

Tumorigenesis is governed by a series of complex genetic and epigenetic changes. Both mechanisms can result in either the silencing or aberrant expression of messages in a cell. Gene expression profiling techniques such as the serial analysis of gene expression (SAGE) or microarray analysis can provide global overviews of these changes, as well identify key genes and pathways involved in

Ashani T. Weeraratna

2005-01-01

50

Functional premature polyadenylation signals and aberrant splicing within a recombinant protein coding sequence limit expression.  

PubMed

Recombinant glycoproteins can be produced at high levels in permanently transfected mammalian cells using expression vectors with strong viral promoters. CHO-K1 cell lines developed to produce the recombinant complement activator blocking protein, CAB-2 (a fusion of membrane co-factor protein, MCP, and decay accelerating factor, DAF), showed unexpectedly low expression. Northern blot analysis revealed that in addition to the expected 2300 base CAB-2 mRNA species, these cell lines expressed 790 and 1500 base mRNA species accounting for ?50% and ?10% of the total CAB-2 mRNA, respectively. RT-PCR studies established that the 1500 base species resulted from aberrant splicing from within the DAF region of the CAB-2 coding sequence to a site within the 3' untranslated region. 3' RACE analysis confirmed that the 790 base species resulted from premature polyadenylation at an AATAAA site within the MCP coding region of CAB-2. Another prematurely polyadenylated species, not observed on Northern blots, was observed in the DAF region by 3' RACE. Analysis of human tissues and cell lines revealed that these internal polyadenylation signals in native MCP and DAF coding regions also generated prematurely polyadenylated mRNAs. Genetic modification of these functional RNA processing elements within the CAB-2 gene eliminated the aberrant mRNA species and significantly increased recombinant CAB-2 expression. These results illustrate that protein expression can be limited by aberrant mRNA processing and demonstrate the importance of identifying and eliminating these mRNA processing signals from within coding DNA to maximize recombinant protein expression. PMID:23994311

Wijesuriya, Sujeewa D; Cotter, Robyn L; Horwitz, Arnold H

2013-08-28

51

Renormalization of Buchdahl-Rimmer aberration coefficients to RMS expressions  

NASA Astrophysics Data System (ADS)

The Buchdahl-Rimmer aberration coefficients are commonly used in optical design programs for the evaluation of third- and fifth-order aberrations. The information given by these coefficients is difficult to interpret since there is no direct relationship between the numerical value of the coefficient and its effect on the image quality, i.e. the most important aberration is not necessarily the one with the largest numerical value. To look at the effect that each aberration has on the image quality it is necessary to re-normalize the Buchdahl-Rimmer coefficients. The purpose of this work is to re-normalize the Buchdahl-Rimmer coefficients of the wave aberration function in terms of the strehl intensity ratio as well as to re-normalize the Buchdahl-Rimmer coefficients of the geometric aberration function in terms of the RMS spot size.

Rosete-Aguilar, Martha; Rayces, Juan L.

1996-02-01

52

Aberrant expression of Igf2/H19 in porcine parthenogenetic fetuses and placentas.  

PubMed

The aberrant expression of imprinted genes induces parthenogenetic fetal and placental dysplasia, thus leading to failures in embryonic development. Igf2 and H19 are co-expressed in endoderm and mesoderm-derived tissues and play an important role in normal embryo and extraembryonic development. In this study, the expression and methylation of Igf2/H19 in porcine parthenogenetic fetuses and placentas which had grown 28 days was examined first time to further characterize mammalian parthenogenesis. Weight and morphological comparisons were conducted between parthenogenetic embryos on Day 28 and normal fertilized embryos (control). The results indicated that parthenogenetic fetuses and placentas had smaller weights and volumes than those of the control. In addition, quantitative RT-PCR (qRT-PCR) analysis was performed to determine Igf2/H19 expression levels, showing that the expression of H19 was up-regulated, while Igf2 expression was almost undetectable in both parthenogenetic fetuses and placentas. As a potential mechanism underlying this disrupted expression, the methylation of Igf2/H19 DMR3 was detected using bisulfite sequencing PCR analysis, which revealed the significant hypomethylation of DMR3 in parthenogenetic fetuses and placentas. These results suggest that disruption of Igf2/H19 expression in parthenogenetic fetuses and placentas contributes to implantation failure and/or abortion in swine parthenogenesis, which might be associated with differential methylation patterns in the imprinting control region of imprinted genes. PMID:23660367

Han, Xiaolei; Ouyang, Hongsheng; Chen, Xianju; Huang, Yongye; Song, Yuning; Zhang, Mingjun; Pang, Daxin; Lai, Liangxue; Li, Zhanjun

2013-04-19

53

The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways.  

PubMed

MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation. In cancer research, a growing body of evidence has indicated that miRNAs are aberrantly expressed in many types of human cancers and can function either as tumor suppressors or oncogenes. Bioinformatic predictions suggest that miRNAs regulate more than 30% of protein-coding genes. Aberrant expression of miRNAs in cancer cells causes destruction of miRNA-regulated messenger RNA networks. Therefore, the identification of miRNA-regulated cancer pathways is important for understanding the molecular mechanisms of human cancer. Searching for the aberrant expression of miRNAs in cancer cells is the first step in the functional analysis of miRNAs in cancer cells. Genome-wide miRNA expression signatures can rapidly and precisely reveal aberrant expression of miRNA in cancers. The miRNA expression signatures of human cancers have revealed that miR-375 is significantly downregulated in cancer cells. Our recent data on maxillary sinus, hypopharyngeal and esophageal squamous cell carcinomas have suggested that miR-375 is frequently downregulated and functions as a tumor suppressor that targets several oncogenic genes in cancer cells. In this review, we focus on several types of human squamous cell carcinoma and describe the aberrant expression of miRNAs and the cancer pathways they regulate in these diseases. PMID:22718022

Kinoshita, Takashi; Hanazawa, Toyoyuki; Nohata, Nijiro; Okamoto, Yoshitaka; Seki, Naohiko

2012-06-21

54

Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle.  

PubMed

Vascular endothelial growth factor A (VEGF-A) induces strong angiogenesis and it has been widely used in proangiogenic gene therapy studies. However, little is known about long-term effects of VEGF-A expression in skeletal muscle. Here the long- term effects of adeno-associated virus (AAV) encoding human VEGF-A(165) (AAV-VEGF-A) gene transfer in normal and ischemic rabbit hindlimb skeletal muscles were studied. AAV-LacZ was used as a control. In one-year follow-up, a remarkable increase in skeletal muscle perfusion compared with AAV-LacZ was observed measured with Doppler and contrast pulse sequence ultrasound. Angiogenesis was also seen in histology as enlarged and sprouting capillaries. In addition to favorable angiogenic effects, aberrant vascular structures with CD31 positive cell layers were seen inside muscle fibers after AAV-VEGF-A gene transfer. Importantly, we found increased amounts of extracellular matrix with a high number of macrophages and fibrosis in AAV-VEGF-A transduced muscles. No changes in skeletal muscle morphology were detected in AAV-LacZ transduced muscles. Our results indicate that local AAV-VEGF-A gene transfer efficiently promotes long-term angiogenesis in large animal model. However, non-regulated expression of VEGF-A causes unfavorable changes in muscle morphology, which suggests the need for regulation of the transgene expression in long-term AAV-mediated VEGF-A gene transfer applications. PMID:21562595

Karvinen, H; Pasanen, E; Rissanen, T T; Korpisalo, P; Vähäkangas, E; Jazwa, A; Giacca, M; Ylä-Herttuala, S

2011-05-12

55

Aberrant Gene Promoter Methylation Associated with Sporadic Multiple Colorectal Cancer  

PubMed Central

Background Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect. Methodology/Principal Findings We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p?=?0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p?=?0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p?=?0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r?=?0.64, p?=?0.17), SFRP1 (r?=?0.83, 0.06), HPP1 (r?=?0.64, p?=?0.17), 3OST2 (r?=?0.83, p?=?0.06) and GATA4 (r?=?0.6, p?=?0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene. Conclusions These results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.

Gonzalo, Victoria; Lozano, Juan Jose; Munoz, Jenifer; Balaguer, Francesc; Pellise, Maria; de Miguel, Cristina Rodriguez; Andreu, Montserrat; Jover, Rodrigo; Llor, Xavier; Giraldez, M. Dolores; Ocana, Teresa; Serradesanferm, Anna; Alonso-Espinaco, Virginia; Jimeno, Mireya; Cuatrecasas, Miriam; Sendino, Oriol; Castellvi-Bel, Sergi; Castells, Antoni

2010-01-01

56

Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL.  

PubMed

Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1) involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6) and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression. PMID:23487523

Simko, Stephen J; Voicu, Horatiu; Carofino, Brandi L; Justice, Monica J

2012-10-18

57

Mouse Lymphoblastic Leukemias Induced by Aberrant Prdm14 Expression Demonstrate Widespread Copy Number Alterations Also Found in Human ALL  

PubMed Central

Aberrant expression and activation of oncogenes in somatic cells has been associated with cancer initiation. Required for reacquisition of pluripotency in the developing germ cell, PRDM14 initiates lymphoblastic leukemia when misexpressed in murine bone marrow. Activation of pluripotency in somatic cells can lead to aneuploidy and copy number alterations during iPS cell generation, and we hypothesized that PRDM14-induced lymphoblastic leukemias would demonstrate significant chromosomal damage. High-resolution oligo array comparative genomic hybridization demonstrated infrequent aneuploidy but frequent amplification and deletion, with amplifications occurring in a 5:1 ratio with deletions. Many deletions (i.e., Cdkn2a, Ebf1, Pax5, Ikzf1) involved B-cell development genes and tumor suppressor genes, recapitulating deletions occurring in human leukemia. Pathways opposing senescence were frequently deactivated via Cdkn2a deletion or Tbx2 amplification, with corollary gene expression. Additionally, gene expression studies of abnormal pre-leukemic B-precursors showed downregulation of genes involved in chromosomal stability (i.e., Xrcc6) and failure to upregulate DNA repair pathways. We propose a model of leukemogenesis, triggered by pluripotency genes like Prdm14, which involves ongoing DNA damage and failure to activate non-homologous end-joining secondary to aberrant gene expression.

Simko, Stephen J.; Voicu, Horatiu; Carofino, Brandi L.; Justice, Monica J.

2012-01-01

58

Specific Chromosomal Aberrations and Amplification of the AIB1 Nuclear Receptor Coactivator Gene in Pancreatic Carcinomas  

PubMed Central

To screen pancreatic carcinomas for chromosomal aberrations we have applied molecular cytogenetic techniques, including fluorescent in situ hybridization, comparative genomic hybridization, and spectral karyotyping to a series of nine established cell lines. Comparative genomic hybridization revealed recurring chromosomal gains on chromosome arms 3q, 5p, 7p, 8q, 12p, and 20q. Chromosome losses were mapped to chromosome arms 8p, 9p, 17p, 18q, 19p, and chromosome 21. The comparison with comparative genomic hybridization data from primary pancreatic tumors indicates that a specific pattern of chromosomal copy number changes is maintained in cell culture. Metaphase chromosomes from six cell lines were analyzed by spectral karyotyping, a technique that allows one to visualize all chromosomes simultaneously in different colors. Spectral karyotyping identified multiple chromosomal rearrangements, the majority of which were unbalanced. No recurring reciprocal translocation was detected. Cytogenetic aberrations were confirmed using fluorescent in situ hybridization with probes for the MDR gene and the tumor suppressor genes p16 and DCC. Copy number increases on chromosome 20q were validated with a probe specific for the nuclear receptor coactivator AIB1 that maps to chromosome 20q12. Amplification of this gene was identified in six of nine pancreatic cancer cell lines and correlated with increased expression.

Ghadimi, B. Michael; Schrock, Evelin; Walker, Robert L.; Wangsa, Danny; Jauho, Annukka; Meltzer, Paul S.; Ried, Thomas

1999-01-01

59

Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology.  

PubMed

Cone-rod dystrophy 6 (CORD6) is an inherited blindness that presents with defective cone photoreceptor function in childhood, followed by loss of rod function. CORD6 results from mutations in GUCY2D, the human gene encoding retinal guanylate cyclase 1 (RETGC-1). RETGC-1 functions in phototransduction, synthesising cGMP to open ion channels in photoreceptor outer segments. As there is limited histopathological data on the CORD6 retina, our goal was to generate a CORD6 model by expressing mutant human RETGC-1 in zebrafish cone photoreceptors and to investigate effects on retinal morphology and function. cDNAs encoding wildtype and mutant (E837D R838S) RETGC-1 were cloned under the control of the cone-specific gnat2 promoter and microinjected into zebrafish embryos to generate transgenic lines. RETGC-1 mRNA expression in zebrafish eyes was confirmed by RT-PCR. Fluorescent microscopy analysed retinal morphology and visual behaviour was quantified by the optokinetic response (OKR). Stable transgenic lines expressing mutant or wildtype human RETGC-1 in zebrafish eyes were generated. OKR assays of 5-day-old larvae did not uncover any deficits in visual behaviour. However, transgenic (E837D R838S) RETGC-1 expression results in aberrant cone morphology and a reduced cone density. A reduction in the number of photoreceptor nuclei, the thickness of the outer nuclear layer and the labelling of rod outer segments, particularly in the central retina, was evident. Expression of mutant human RETGC-1 leads to a retinal phenotype that includes aberrant photoreceptor morphology and a reduced number of photoreceptors. This phenotype likely explains the compromised visual function, characteristic of CORD6. PMID:23328348

Collery, Ross F; Cederlund, Maria L; Kennedy, Breandán N

2013-01-15

60

Prioritizing cancer-related genes with aberrant methylation based on a weighted protein-protein interaction network  

PubMed Central

Background As an important epigenetic modification, DNA methylation plays a crucial role in the development of mammals and in the occurrence of complex diseases. Genes that interact directly or indirectly may have the same or similar functions in the biological processes in which they are involved and together contribute to the related disease phenotypes. The complicated relations between genes can be clearly represented using network theory. A protein-protein interaction (PPI) network offers a platform from which to systematically identify disease-related genes from the relations between genes with similar functions. Results We constructed a weighted human PPI network (WHPN) using DNA methylation correlations based on human protein-protein interactions. WHPN represents the relationships of DNA methylation levels in gene pairs for four cancer types. A cancer-associated subnetwork (CASN) was obtained from WHPN by selecting genes associated with seed genes which were known to be methylated in the four cancers. We found that CASN had a more densely connected network community than WHPN, indicating that the genes in CASN were much closer to seed genes. We prioritized 154 potential cancer-related genes with aberrant methylation in CASN by neighborhood-weighting decision rule. A function enrichment analysis for GO and KEGG indicated that the optimized genes were mainly involved in the biological processes of regulating cell apoptosis and programmed cell death. An analysis of expression profiling data revealed that many of the optimized genes were expressed differentially in the four cancers. By examining the PubMed co-citations, we found 43 optimized genes were related with cancers and aberrant methylation, and 10 genes were validated to be methylated aberrantly in cancers. Of 154 optimized genes, 27 were as diagnostic markers and 20 as prognostic markers previously identified in literature for cancers and other complex diseases by searching PubMed manually. We found that 31 of the optimized genes were targeted as drug response markers in DrugBank. Conclusions Here we have shown that network theory combined with epigenetic characteristics provides a favorable platform from which to identify cancer-related genes. We prioritized 154 potential cancer-related genes with aberrant methylation that might contribute to the further understanding of cancers.

2011-01-01

61

Aberrant Promoter Methylation of Multiple Genes in Non-Small Cell Lung Cancers1  

Microsoft Academic Search

Aberrant methylation of CpG islands acquired in tumor cells in pro- moter regions is one method for loss of gene function. We determined the frequency of aberrant promoter methylation (referred to as methylation) of the genes retinoic acid receptor b-2 (RARb), tissue inhibitor of metal- loproteinase 3 (TIMP-3), p16INK4a, O6-methylguanine-DNA-methyltrans- ferase (MGMT), death-associated protein kinase (DAPK), E-cadherin (ECAD), p14ARF, and

Sabine Zochbauer-Muller; Kwun M. Fong; Arvind K. Virmani; Joseph Geradts; Adi F. Gazdar; John D. Minna

2001-01-01

62

Identical Splicing of Aberrant Epidermal Growth Factor Receptor Transcripts from Amplified Rearranged Genes in Human Glioblastomas  

Microsoft Academic Search

The epidermal growth factor receptor gene has been found to be amplified and rearranged in human glioblastomas in vivo. Here we present the sequence across a splice junction of aberrant epidermal growth factor receptor transcripts derived from corresponding and uniquely rearranged genes that are coamplified and coexpressed with non-rearranged epidermal growth factor receptor genes in six primary human glioblastomas. Each

Noriaki Sugawa; A. Jonas Ekstrand; C. David James; V. Peter Collins

1990-01-01

63

The contribution of chromosome aberrations to the precision of human gene mapping  

Microsoft Academic Search

Unbalanced chromosome aberrations detected by routine chromosome diagnostic services can be used for gene mapping by gene dosage. This procedure, once discredited by early observations in Down’s syndrome, has now provided some of the most precise intrachromosomal gene localizations known and these are reviewed. Cytogeneticists have an obligation to see that every opportunity is taken to obtain mapping information from

M. A. Ferguson-Smith; D. A. Aitken

1982-01-01

64

Biclonal light chain gammopathy with aberrant CD33 expression in secondary plasma cell leukemia  

PubMed Central

Plasma cell leukemia is a rare neoplastic proliferation of circulating plasma cells. Clonal proliferations of plasma cells, such as in plasma cell leukemia or plasma cell myeloma, are typically characterized by production of a monoclonal heavy and/or light chain immunoglobulin. We present a case of a secondary plasma cell leukemia arising from plasma cell myeloma with dual expression of lambda and kappa light chains along with aberrant expression of CD33, CD20, and dim CD56. This case emphasizes the importance of recognizing aberrant immunophenotypes in plasma cell leukemias and represents the first reported case of biclonal light chain expression in a secondary plasma cell leukemia.

Gentry, Michael; Pettenati, Mark; Pang, Changlee S

2013-01-01

65

Renormalization of the Buchdahl-Rimmer third- and fifth-order geometric aberration coefficients to RMS wave aberration function expressions.  

NASA Astrophysics Data System (ADS)

The Buchdahl-Rimmer third- and fifth-order geometric aberration coefficients are converted or renormalized to a RMS value of the wave aberration function. The purpose of this is to make it possible to compare different aberration coefficients directly since any aberrations which have the same renormalized coefficients will have the same effect on the image quality in terms of the Strehl intensity ratio. This is an advantage which, until now, has only been obtained using the renormalized Zernike coefficients.

Rosete-Aguilar, M.; Rayces, J.

1995-12-01

66

Role of inducible nitric oxide synthase expression in aberrant crypt foci-adenoma-carcinoma sequence  

Microsoft Academic Search

AIM: To investigate the expression of inducible nitric oxide synthase (iNOS) in aberrant crypt foci (ACF) -adenoma- carcinoma sequence and its relation with tumor cell apoptosis, proliferation and angiogenesis. METHODS: The expression of iNOS, proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) in different stages of colorectal cancer were studied by immunohistochemical method from 30 normal tissues, 30 nonhyperplastic

Mei-Hua Xu; Chang-Sheng Deng; You-Qing Zhu; Jun Lin

2003-01-01

67

Aberrant Promoter Methylation of the ABCG2 Gene in Renal Carcinoma?  

PubMed Central

ABCG2 is a ubiquitous ATP-binding cassette transmembrane protein that is important in clinical drug resistance. Little is known about the mechanism(s) regulating the expression of ABCG2. We hypothesized that DNA methylation could play a role in the epigenetic regulation of ABCG2 gene expression. The promoter methylation status of three renal carcinoma cell lines was assessed with restriction enzyme digestion-coupled PCR and bisulfite genomic sequencing. Both UOK121 and UOK143, with known methylation of the VHL promoter, showed induction of ABCG2 expression after 5-aza-2?-deoxycytidine (5-aza-dC) treatment, suggesting that aberrant methylation of the ABCG2 gene was associated with gene silencing. In vitro methylation of the ABCG2 promoter-driven luciferase reporter vector resulted in a significant inhibition of transcription. Our data suggested that the ABCG2 gene is regulated coordinately at both histone and DNA levels. A chromatin immunoprecipitation assay demonstrated that the methylated promoter in UOK121 and UOK143, but not the unmethylated one in UOK181, is associated with the methyl CpG binding domain proteins (MBDs), MBD2 and MeCP2. Histone deacetylase 1 and a corepressor, mSin3A, were identified binding to the promoter region containing the CpG island, thereby suppressing ABCG2 transcription. Reactivation of ABCG2 was achieved by treatment with 5-aza-dC, a demethylating agent, concomitant with the release of MBDs from the promoter. Furthermore, the association of methylated lysine 9 on histone H3, a hallmark of promoter methylation, with the promoter was reduced following 5-aza-dC treatment. These data suggest that DNA methylation-dependent formation of a repressor complex in the CpG island contributes to inactivation of ABCG2.

To, Kenneth K. W.; Zhan, Z.; Bates, Susan E.

2006-01-01

68

Aberrant hypermethylation of miR-9 genes in gastric cancer  

PubMed Central

Carcinogenesis of the stomach involves multiple steps including genetic mutation or epigenetic alteration of tumor suppressor genes or oncogenes. Recently, tumor suppressive miRNAs have been shown to be deregulated by aberrant hypermethylation during gastric cancer progression. In this study, we demonstrate that three independent genetic loci encoding for miR-9 (miR-9-1, miR-9-2 and miR-9-3) are simultaneously modified by DNA methylation in gastric cancer cells. Methylation-mediated silencing of these three miR-9 genes can be reactivated in gastric cancer cells through 5-Aza-dC treatment. Subsequent analysis of the expression levels of miR-9 showed that it was significantly downregulated in gastric cancers compared with adjacent normal tissues (p value < 0.005). A similar tendency toward a tumor-specific DNA methylation pattern was shown for miR-9-1, miR-9-2 and miR-9-3 in 72 primary human gastric cancer specimens. Ectopic expression of miR-9 inhibited cell proliferation, migration and invasion, suggesting its tumor suppressive potential in gastric cancer progression.

Tsai, Kuo-Wang; Liao, Yu-Lun; Wu, Chew-Wun; Hu, Ling-Yueh; Li, Sung-Chou; Chan, Wen-Ching; Ho, Meng-Ru; Lai, Chun-Hung; Kao, Hsiao-Wei; Fang, Wen-Liang; Huang, Kuo-Hung

2011-01-01

69

Viral Gene Expression Assays  

Center for Biologics Evaluation and Research (CBER)

Text Version... Development of reagents. 9 XMRV gene products (VP62). ... 3 forms of sequence-verified Gateway Entry clones; 4 types of protein expression clones; ... More results from www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials

70

GENE EXPRESSION NETWORKS  

EPA Science Inventory

"Gene expression network" is the term used to describe the interplay, simple or complex, between two or more gene products in performing a specific cellular function. Although the delineation of such networks is complicated by the existence of multiple and subtle types of intera...

71

GENE EXPRESSION PROFILING  

Technology Transfer Automated Retrieval System (TEKTRAN)

DNA microarray technology is fast becoming a standard tool for gene expression analysis. The laboratory methods and protocols for array construction, processing, and hybridization are well established. Many of the initial plant genome sequencing projects are providing large sets of expressed seque...

72

Regulation of Major Histocompatibility Class II Gene Expression in FRTL-5 Thyrocytes: Opposite Effects of Interferon and Methimazole  

Microsoft Academic Search

Aberrant expression of major histocompatibility complex (MHC) class II antigens is associated with autoimmune thyroid disease; aberrant expression duplicating the autoimmune state can be induced by interferon-g (IFNg). We have studied IFNg-induced human leu- kocyte antigen (HLA)-DRa gene expression in rat FRTL-5 thyroid cells to identify the elements and factors important for aberrant expression. Using an HLA-DRa 59-flanking region construct

VALERIA MONTANI; MINHO SHONG; SHIN-ICHI TANIGUCHI; KOICHI SUZUKI; CESIDIO GIULIANI; GIORGIO NAPOLITANO; JUN SAITO; MOTOYASU SAJI; BRUNO FIORENTINO; ANDREAS M. REIMOLD; DINAH S. SINGER; LEONARD D. KOHN

1998-01-01

73

Gene expression in bladder tumors  

US Patent & Trademark Office Database

Methods for analyzing tumor cells, particularly bladder tumor cells employ gene expression analysis of samples. Gene expression patterns are formed and compared to reference patterns. Alternatively gene expression patterns are manipulated to exclude genes which are expressed in contaminating cell populations. Another alternative employs subtraction of the expression of genes which are expressed in contaminating cell types. These methods provide improved accuracy as well as alternative basis for analysis from diagnostic and prognostic tools currently available.

2002-01-01

74

Hypermethylation and aberrant expression of Wnt antagonist secreted frizzled-related protein 1 in gastric cancer  

Microsoft Academic Search

AIM: To identify the methylation of secreted frizzled- related protein 1 (SFRP1) in gastric cancer and to investigate the aberrant expression of SFRP1 and its correlation with the clinical pathological features of patients. METHODS: We determined SFRP1 methylation and SFRP1 mRNA expression in 3 gastric cancer cell lines SGC-7901, BGC-823, HGC-27, from 52 primary gastric cancer specimens and matched tumor

Cheng-Hai Zhao; Xian-Min Bu; Ning Zhang

75

Up-Regulated Expression and Aberrant DNA Methylation of LEP and SH3PXD2A in Pre-Eclampsia  

PubMed Central

The primary mechanism underlying pre-eclampsia (PE) remains one of the most burning problems in the obstetrics and gynecology. In this study, we performed an expression profiling screen and detected 1312 genes that were differentially expressed (p<0.05 and fold change >1.5) in PE placentas, including LEP and SH3PXD2A. After validating the microarray results, we conducted the quantitative methylation analysis of LEP and SH3PXD2A in preeclamptic (n?=?16) versus normal placentas (n?=?16). Our results showed that many CpG sites close to the transcriptional start site (TSS) of LEP gene were hypomethylated in placentas from pregnancies with PE compared with those of in controls, including the TSS position (p?=?0.001), the binding sites of Sp1 (p?=?1.57×10?4), LP1 (p?=?0.023) and CEBP? (p?=?0.031). Luciferase reporter analysis confirmed the aberrant methylation of LEP promoter and CEBP? co-transfection had a role in the regulation of gene expression. Our results indicated the aberrant LEP promoter methylation was involved in the development of PE. We did not find a significant methylation differences between groups in the promoter region of SH3PXD2A, however, a CGI region in the gene body (CGI34) presented a higher methylation in preeclamptic placentas (p?=?1.57×10?4), which might promote the efficiency of gene transcription. We speculated that SH3PXD2A may take part in the pathogenesis of PE through its role in the regulation of trophoblast cell invasion in the period of placenta formation.

Li, Xiaotian; Li, Qiaoli; Xu, Jiawei; Zhang, Junyu; Liu, Yun; Xing, Qinghe; Wang, Lei; He, Lin; Zhao, Xinzhi

2013-01-01

76

Heterogeneity of aberrant immunoglobulin expression in cancer cells  

Microsoft Academic Search

Accumulating evidence has shown that immunoglobulin (Ig) is ‘unexpectedly’ expressed by epithelial cancer cells and that it can promote tumor growth. The main purpose of this study was to explore the components of the cancerous Ig and its possible function. The presence of cancerous Ig in the Golgi apparatus was confirmed by immunofluorescence, indirectly suggesting that the cancerous Ig was

Duosha Hu; Zhi Duan; Ming Li; Yiqun Jiang; Haidan Liu; Hui Zheng; Lili Li; Ann M Bode; Zigang Dong; Ya Cao

2011-01-01

77

Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma  

PubMed Central

Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.

Shen, Jing; Wang, Shuang; Zhang, Yu-Jing; Kappil, Maya A.; Chen Wu, Hui; Kibriya, Muhammad G.; Wang, Qiao; Jasmine, Farzana; Ahsan, Habibul; Lee, Po-Huang; Yu, Ming-Whei; Chen, Chien-Jen; Santella, Regina M.

2012-01-01

78

Quantifying gene expression.  

PubMed

Identifying those genes that are expressed and at what levels is an essential part of almost any biological inquiry at the cellular level. Techniques such as Northern blot have been in existence for decades to perform this task, but advances in molecular biology and bioinstrumentation have led to the development of a variety of new techniques with a range of sensitivities, throughputs and quantitative capabilities. This review focuses on the latter issue. For several commonly used gene expression techniques, the extent and range of quantitative applicability are reviewed, and approaches for maximizing the accuracy and precision of these measurements are discussed. PMID:12074198

Roth, Charles M

2002-07-01

79

Aberrant expression and phosphorylation of ?-catenin in human colorectal cancer  

Microsoft Academic Search

The cytoplasmic domain of cadherins is known to associate with the intracellular proteins, catenins, which link cadherins to the actin-based cytoskeleton. In this study, we immunohistochemically investigated the expression of beta-catenin as well as E-cadherin and alpha-catenin in 86 human colorectal cancers, and we analysed their coexpression pattern and relationship to clinicopathological factors. In cancerous tissues, the frequency of reduced

T Takayama; H Shiozaki; Y Doki; H Oka; M Inoue; M Yamamoto; S Tamura; S Shibamoto; F Ito; M Monden

1998-01-01

80

Chromatin Structure Gene Expression  

Microsoft Academic Search

It is now well understood that chromatin structure is perturbed in the neighborhood of expressed genes. This is most obvious in the neighborhood of promoters and enhancers, where hypersensitivity to nucleases marks sites that no longer carry canonical nucleosomes, and to which transcription factors bind. To study the relationship between transcription factor binding and the generation of these hypersensitive regions,

Gary Felsenfeld; Joan Boyes; Jay Chung; David Clark; Vasily Studitsky

1996-01-01

81

Interleukin-6 is responsible for aberrant B-cell receptor-mediated regulation of RAG expression in systemic lupus erythematosus  

PubMed Central

Defective regulation of secondary immunoglobulin V(D)J gene rearrangement promotes the production of autoantibodies in systemic lupus erythematosus (SLE). It remains unclear, however, whether the regulation of the recombination-activating genes RAG1 and RAG2 is effective in SLE. RAG1 and RAG2 messenger RNA expression was analysed before and after in vitro activation of sorted CD19+ CD5– B cells with anti-immunoglobulin M antibodies, in 20 SLE patients and 17 healthy controls. The expression of CDK2 and p27Kip1 regulators of the RAG2 protein, were examined. The levels of interleukin-6 (IL-6) and its influence on RAG regulation were also evaluated in vitro. SLE patients had increased frequency of RAG-positive B cells. B-cell receptor (BCR) engagement induced a shift in the frequency of ?- and ?-positive cells, associated with a persistence of RAG messenger RNA and the maintenance of RAG2 protein within the nucleus. While expression of the RAG2-negative regulator CDK2 was normal, the positive regulator p27Kip1 was up-regulated and enhanced by BCR engagement. This effect was the result of the aberrant production of IL-6 by SLE B cells. Furthermore, IL-6 receptor blockade led to a reduction in p27Kip1 expression, and allowed the translocation of RAG2 from the nucleus to the cytoplasm. Our study indicates that aberrant production of IL-6 contributes to the inability of SLE B cells to terminate RAG protein production. Therefore, we hypothesize that because of constitutive IL-6 signalling in association with BCR engagement, SLE B cells would become prone to secondary immunoglobulin gene rearrangements and autoantibody production.

Hillion, Sophie; Garaud, Soizic; Devauchelle, Valerie; Bordron, Anne; Berthou, Christian; Youinou, Pierre; Jamin, Christophe

2007-01-01

82

Chromosomal profiles of gene expression in Huntington's disease  

Microsoft Academic Search

Recent studies suggested that Huntington's disease is due to aberrant interactions between mutant huntingtin protein, transcription factors and transcriptional co-activators resulting in widespread transcriptional dysregu- lation. Mutant huntingtin also interacts with histone acetyltransferases, consequently interfering with the acet- ylation and deacetylation states of histones. Because histone modifications and chromatin structure coordinate the expression of gene clusters, we have applied a

Alexander N. Anderson; Federico Roncaroli; Angela Hodges; Manuel Deprez; Federico E. Turkheimer

2008-01-01

83

Aberrant Regulation of the MRP3 Gene in Non-Small Cell Lung Carcinoma  

PubMed Central

Introduction Multidrug-resistance Protein-3 (MRP3), a membrane bound transporter, facilitates efflux of toxic compounds, including certain chemotherapies, out of cells. Aberrant MRP3 expression has been linked to drug resistance in NSCLC. We sought to determine if tumor MRP3 expression patterns correlate with the mutational status of upstream regulators, including nuclear factor erythroid-2–related factor 2 (Nrf2) and its functional repressor Keap1 in NSCLC cell lines and patient samples. Methods To identify putative Nrf2 binding sites in the MRP3 promoter and to evaluate Keap1, Nrf2, and p53 mutations status in 4 cell lines and 33 NSCLC surgically resected tumor specimens with regard to their impact on MRP3 levels. Results ChIP analysis of the MRP3 promoter revealed an almost threefold increase in Nrf2 binding to the third putative Nrf2 binding sequence distal to the start site, demonstrating direct regulation of MRP3 by Nrf2. In NSCLC cell lines elevated Nrf2 protein was observed in cell lines with increased MRP3 RNA expression. In patient tumor specimens, the presence of mutations in Keap1/Nrf2 correlated with MRP3 RNA levels (p<0.05). p53 mutations were observed in 33% of cases, and all Keap1 mutant-positive tumors possessed a p53 mutation (n=5; p=0.0019). Conclusions We demonstrate direct involvement between the transcription factor Nrf2 and the MRP3 promoter, which leads to the upregulation of the MRP3 gene. Additionally, we found a statistically significant correlation between the presence of Keap1/Nrf2 mutations and increased MRP3 mRNA levels in our NSCLC patient samples.

Mahaffey, Christopher M.; Mahaffey, Nichole C.; Holland, William; Zhang, Hongqiao; Gandara, David R.; Mack, Philip C.; Forman, Henry Jay

2011-01-01

84

C4 GENE EXPRESSION.  

PubMed

C4 plants, including maize, Flaveria, amaranth, sorghum, and an amphibious sedge Eleocharis vivipara, have been employed to elucidate the molecular mechanisms and signaling pathways that control C4 photosynthesis gene expression. Current evidence suggests that pre-existing genes were recruited for the C4 pathway after acquiring potent and surprisingly diverse regulatory elements. This review emphasizes recent advances in our understanding of the creation of C4 genes, the activities of the C4 gene promoters consisting of synergistic and combinatorial enhancers and silencers, the use of 5' and 3' untranslated regions for transcriptional and posttranscriptional regulations, and the function of novel transcription factors. The research has also revealed new insights into unique or universal mechanisms underlying cell-type specificity, coordinate nuclear-chloroplast actions, hormonal, metabolic, stress and light responses, and the control of enzymatic activities by phosphorylation and reductive processes. PMID:15012208

Sheen, Jen

1999-06-01

85

Gene expression in aggressive fibromatosis.  

PubMed

Aggressive fibromatosis represents a group of tumors with heterogeneous patterns of biologic behavior. In this study, gene expression in 12 samples of aggressive fibromatosis, as well as that in samples of normal skeletal muscle and a variety of normal tissues, was determined at Gene Logic Inc (Gaithersburg, MD), with the use of Affymetrix GeneChip U_133 arrays containing approximately 33,000 genes. Gene-expression analysis was performed with the Gene Logic Gene Express software system. Differences in gene expression were quantified as the fold change in gene expression between the sets of fibromatosis tissue and normal skeletal muscle. A set of genes was then identified that was significantly overexpressed in aggressive fibromatosis compared with expression in normal muscle. This set of genes was then further examined for expression in a variety of normal tissues. We identified genes that were selectively overexpressed in aggressive fibromatosis compared with expression in 448 samples comprising 16 different nonneoplastic tissues. In particular, ADAM12, WISP-1, SOX-11, and fibroblast activation protein-alpha were uniquely overexpressed in aggressive fibromatosis compared with expression in normal tissues. In addition, the technique of Eisen clustering identified 2 distinct subgroups of aggressive fibromatosis with regard to gene expression. We conclude that gene-expression patterns may be useful in the further classification of subtypes of aggressive fibromatosis and that such classification could have clinical significance. PMID:14966464

Skubitz, Keith M; Skubitz, Amy P N

2004-02-01

86

Potential Downstream Target Genes of Aberrant ETS Transcription Factors Are Differentially Affected in Ewing's Sarcoma and Prostate Carcinoma  

PubMed Central

FLI1 and ERG, the major ETS transcription factors involved in rearrangements in the Ewing’s sarcoma family of tumors (ESFT) and in prostate carcinomas (PCa), respectively, belong to the same subfamily, having 98% sequence identity in the DNA binding domain. We therefore decided to investigate whether the aberrant transcription factors in both malignancies have some common downstream targets. We crossed a publicly available list of all putative EWSR1-FLI1 target genes in ESFT with our microarray expression data on 24 PCa and 6 non-malignant prostate tissues (NPT) and choose four genes among the top-most differentially expressed between PCa with (PCa ERG+) and without (PCa ETS-) ETS fusion genes (HIST1H4L, KCNN2, ECRG4 and LDOC1), as well as four well-validated direct targets of the EWSR1-FLI1 chimeric protein in ESFT (NR0B1, CAV1, IGFBP3 and TGFBR2). Using quantitative expression analysis in 16 ESFT and seven alveolar rhabdomyosarcomas (ARMS), we were able to validate the four genes previously described as direct targets of the EWSR1-FLI1 oncoprotein, showing overexpression of CAV1 and NR0B1 and underexpression of IGFBP3 and TGFBR2 in ESFT as compared to ARMS. Although none of these four genes showed significant expression differences between PCa ERG+ and PCa ETS-, CAV1, IGFBP3 and TGFBR2 were less expressed in PCa in an independent series of 56 PCa and 15 NPT, as also observed for ECRG4 and LDOC1, suggesting a role in prostate carcinogenesis in general. On the other hand, we demonstrate for the first time that both HIST1H4L and KCNN2 are significantly overexpressed in PCa ERG+ and that ERG binds to the promoter of these genes. Conversely, KCNN2 was found underexpressed in ESFT relative to ARMS, suggesting that the EWSR1-ETS oncoprotein may have the opposite effect of ERG rearrangements in PCa. We conclude that aberrant ETS transcription factors modulate target genes differently in ESFT and PCa.

Ribeiro, Franclim R.; Barros-Silva, Joao D.; Almeida, Mafalda; Costa, Vera L.; Cerveira, Nuno; Skotheim, Rolf I.; Lothe, Ragnhild A.; Henrique, Rui; Jeronimo, Carmen; Teixeira, Manuel R.

2012-01-01

87

MicroRNAs function as tumor suppressors or oncogenes: aberrant expression of microRNAs in head and neck squamous cell carcinoma.  

PubMed

MicroRNAs (miRNAs) are endogenous short non-coding RNA molecules that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Bioinformatic analyses predict that miRNAs regulate more than 30% of protein coding genes. To date, 1921 human mature miRNAs have been registered in miRBase release 18.0 (http://microrna.sanger.ac.uk/). A growing body of evidence suggests that miRNAs are aberrantly expressed in many human carcinomas and that they play key roles in the initiation, development and metastasis of human cancers, including head and neck squamous cell carcinoma (HNSCC). In this review, eight genome-wide miRNA expression profiles were used to selected aberrantly expressed miRNAs (up-regulated and down-regulated miRNAs) in HNSCC clinical specimens including our miRNA profiles of hypopharyngeal and maxillary sinus squamous cell carcinoma. We discuss recent findings on the aberrant expression of miRNAs and their contribution to human HNSCC oncogenesis. PMID:22831895

Nohata, Nijiro; Hanazawa, Toyoyuki; Kinoshita, Takashi; Okamoto, Yoshitaka; Seki, Naohiko

2012-07-24

88

Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma.  

PubMed

About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy (MYCN-) tumors; G2, stage 4 patients, ? 18 months of age, MYCN- tumors and favorable outcome and G3, Stage 4 patients, ? 19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 (p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 (p < 2.35 E-05). Noteworthy, G3/MYCN- NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/MYCN- NBs than in MYCN-amplified G3 may also explain why patients ? 19 months have a poor outcome independently by MYCN status. PMID:22234802

Coco, Simona; Theissen, Jessica; Scaruffi, Paola; Stigliani, Sara; Moretti, Stefano; Oberthuer, André; Valdora, Francesca; Fischer, Matthias; Gallo, Fabio; Hero, Barbara; Bonassi, Stefano; Berthold, Frank; Tonini, Gian Paolo

2012-02-18

89

Aberrant Expression of Human Luteinizing Hormone Receptor by Adrenocortical Cells Is Sufficient to Provoke Both Hyperplasia and Cushing's Syndrome Features  

Microsoft Academic Search

Context: Aberrant expression of LH\\/human chorionic gonadotropin (hCG) receptor has been suggested in several cases of bilateral ma- cronodular adrenal hyperplasia with Cushing's syndrome. The cor- tisol production is then directly controlled by endogenous secretion of LH\\/hCG. However, the direct involvement of this aberrant LH\\/hCG receptor expression in the development of the hyperplasia has not been demonstrated. Moreover in most

Tania L. Mazzuco; Olivier Chabre; Jean-Jacques Feige; Michael Thomas

90

Viral insertion in Evi12 causes expression of aberrant Grp94 mRNAs containing the viral gag myristylation motif  

SciTech Connect

Ecotropic Virus Integration site 12 (Evi12) is a common virus insertion site (cVIS) in retrovirally induced murine models of leukemia and lymphoma, suggesting an important role for this locus in these hematopoietic disorders. Evi12 is located near the promoter of the ER chaperone protein and Hsp90 family member Grp94. Here we show that viral insertion in Evi12 results in the expression of aberrant Grp94 transcripts in Cas-Br-MuLV as well as in AKXD induced hematopoietic tumors, demonstrating that Grp94 is a common viral target gene. While most transcripts encode for truncated forms of Grp94, transcripts containing viral gag sequences were detected in the leukemia cell line NFS107. Interestingly, these fusion transcripts encode for myristylated viral-Grp94 fusion proteins that localize to the plasma membrane. Combined with recent evidence that myristylated forms of Hsp90 transform cells, our data suggest that myristylation of target genes may be an important mechanism in retrovirally mediated oncogenesis. Since retroviral insertion in Evi12 also affects the expression of a recently identified novel gene Grp94 neighboring nucleotidase (Gnn), located at the other side of Evi12, it appears that proviral insertion can lead to deregulation of two genes present in the same locus.

Akker, Eric van den; Aarts, Lambertus H.J. [Department of Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam (Netherlands); Delwel, Ruud [Department of Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam (Netherlands)], E-mail: h.delwel@erasmusmc.nl

2007-09-30

91

Gene Expression in Bone  

NASA Astrophysics Data System (ADS)

Skeletal system has two main functions, to provide mechanical integrity for both locomotion and protection and to play an important role in mineral homeostasis. There is extensive evidence showing loss of bone mass during long-term Space-Flights. The loss is due to a break in the equilibrium between the activity of osteoblasts (the cells that forms bone) and the activity of osteoclasts (the cells that resorbs bone). Surprisingly, there is scanty information about the possible altered gene expression occurring in cells that form bone in microgravity.(Just 69 articles result from a "gene expression in microgravity" MedLine query.) Gene-chip or microarray technology allows to screen thousands of genes at the same time: the use of this technology on samples coming from cells exposed to microgravity could provide us with many important informations. For example, the identification of the molecules or structures which are the first sensors of the mechanical stress derived from lack of gravity, could help in understanding which is the first event leading to bone loss due to long-term exposure to microgravity. Consequently, this structure could become a target for a custom-designed drug. It is evident that bone mass loss, observed during long-time stay in Space, represents an accelerated model of what happens in aging osteoporosis. Therefore, the discovery and design of drugs able to interfere with the bone-loss process, could help also in preventing negative physiological processes normally observed on Earth. Considering the aims stated above, my research is designed to:

D'Ambrogio, A.

92

Increased expression and aberrant localization of mucin 13 in metastatic colon cancer.  

PubMed

MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (p<0.001) MUC13 expression in non-metastatic colon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (p<0.05) higher cytoplasmic and nuclear MUC13 expression compared with non-metastatic colon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer. PMID:22914648

Gupta, Brij K; Maher, Diane M; Ebeling, Mara C; Sundram, Vasudha; Koch, Michael D; Lynch, Douglas W; Bohlmeyer, Teresa; Watanabe, Akira; Aburatani, Hiroyuki; Puumala, Susan E; Jaggi, Meena; Chauhan, Subhash C

2012-08-20

93

Aberrant expression of the neuronal-specific protein DCDC2 promotes malignant phenotypes and is associated with prostate cancer progression.  

PubMed

By integrating gene profiling and immunohistochemical data with functional experiments in cell lines in this study we show for the first time that doublecortin (DCX) domain containing 2 (DCDC2), a protein belonging to the DCX family and involved in neuronal cell migration, is aberrantly expressed in prostate tumors whereas absent in normal prostate. Furthermore, in patients treated with radical prostatectomy, high levels of DCDC2 RNA were significantly associated with increased biochemical relapse (LogRank Mantel-Cox=0.012). Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. Consistently, in prostate tumors and in cellular models of gain and loss of ESE3/EHF, the expression of DCDC2 and ESE3/EHF were inversely correlated. In prostate cancer cells, DCDC2 colocalized with microtubules and promoted cell migration and resistance to the microtubule-targeting drug taxol. Collectively, this study establishes DCDC2 as a novel ESE3/EHF oncogenic target in prostate cancer. These findings may be relevant for the clinical management of prostate cancer as DCDC2 may signal tumors more prone to relapse and resistant to taxol treatment. PMID:22733135

Longoni, N; Kunderfranco, P; Pellini, S; Albino, D; Mello-Grand, M; Pinton, S; D'Ambrosio, G; Sarti, M; Sessa, F; Chiorino, G; Catapano, C V; Carbone, G M

2012-06-25

94

Aberrant pre-mRNA maturation is caused by LINE insertions into introns of the white gene of Drosophila melanogaster.  

PubMed Central

Insertional mutagenesis screens have provided thousands of mutant alleles for analysing genes of varied functions in Drosophila melanogaster. We here document mechanisms of insertional mutagenesis by a LINE element, the I factor, by determining the molecular structure of RNAs produced from two alleles of the white gene of D.melanogaster, wIR1 and wIR6. These alleles result from insertion of the I factor into introns of the gene. We show that sequences present within the element direct aberrant splicing and termination events. When the I factor is inserted within the white first intron it may lead to the use of a cryptic 3' splice site which does not contain the dinucleotide AG. This splicing gives rise to a chimeric messenger RNA whose synthesis is controlled differently in tissues where the mutated gene is expressed. When the I factor is inserted within the white last intron it induces synthesis of truncated mRNAs. These results provide, for the first time, mechanisms for I factor insertional mutagenesis. They are discussed in the more general context of RNA processing in Drosophila and the evolution of eukaryotic gene introns. Images

Lajoinie, O; Drake, M E; Dastugue, B; Vaury, C

1995-01-01

95

CD19 expression in acute leukemia is not restricted to the cytogenetically aberrant populations.  

PubMed

Aberrant expression of the B lymphoid marker, CD19, in acute myeloid leukemia (AML) has frequently been associated with t(8;21)(q22;q22). However, AML cases lacking t(8;21) may occasionally express CD19. We asked whether CD19 expression is restricted to the karyotypically abnormal leukemic cells in primary leukemia samples. We compared, by fluorescence in situ hybridization, CD19-positive and CD19-negative cells from nine patients with acute leukemia: three non-t(8;21) AML, three t(8;21) AML and three cases of acute lymphoblastic leukemia. There were no significant differences in karyotypic pattern between the CD19-positive and CD19-negative leukemic cells, raising the concern that therapeutically targeting CD19 for acute leukemia may not eradicate all malignant clones. PMID:23193950

Francis, Jawad; Dharmadhikari, Avinash V; Sait, Sheila N J; Deeb, George; Wallace, Paul K; Thompson, James E; Wang, Eunice S; Wetzler, Meir

2013-01-03

96

Activation of Expression of Hedgehog Target Genes in Basal Cell Carcinomas  

Microsoft Academic Search

Mutations in hedgehog signaling pathway genes, especially PTC1 and SMO, are pivotal to the development of basal cell carcinomas. The study of basal cell carcinoma gene expression not only may elucidate mechanisms by which hedgehog signaling abnormalities produce aberrant tumor cell behavior but also can provide data on in vivo hedgehog target gene control in humans. We have found, in

Jeannette M Bonifas; Sally Pennypacker; Pao-Tien Chuang; Andrew P McMahon; Mickey Williams; Arnon Rosenthal; Frederic J de Sauvage; Ervin H Epstein

2001-01-01

97

Clinicopathologic features of B-Cell lineage neoplasms with aberrant expression of CD3: a study of 21 cases.  

PubMed

CD3 expression by immunohistochemistry was historically considered restricted to T-lineage or NK-lineage neoplasms but recently has been reported in rare cases of mature B-cell neoplasms, frequently in association with Epstein-Barr virus. Here, we describe the pathologic features of 21 B-cell lineage neoplasms that express CD3 protein by immunohistochemistry: 12 diffuse large B-cell lymphomas (DLBCLs); 2 plasmablastic lymphomas (PBLs); 4 plasma cell neoplasms; 2 Burkitt lymphomas; and 1 nodal follicular lymphoma, grade 3A. CD20 expression was negative or only partially positive in 13/21 cases. Epstein-Barr virus was positive in 3/20 tested cases (2 PBLs and 1 DLBCL). All tested neoplasms (14/14) had clonal immunoglobulin gene rearrangements, and no clonal T-cell gene rearrangements were detected (0/14). The 12 DLBCLs segregated into 2 main groups: 7 demonstrated features of plasmacytic differentiation but did not meet criteria for PBL, and 5 had anaplastic features. In addition to morphology, other features shared among the DLBCLs with plasmacytic differentiation, the plasma cell neoplasms, and the PBLs included extranodal presentation, cytoplasmic localization of CD3, and lack of expression of other T-cell antigens in most cases. In contrast, DLBCLs with anaplastic features and the single follicular lymphoma coexpressed multiple T-cell antigens in a predominantly membranous pattern and presented with nodal disease in a relatively younger patient population. Our data expand the spectrum of morphologic, phenotypic, and clinical features of B-cell neoplasms aberrantly expressing CD3. As these neoplasms often lack typical expression of B-cell antigens, knowledge of these features will help avoid misclassification. PMID:22895269

Oliveira, Jennifer L; Grogg, Karen L; Macon, William R; Dogan, Ahmet; Feldman, Andrew L

2012-09-01

98

Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains*  

PubMed Central

Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive impairment and congenital heart defects in the human population. Bioinformatic annotation has established that human chromosome 21 (Hsa21) harbors five microRNA (miRNAs) genes: miR-99a, let-7c, miR-125b-2, miR-155, and miR-802. Our laboratory recently demonstrated that Hsa21-derived miRNAs are overexpressed in DS brain and heart specimens. The aim of this study was to identify important Hsa21-derived miRNA/mRNA target pairs that may play a role, in part, in mediating the DS phenotype. We demonstrate by luciferase/target mRNA 3?-untranslated region reporter assays, and gain- and loss-of-function experiments that miR-155 and -802 can regulate the expression of the predicted mRNA target, the methyl-CpG-binding protein (MeCP2). We also demonstrate that MeCP2 is underexpressed in DS brain specimens isolated from either humans or mice. We further demonstrate that, as a consequence of attenuated MeCP2 expression, transcriptionally activated and silenced MeCP2 target genes, CREB1/Creb1 and MEF2C/Mef2c, are also aberrantly expressed in these DS brain specimens. Finally, in vivo silencing of endogenous miR-155 or -802, by antagomir intra-ventricular injection, resulted in the normalization of MeCP2 and MeCP2 target gene expression. Taken together, these results suggest that improper repression of MeCP2, secondary to trisomic overexpression of Hsa21-derived miRNAs, may contribute, in part, to the abnormalities in the neurochemistry observed in the brains of DS individuals. Finally these results suggest that selective inactivation of Hsa21-derived miRNAs may provide a novel therapeutic tool in the treatment of DS.

Kuhn, Donald E.; Nuovo, Gerard J.; Terry, Alvin V.; Martin, Mickey M.; Malana, Geraldine E.; Sansom, Sarah E.; Pleister, Adam P.; Beck, Wayne D.; Head, Elizabeth; Feldman, David S.; Elton, Terry S.

2010-01-01

99

Mice expressing aberrant sperm-specific protein PMIS2 produce normal-looking but fertilization-incompetent spermatozoa  

PubMed Central

Eight kinds of gene-disrupted mice (Clgn, Calr3, Pdilt, Tpst2, Ace, Adam1a, Adam2, and Adam3) show impaired sperm transition into the oviducts and defective sperm binding to the zona pellucida. All of these knockout strains are reported to lack or show aberrant expression of a disintegrin and metallopeptidase domain 3 (ADAM3) on the sperm membrane. We performed proteomic analyses of the proteins of these infertile spermatozoa to clarify whether the abnormal function is caused exclusively by a deficiency in ADAM3 expression. Two proteins, named PMIS1 and PMIS2, were missing in spermatozoa from Clgn-disrupted mice. To study their roles, we generated two gene-disrupted mouse lines. Pmis1-knockout mice were fertile, but Pmis2-knockout males were sterile because of a failure of sperm transport into the oviducts. Pmis2-deficient spermatozoa also failed to bind to the zona pellucida. However, they showed normal fertilizing ability when eggs surrounded with cumulus cells were used for in vitro fertilization. Further analysis revealed that these spermatozoa lacked the ADAM3 protein, but the amount of PMIS2 was also severely reduced in Adam3-deficient spermatozoa. These results suggest that PMIS2 might function both as the ultimate factor regulating sperm transport into the oviducts and in modulating sperm–zona binding.

Yamaguchi, Ryo; Fujihara, Yoshitaka; Ikawa, Masahito; Okabe, Masaru

2012-01-01

100

Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy  

PubMed Central

Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMN?7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV.

Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan; Price, Loren; Muntoni, Francesco; Fletcher, Sue; Wilton, Steve D.; Burghes, Arthur H. M.

2013-01-01

101

Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy.  

PubMed

Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMN?7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV. PMID:23630626

Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan; Price, Loren; Muntoni, Francesco; Fletcher, Sue; Wilton, Steve D; Burghes, Arthur H M

2013-04-22

102

Aberrant hypermethylation and reduced expression of disabled-2 promote the development of lung cancers.  

PubMed

Disabled-2 (Dab2) is considered a tumor suppressor and is downregulated in cancers. We examined the promoter methylation status and expression levels of Dab2, and investigated their roles in the development of lung cancers. Methylation-specific PCR was employed to analyze the methylation status of Dab2 in 100 lung cancer tissues. The cytoplasmic and nuclear expression of the Dab2 protein was determined using western blot analysis. Demethylation treatment using 5-Aza-2-deoxycytidine (5-Aza-dC) was performed in three lung cancer cell lines. Dab2 expression was upregulated by Dab2 transfection or interrupted by Dab2 siRNA in lung cancer cells. Proliferative and invasive ability tests were performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTS) and a Matrigel invasion assay, respectively. The methylation rate of Dab2 was significantly higher in lung cancer tissues compared to normal lung tissues. Dab2 methylation correlated with the reduced nuclear and cytoplasmic expression of Dab2, as well as the TNM stage and lymphatic metastasis of lung cancers. Treatment with 5-Aza-dC was able to eliminate the hypermethylation of Dab2, enhance Dab2 expression, and inhibit ?-catenin expression, and the proliferative and invasive ability of lung cancer cells. Upregulation of Dab2 expression reduced ?-catenin expression and proliferation and invasiveness of lung cancer cells. However, interruption of Dab2 expression induced the opposite results. Dab2 methylation is common in lung cancers, and is one of the most important factors responsible for the reduced expression of Dab2. Aberrant hypermethylation and reduced expression of Dab2 promote the development of lung cancers. PMID:24002585

Xie, Xue-Mei; Zhang, Zi-Yin; Yang, Lian-He; Yang, Da-Lei; Tang, Na; Zhao, Huan-Yu; Xu, Hong-Tao; Li, Qing-Chang; Wang, En-Hua

2013-08-29

103

Jasmonate-Responsive Gene Expression  

Microsoft Academic Search

Jasmonic acid (JA) and its volatile methyl ester (MeJA) belong to a family of lipid-derived signalling molecules that affect many aspects of plant life, including defense against certain pathogens and insects and some developmental processes. JA signal transduction leads to modulation of the expression of primary response genes, the products of which lead to the expression of secondary response genes.

Bea Pauw; Johan Memelink

2004-01-01

104

Expression of mammalian defensin genes  

Microsoft Academic Search

Antimicrobial peptides are a prevalent mechanism of host defense found throughout na- ture. In mammals, defensins are among the most abundant of these broad-spectrum antibiotics, and are expressed in epithelial and hematopoietic cells. The defensin peptides are especially abundant in neutrophils; however, gene expression is limited to the promyelocyte stage. In epithelial cells, defensin genes are found as both constitutively

Vicki Kaiser; Gill Diamond

2000-01-01

105

Chromatin loops, gene positioning, and gene expression  

PubMed Central

Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the ?- and ?-globin gene loci, the antigen receptor loci, the imprinted H19–Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.

Holwerda, Sjoerd; de Laat, Wouter

2012-01-01

106

Aberrant DNA methylation profile and frequent methylation of KLK10 and OXGR1 genes in hepatocellular carcinoma.  

PubMed

Investigating aberrant DNA methylation in the cancer genome may identify genes that play an important role in tumor progression. In this study, we combined differential methylation hybridization and a CpG microarray platform to characterize methylation profiles and identify novel candidate genes associated with hepatocellular carcinoma (HCC). The genomic DNA of 21 paired adjacent normal and HCC samples was used, and results were analyzed by hierarchical clustering. Twenty-seven hypermethylated candidates and 38 hypomethylated candidates were obtained. Six candidate genes from the hypermethylated group were validated by combined bisulfite restriction analysis; two genes, human kallikrein 10 gene (KLK10) and oxoglutarate (alpha-ketoglutarate) receptor 1 gene (OXGR1), were further analyzed by bisulfite sequencing. The DNA hypermethylation status of KLK10 and OXGR1 were subsequently examined in HCC cell lines and clinical samples using methylation-specific PCR. In 49 HCC samples, 46 (94%) showed that at least one of these two genes was highly methylated. Moreover, KLK10 and OXGR1 mRNA levels were inversely correlated (r = -0.435 and -0.497, P < 0.05) with DNA methylation as examined in paired adjacent normal and tumor samples. Statistical analyses further indicated that KLK10 hypermethylation was significantly associated with cirrhosis (P = 0.042) and HCV infection (P = 0.017) as well as inversely associated with HBV infection (P = 0.023). Furthermore, restoration of KLK10 and OXGR1 expression reduced the ability of anchorage-independent growth, and sensitized HCC cells to doxorubicin- or 5-fluorouracil-induced cytotoxicity. Our results suggest that the hypermethylated KLK10 and OXGR1 are frequent in HCC and may be useful as markers for clinical application. PMID:19760608

Lu, Chang-Yi; Hsieh, Sen-Yung; Lu, Yen-Jung; Wu, Chi-Sheng; Chen, Lih-Chyang; Lo, Shao-Jung; Wu, Cheng-Tao; Chou, Min-Yuan; Huang, Tim Hui-Ming; Chang, Yu-Sun

2009-12-01

107

Gene Expression Phenotypes of Atherosclerosis  

Microsoft Academic Search

Objective—Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with

David Seo; Tao Wang; Holly Dressman; Edward E. Herderick; Edwin S. Iversen; Chunming Dong; Korkut Vata; Carmelo A. Milano; Fabio Rigat; Jennifer Pittman; Joseph R. Nevins; Mike West; Pascal J. Goldschmidt-Clermont

2010-01-01

108

Frequency variations in the methylated pattern of p73/p21 genes and chromosomal aberrations correlating with different grades of glioma among south Indian population.  

PubMed

Gliomas are the most common primary brain tumors in India. The main epigenetic modification in glioma is aberrant DNA methylation that is now renowned to be a common hallmark of brain tumors. This study was designed to determine the frequency of aberrant CpG island methylation in the promoter regions of p21 and p73 in different grades of glioma and to explore their respective chromosomal aberrations. Total of 160 patients with histologically confirmed grades of glioma (I, II, III, and IV) were included in the study. DNA samples from blood and brain tissues, including benign lesions were subjected to sodium bisulfite conversion and hypermethylation detection using methylation-specific PCR followed by RT-PCR. Western blotting was also carried out for p21 and its related protein, p53. A total of 124 of 160 glioma samples (77.5%) displayed CpG island hypermethylation of both p73, p21 genes associated with the loss of mRNA expression (P < 0.001) and the loss of protein expressions (p53 independent p21 expression). p73 gene showed increased methylation frequency in all grades, 40 of 60 (66%) glioblastomas and 16 of 30 (53.3%) anaplastic astrocytoma, 10 of 20(50%) oligodendrogliomas, 8 of 20 (40%) ependymoma, and low-grade glioma 6 of 20 (30%). The percentage of methylation significantly well correlated with the overall survival and also with chromosomal loss. Thus, the studied glioma patients among south Indians showed a high frequency of aberrant methylation with varied chromosomal signatures in different grades, playing a role in aggressiveness and characterization of a particular grade, the appreciation of which might help for designing a specific therapy. PMID:20844987

Palani, Mahalakshmi; Devan, Sabarinathan; Arunkumar, R; Vanisree, A J

2010-09-16

109

Histone modification mapping in human brain reveals aberrant expression of histone H3 lysine 79 dimethylation in neural tube defects.  

PubMed

Neural tube defects (NTDs) are severe, common birth defects that result from failure of neural tube closure, but their pathological mechanisms are not yet fully understood. Histone modifications have an important role in gene regulation during fetal development. We therefore hypothesized that the human NTDs may be partly caused by an imbalance in metabolism, perhaps caused by nutritional deficiencies, that leads to aberrant histone modifications. Here, we report a screen of fetal brain histone modifications using 2D nano-LC strong cation exchange reverse phase (SCX/RP) MS/MS and the identification of 61 unique post-translational modification sites on histones H1, H2a, H2b, H3, and H4. Of these, 38 sites are novel (not already found in the Uniprot database). Furthermore, we compared the histone modification patterns between normal brains and NTD brains special of which maternal folate levels were lower than of normal control. The results showed that histone H3 lysine 79 dimethylation (H3K79me2) and a novel identified site, H2bK5 monomethylation (H2bK5me1), were completely absent in individuals with NTDs. Follow-up Western blotting validated the decreased H3K79me2 expression in brains with NTDs, but the amplified samples experiments displayed that decreased H3K79me2 expression was not suitable for all samples with NTDs. Furthermore, folate-free treated mouse embryonic stem cells induced the decreased H3K79me2 level. Subsequently, our ChIP results in normal fetal brain tissues showed that H3K79me2 binds to SUFU, RARA and ITGA3 which induce NTDs phenotype after knockout in mice, and in NTDs brain tissues the bindings of H3K79me2 to these three genes were significantly altered. Taken together, our study indicated that low folate treatment might attenuate H3K79 dimethylation, further affect its regulate activation on target genes, some of which are NTDs-resulting associated, lastly interrupt early embryo developing. Our study increases the understanding of normal fetal brain histone modifications and provides a platform for investigating histone modifications in neural disease and also has an insight into a potential role of aberrant histone modification in etiology of NTDs. PMID:23376398

Zhang, Qin; Xue, Peng; Li, Huili; Bao, Yihua; Wu, Lihua; Chang, Shaoyan; Niu, Bo; Yang, Fuquan; Zhang, Ting

2013-01-29

110

Predicting Gene Expression from Sequence  

Microsoft Academic Search

We describe a systematic genome-wide approach for learning the complex combinatorial code underlying gene expression. Our probabilistic approach identifies local DNA-sequence elements and the positional and combinatorial constraints that determine their context-dependent role in transcriptional regulation. The inferred regulatory rules correctly predict expression patterns for 73% of genes in Saccharomyces cerevisiae, utilizing microarray expression data and sequences in the 800

Michael A. Beer; Saeed Tavazoie

2004-01-01

111

Aberrant gene expression associated with recurrent pregnancy loss  

Microsoft Academic Search

Recent studies indicate that a number of factors including chromosomal abnormalities, immunological feto-maternal rejection, hormonal irregulation and anatomical factors are involved in provoking recurrent pregnancy loss (RPL). This indicates that normal cellular regulation of these factors is required for maintaining normal pregnancy. In addition, it is expected that bio- logical processes for maintaining normal pregnancy require a series of differential

Kwang-Hyun Baek

2004-01-01

112

Aberrant Expression of N-Methylpurine-DNA Glycosylase Influences Patient Survival in Malignant Gliomas  

PubMed Central

Aim. To examine the expression of N-methylpurine-DNA glycosylase (MPG) gene and protein in glioma samples with different WHO grades and its association with patients' survival. Methods. Immunohistochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of MPG gene and protein in 128 glioma and 10 non-neoplastic brain tissues. Results. MPG gene expression level in glioma tissues was significantly higher than that in non-neoplastic brain tissues (P < 0.001). Immunohistochemistry also showed that MPG protein was over-expressed in glioma tissues, which was consistent with the resutls of Western blot analysis. Additionally, the expression levels of MPG gene and protein both increase from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry and western blot analysis. Moreover, the survival rate of MPG-positive patients was significantly lower than that of MPG-negative patients (P < 0.001). We further confirmed that the over-expression of MPG was a significant and independent prognostic indicator in glioma by multivariate analysis (P < 0.001). Conclusions. Our data showed the over-expression of MPG gene and protein in human gliomas, and also suggested for the first time that MPG be an unfavorable independent prognostic indicator for glioma patients.

Liu, Ce; Tu, Yanyang; Yuan, Jun; Mao, Xinggang; He, Shiming; Wang, Liang; Fu, Guoqiang; Zong, Jianhai; Zhang, Yongsheng

2012-01-01

113

Aberrant expression of interleukin-7 (IL-7) and its signalling complex in human breast cancer.  

PubMed

Interleukin-7 (IL-7), a haematopoietic growth factor, is known to induce the differentiation and proliferation of some haematological malignancies including certain types of leukaemias and lymphomas. However, little is known about its role in solid tumours, including breast cancer. In this study, the expression level of IL-7, IL-7 receptor (IL-7R) and their downstream signalling molecules, including the Janus kinases (Jak-1 and Jak-3), phosphoinositide 3-kinase (PI3-K) and signal transducers and activators of transcription (Stat-5) were analysed using the reverse transcriptase-polymerase chain reaction (RT-PCR), real-time quantitative PCR and immunohistochemistry in a cohort of patients with breast cancer. The results were analysed in relation to tumour grade, TNM stage, patients' prognosis (using the Nottingham Prognostic Index (NPI)) and survival. The levels of expression of IL-7, IL-7R, Jak-1, Jak-3, PI3-K and Stat-5 were significantly higher in the most aggressive tumours. With the exception of Stat-5 expression, the transcript copies of IL-7 and all other signalling molecules were higher in patients with the worst prognoses (NPI3) and in patients who died from breast cancer after 72 months of follow-up. This aberrant expression of IL-7 and its signalling intermediates in invasive breast cancers could have significant diagnostic and prognostic implications. Measuring these molecules in breast cancer tissues may provide, for the first time, important molecular indicators of tumour differentiation, aggressiveness, nodal status, prognosis and patient survival. PMID:14962714

Al-Rawi, M A A; Rmali, K; Watkins, G; Mansel, R E; Jiang, W G

2004-03-01

114

miR-29a inhibition normalizes HuR over-expression and aberrant AU-rich mRNA stability in invasive cancer.  

PubMed

The activities of RNA-binding proteins are perturbed in several pathological conditions, including cancer. These proteins include tristetraprolin (TTP, ZFP36) and HuR (ELAVL1), which respectively promote the decay or stability of adenylate-uridylate-rich (AU-rich) mRNAs. Here, we demonstrated that increased stabilization and subsequent over-expression of HuR mRNA were coupled to TTP deficiency. These findings were observed in breast cancer cell lines with an invasive phenotype and were further confirmed in ZFP36-knockout mouse fibroblasts. We show that TTP-HuR imbalance correlated with increased expression of AU-rich element (ARE) mRNAs that code for cancer invasion genes. The microRNA miR-29a was abundant in invasive breast cancer cells when compared to non-tumourigenic cell types. When normal breast cells were treated with miR-29a, HuR mRNA and protein expression were up-regulated. MiR-29a recognized a seed target in the TTP 3' UTR and a cell-permeable miR-29a inhibitor increased TTP activity towards HuR 3' UTR. This led to HuR mRNA destabilization and restoration of the aberrant TTP-HuR axis. Subsequently, the cancer invasion factors uPA, MMP-1 and MMP-13, and cell invasiveness, were decreased. The TTP:HuR mRNA ratios were also perturbed in samples from invasive breast cancer patients when compared with normal tissues, and were associated with invasion gene expression. This study demonstrates that an aberrant ARE-mediated pathway in invasive cancer can be normalized by targeting the aberrant and functionally coupled TTP-HuR axis, indicating a potential therapeutic approach. PMID:23401122

Al-Ahmadi, Wijdan; Al-Ghamdi, Maha; Al-Souhibani, Norah; Khabar, Khalid S A

2013-03-21

115

Phylogenetic analysis of gene expression.  

PubMed

Phylogenetic analyses of gene expression have great potential for addressing a wide range of questions. These analyses will, for example, identify genes that have evolutionary shifts in expression that are correlated with evolutionary changes in morphological, physiological, and developmental characters of interest. This will provide entirely new opportunities to identify genes related to particular phenotypes. There are, however, 3 key challenges that must be addressed for such studies to realize their potential. First, data on gene expression must be measured from multiple species, some of which may be field-collected, and parameterized in such a way that they can be compared across species. Second, it will be necessary to develop comparative phylogenetic methods suitable for large multidimensional datasets. In most phylogenetic comparative studies to date, the number n of independent observations (independent contrasts) has been greater than the number p of variables (characters). The behavior of comparative methods for these classic problems is now well understood under a wide variety of conditions. In studies of gene expression, and in studies based on other high-throughput tools, the number n of samples is dwarfed by the number p of variables. The estimated covariance matrices will be singular, complicating their analysis and interpretation, and prone to spurious results. Third, new approaches are needed to investigate the expression of the many genes whose phylogenies are not congruent with species phylogenies due to gene loss, gene duplication, and incomplete lineage sorting. Here we outline general considerations of project design for phylogenetic analyses of gene expression and suggest solutions to these three categories of challenges. These topics are relevant to high-throughput phenotypic data well beyond gene expression. PMID:23748631

Dunn, Casey W; Luo, Xi; Wu, Zhijin

2013-06-07

116

Aberrant Chemokine Receptor Expression and Chemokine Production by Langerhans Cells Underlies the Pathogenesis of Langerhans Cell Histiocytosis  

Microsoft Academic Search

Langerhans cell histiocytosis (LCH) is characterized by a clonal proliferation and retention of cells with a Langerhans cell (LC)-like phenotype at various sites within the body. The present study set out to elucidate whether aberrant expression of chemokine receptors or dysregulation of chemokine production in LCH lesions could explain abnormal retention of these cells. Immunohistochemical analysis on 13 LCH biopsies

Nicola E. Annels; Frans A. Prins; Annemieke Willemze; Pancras C. W. Hogendoorn

117

Glucocorticoid Control of Gene Expression.  

National Technical Information Service (NTIS)

The concept that glucocorticoids function at the nuclear level to control expression of specific genes is discussed. The current views on the mechanism of this control are presented and relevant data from different experimental approaches are reported.

F. T. Kenney S. E. Lane K. L. Lee J. N. Ihle

1975-01-01

118

Nuclear Neighborhoods and Gene Expression  

PubMed Central

Summary The eukaryotic nucleus is a highly compartmentalized and dynamic environment. Chromosome territories are arranged non-randomly within the nucleus and numerous studies have indicated that a gene’s position in the nucleus can impact its transcriptional activity. Here, we focus on recent advances in our understanding of the influence of specific nuclear neighborhoods on gene expression or repression. Nuclear neighborhoods associated with transcriptional repression include the inner nuclear membrane/nuclear lamina and peri-nucleolar chromatin, whereas neighborhoods surrounding the nuclear pore complex, PML nuclear bodies, and nuclear speckles seem to be transcriptionally permissive. While nuclear position appears to play an important role in gene expression, it is likely to be only one piece of a flexible puzzle that incorporates numerous parameters. We are still at a very early, yet exciting stage in our journey toward deciphering the mechanism(s) that govern the permissiveness of gene expression/repression within different nuclear neighborhoods.

Zhao, Rui; Bodnar, Megan S.; Spector, David L.

2009-01-01

119

Peripheral T-Cell Lymphoma with Aberrant Expression of CD19, CD20, and CD79a: Case Report and Literature Review  

PubMed Central

A case of lymphoma of T-cell derivation with aberrant expression of three B-cell lineage markers (CD19, CD20, and CD79a), which was diagnosed on a left axillary excision, is described. Immunohistochemical studies and flow cytometry analysis demonstrated neoplastic cells expressing CD3, CD19, CD20, and CD79a with absence of CD4, CD8, CD10, CD30, CD34, CD56, CD68, TDT, MPO, PAX-5, and surface immunoglobulin. Gene rearrangement studies performed on paraffin blocks demonstrated monoclonal T-cell receptor gamma chain rearrangement with no evidence of clonal heavy chain rearrangement. The neoplastic cells were negative for Epstein-Barr virus (EBV) or Human Herpes Virus 8 (HHV-8). At the time of diagnosis, the PET scan demonstrated hypermetabolic neoplastic cells involving the left axilla, bilateral internal jugular areas, mediastinum, right hilum, bilateral lungs, and spleen. However, bone marrow biopsy performed for hemolytic anemia revealed normocellular bone marrow with trilineage maturation. The patient had no evidence of immunodeficiency or infection with EBV or HHV-8. This is the first reported case of a mature T-cell lymphoma with aberrant expression of three B-cell lineage markers. The current report also highlights the need for molecular gene rearrangement studies to determine the precise lineage of ambiguous neoplastic clones.

Matnani, Rahul G.; Stewart, Rachel L.; Pulliam, Joseph; Jennings, Chester D.; Kesler, Melissa

2013-01-01

120

Peripheral T-Cell Lymphoma with Aberrant Expression of CD19, CD20, and CD79a: Case Report and Literature Review.  

PubMed

A case of lymphoma of T-cell derivation with aberrant expression of three B-cell lineage markers (CD19, CD20, and CD79a), which was diagnosed on a left axillary excision, is described. Immunohistochemical studies and flow cytometry analysis demonstrated neoplastic cells expressing CD3, CD19, CD20, and CD79a with absence of CD4, CD8, CD10, CD30, CD34, CD56, CD68, TDT, MPO, PAX-5, and surface immunoglobulin. Gene rearrangement studies performed on paraffin blocks demonstrated monoclonal T-cell receptor gamma chain rearrangement with no evidence of clonal heavy chain rearrangement. The neoplastic cells were negative for Epstein-Barr virus (EBV) or Human Herpes Virus 8 (HHV-8). At the time of diagnosis, the PET scan demonstrated hypermetabolic neoplastic cells involving the left axilla, bilateral internal jugular areas, mediastinum, right hilum, bilateral lungs, and spleen. However, bone marrow biopsy performed for hemolytic anemia revealed normocellular bone marrow with trilineage maturation. The patient had no evidence of immunodeficiency or infection with EBV or HHV-8. This is the first reported case of a mature T-cell lymphoma with aberrant expression of three B-cell lineage markers. The current report also highlights the need for molecular gene rearrangement studies to determine the precise lineage of ambiguous neoplastic clones. PMID:24066244

Matnani, Rahul G; Stewart, Rachel L; Pulliam, Joseph; Jennings, Chester D; Kesler, Melissa

2013-08-28

121

Linear and non-linear dependencies between copy number aberrations and mRNA expression reveal distinct molecular pathways in breast cancer  

PubMed Central

Background Elucidating the exact relationship between gene copy number and expression would enable identification of regulatory mechanisms of abnormal gene expression and biological pathways of regulation. Most current approaches either depend on linear correlation or on nonparametric tests of association that are insensitive to the exact shape of the relationship. Based on knowledge of enzyme kinetics and gene regulation, we would expect the functional shape of the relationship to be gene dependent and to be related to the gene regulatory mechanisms involved. Here, we propose a statistical approach to investigate and distinguish between linear and nonlinear dependences between DNA copy number alteration and mRNA expression. Results We applied the proposed method to DNA copy numbers derived from Illumina 109 K SNP-CGH arrays (using the log R values) and expression data from Agilent 44 K mRNA arrays, focusing on commonly aberrated genomic loci in a collection of 102 breast tumors. Regression analysis was used to identify the type of relationship (linear or nonlinear), and subsequent pathway analysis revealed that genes displaying a linear relationship were overall associated with substantially different biological processes than genes displaying a nonlinear relationship. In the group of genes with a linear relationship, we found significant association to canonical pathways, including purine and pyrimidine metabolism (for both deletions and amplifications) as well as estrogen metabolism (linear amplification) and BRCA-related response to damage (linear deletion). In the group of genes displaying a nonlinear relationship, the top canonical pathways were specific pathways like PTEN and PI13K/AKT (nonlinear amplification) and Wnt(B) and IL-2 signalling (nonlinear deletion). Both amplifications and deletions pointed to the same affected pathways and identified cancer as the top significant disease and cell cycle, cell signaling and cellular development as significant networks. Conclusions This paper presents a novel approach to assessing the validity of the dependence of expression data on copy number data, and this approach may help in identifying the drivers of carcinogenesis.

2011-01-01

122

Deciphering gene expression regulatory networks  

Microsoft Academic Search

In the past year, great strides have been made in our understanding of the regulatory networks that control gene expression in the model eukaryote Saccharomyces cerevisiae. The development and use of a number of genomic tools, including genome-wide location and expression analysis, has fueled this progress. In addition, a variety of computational algorithms have been devised to mine genomic sequence

John J Wyrick; Richard A Young

2002-01-01

123

Segmental chromosome aberrations converge on overexpression of mitotic spindle regulatory genes in high-risk neuroblastoma.  

PubMed

Integration of genome-wide profiles of DNA copy number alterations (CNAs) and gene expression variations (GEVs) could provide combined power to the identification of driver genes and gene networks in tumors. Here we merge matched genome and transcriptome microarray analyses from neuroblastoma samples to derive correlation patterns of CNAs and GEVs, irrespective of their genomic location. Neuroblastoma correlation patterns are strongly asymmetrical, being on average 10 CNAs linked to 1 GEV, and show the widespread prevalence of long range covariance. Functional enrichment and network analysis of the genes covarying with CNAs consistently point to a major cell function, the regulation of mitotic spindle assembly. Moreover, elevated expression of 14 key genes promoting this function is strongly associated to high-risk neuroblastomas with 1p loss and MYCN amplification in a set of 410 tumor samples (P < 0.00001). Independent CNA/GEV profiling on neuroblastoma cell lines shows that increased levels of expression of these genes are linked to 1p loss. By this approach, we reveal a convergence of clustered neuroblastoma CNAs toward increased expression of a group of prognostic and functionally cooperating genes. We therefore propose gain of function of the spindle assembly machinery as a lesion potentially offering new targets for therapy of high-risk neuroblastoma. PMID:22337647

Ooi, Wen Fong; Re, Angela; Sidarovich, Viktoryia; Canella, Valentina; Arseni, Natalia; Adami, Valentina; Guarguaglini, Giulia; Giubettini, Maria; Scaruffi, Paola; Stigliani, Sara; Lavia, Patrizia; Tonini, Gian Paolo; Quattrone, Alessandro

2012-02-15

124

CD34(+) /CD38(-) acute myelogenous leukemia cells aberrantly express Aurora kinase A.  

PubMed

We previously showed that Aurora kinase A (AURKA) is aberrantly expressed in acute myelogenous leukemia (AML) cells when compared to bone marrow mononuclear cells isolated from healthy volunteers. We have also shown that CD34(+) /CD38(-) AML cells, one of compartments enriched for leukemia stem cells in most leukemia subgroups, were relatively resistant to cytarabine-mediated growth inhibition when compared to their CD34(+) /CD38(+) counterparts. Our study attempted to identify therapeutic targets in CD34(+) /CD38(-) AML cells and found that CD34(+) /CD38(-) AML cells isolated from patients (n?=?26) expressed larger amounts of AURKA than their CD34(+) /CD38(+) counterparts and CD34(+) normal hematopoietic stem/progenitor cells isolated from healthy volunteers (n?=?6), as measured by real-time reverse-transcriptase polymerase chain reaction. Blockade of AURKA by the specific inhibitor MLN8237 or a short hairpin RNA (shRNA) against AURKA significantly inhibited proliferation, impaired self-renewal capability and induced apoptosis of CD34(+) /CD38(-) AML cells, in association with modulation of levels of Bcl-2 family member proteins. Importantly, inhibition of AURKA in CD34(+) /CD38(-) AML cells by MLN8237 or an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice and appeared to prolong their survival. These results suggest that AURKA is a promising molecular target to eliminate chemotherapy-resistant CD34(+) /CD38(-) AML cells. PMID:23686525

Yang, Jing; Ikezoe, Takayuki; Nishioka, Chie; Nobumoto, Atsuya; Udaka, Keiko; Yokoyama, Akihito

2013-06-10

125

Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation  

PubMed Central

Autism spectrum condition (ASC) is recognized as having an inflammatory component. Post-mortem brain samples from patients with ASC display neuroglial activation and inflammatory markers in cerebrospinal fluid, although little is known about the underlying molecular mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) is a protein found in almost all cell types and mediates regulation of immune response by inducing the expression of inflammatory cytokines and chemokines, establishing a feedback mechanism that can produce chronic or excessive inflammation. This article describes immunodetection and immunofluorescence measurements of NF-?B in human post-mortem samples of orbitofrontal cortex tissue donated to two independent centers: London Brain Bank, Kings College London, UK (ASC: n?=?3, controls: n?=?4) and Autism Tissue Program, Harvard Brain Bank, USA (ASC: n?=?6, controls: n?=?5). The hypothesis was that concentrations of NF-?B would be elevated, especially in activated microglia in ASC, and pH would be concomitantly reduced (i.e., acidification). Neurons, astrocytes, and microglia all demonstrated increased extranuclear and nuclear translocated NF-?B p65 expression in brain tissue from ASC donors relative to samples from matched controls. These between-groups differences were increased in astrocytes and microglia relative to neurons, but particularly pronounced for highly mature microglia. Measurement of pH in homogenized samples demonstrated a 0.98-unit difference in means and a strong (F?=?98.3; p?=?0.00018) linear relationship to the expression of nuclear translocated NF-?B in mature microglia. Acridine orange staining localized pH reductions to lysosomal compartments. In summary, NF-?B is aberrantly expressed in orbitofrontal cortex in patients with ASC, as part of a putative molecular cascade leading to inflammation, especially of resident immune cells in brain regions associated with the behavioral and clinical symptoms of ASC.

Young, Adam M. H.; Campbell, Elaine; Lynch, Sarah; Suckling, John; Powis, Simon J.

2011-01-01

126

Aberrantly decreased levels of NKG2D expression in children with kawasaki disease.  

PubMed

This study is designed to investigate the changes of NKG2D expression on CD8(+) T cells and CD3(-) CD56(+) NK cells in Kawasaki disease (KD). NKG2D/NKG2A expression on CD3(-) CD56(+) NK cells and CD8(+) T lymphocytes, and NKG2D ligands such as major histocompatibility complex I chain-related molecules A(MICA) and UL-16-binding proteins (ULBP-1) expression on CD14(+) mononuclear cells (MC) were analysed by flow cytometry in patients with KD. Real-time polymerase chain reaction (PCR) was used to evaluate the mRNA levels of interleukin (IL)-1?, IL-6 and tumour necrosis factor (TNF)-? in CD14(+) cells. Plasma cytokine [IL-7, IL-12, IL-15, interferon (IFN)-? and transforming growth factor (TGF)-?] concentrations were measured by ELISA. The levels of NKG2D on NK cells and CD8(+) T cells expression in acute phase of KD were significantly lower than those in normal controls (P < 0.05), and the levels of NKG2D expression in the patients with coronary artery lesion (KD-CAL(+) ) were lower than those in patients with KD-CAL(-) . There was an upregulated tendency after treatment with IVIG. We found higher expression levels of proinflammatory cytokines from MC, such as IL-1?, IL-6 and TNF-? in patients with KD compared with the healthy controls (P < 0.05). The concentrations of IL-7 and IL-15 were significantly decreased in acute phase of KD (P < 0.05) and to some extent elevated after therapy with IVIG (P < 0.05), while antagonistic cytokines like IFN-? were increased in acute phase of KD (P < 0.05) and reduced after therapy with IVIG (P < 0.05). These results suggest that aberrantly decreased levels of NKG2D expression on NK cells and CD8(+) T cells might be one of the factors led to disturbed immunological function in patients with KD. Cytokines milieu could be important factors causing reduced expression of NKG2D. PMID:23298273

Ge, X; Li, C-R; Yang, J; Wang, G-B

2013-05-01

127

Aberrant hypomethylation of SALL4 gene in patients with myelodysplastic syndrome.  

PubMed

The abnormalities of SALL4 gene, which encodes a zinc-finger transcription factor and is essential for developmental events, have been found to be involved in tumorigenesis. In this study, we investigated the methylation status of the CpG island of SALL4 promoter region in myelodysplastic syndrome (MDS) using methylation-specific PCR (MSP). Aberrant hypomethylation of SALL4 gene was found in 21.7% (18/83) of the cases analyzed. A significantly positive correlation was identified between the level of SALL4 transcript and the status of SALL4 hypomethylation (R=0.641, P<0.001). No correlation was found between SALL4 hypomethylation and clinical parameters. However, the frequency of SALL4 hypomethylation significantly increased in higher risk MDS (14% in Low/Int-1 versus 39% in Int-2/High, P=0.031). The association between SALL4 hypomethylation and the mutations in three methylation modifiers (IDH1, IDH2 and DNMT3A) was not observed. Although the estimated 50% survival time of the SALL4-hypomethylated group was shorter than that of SALL4-methylated group (11.0 months vs. 20.0 months), the difference was not statistically significant (P=0.430). These findings suggest that hypomethylation of SALL4 promoter is a common event in MDS. PMID:23122807

Lin, Jiang; Qian, Jun; Yao, Dong-ming; Qian, Wei; Yang, Jing; Wang, Cui-zhu; Chai, Hai-yan; Ma, Ji-chun; Deng, Zhao-qun; Li, Yun; Chen, Qin

2012-11-02

128

Aberrant Otx2 Expression Enhances Migration and Induces Ectopic Proliferation of Hindbrain Neuronal Progenitor Cells  

PubMed Central

Dysregulation of Otx2 is a hallmark of the pediatric brain tumor medulloblastoma, yet its functional significance in the establishment of these tumors is unknown. Here we have sought to determine the functional consequences of Otx2 overexpression in the mouse hindbrain to characterize its potential role in medulloblastoma tumorigenesis and identify the cell types responsive to this lineage-specific oncogene. Expression of Otx2 broadly in the mouse hindbrain resulted in the accumulation of proliferative clusters of cells in the cerebellar white matter and dorsal brainstem of postnatal mice. We found that brainstem ectopia were derived from neuronal progenitors of the rhombic lip and that cerebellar ectopia were derived from granule neuron precursors (GNPs) that had migrated inwards from the external granule layer (EGL). These hyperplasias exhibited various characteristics of medulloblastoma precursor cells identified in animal models of Shh or Wnt group tumors, including aberrant localization and altered spatiotemporal control of proliferation. However, ectopia induced by Otx2 differentiated and dispersed as the animals reached adulthood, indicating that factors restricting proliferative lifespan were a limiting factor to full transformation of these cells. These studies implicate a role for Otx2 in altering the dynamics of neuronal progenitor cell proliferation.

Wortham, Matthew; Jin, Genglin; Sun, Julia Lailai; Bigner, Darell D.; He, Yiping; Yan, Hai

2012-01-01

129

Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells.  

PubMed

Dysregulation of Otx2 is a hallmark of the pediatric brain tumor medulloblastoma, yet its functional significance in the establishment of these tumors is unknown. Here we have sought to determine the functional consequences of Otx2 overexpression in the mouse hindbrain to characterize its potential role in medulloblastoma tumorigenesis and identify the cell types responsive to this lineage-specific oncogene. Expression of Otx2 broadly in the mouse hindbrain resulted in the accumulation of proliferative clusters of cells in the cerebellar white matter and dorsal brainstem of postnatal mice. We found that brainstem ectopia were derived from neuronal progenitors of the rhombic lip and that cerebellar ectopia were derived from granule neuron precursors (GNPs) that had migrated inwards from the external granule layer (EGL). These hyperplasias exhibited various characteristics of medulloblastoma precursor cells identified in animal models of Shh or Wnt group tumors, including aberrant localization and altered spatiotemporal control of proliferation. However, ectopia induced by Otx2 differentiated and dispersed as the animals reached adulthood, indicating that factors restricting proliferative lifespan were a limiting factor to full transformation of these cells. These studies implicate a role for Otx2 in altering the dynamics of neuronal progenitor cell proliferation. PMID:22558385

Wortham, Matthew; Jin, Genglin; Sun, Julia Lailai; Bigner, Darell D; He, Yiping; Yan, Hai

2012-04-27

130

Gene expression and methylation patterns in cloned embryos.  

PubMed

A considerable proportion of the offspring, in particular in ruminants and mouse, born from nuclear transfer (NT)-derived and in vitro-produced (IVP) embryos are affected by multiple abnormalities, of which a high birthweight and an extended gestation length are the predominant features; a phenomenon that has been termed "Large Offspring syndrome" (LOS). According to a current hypothesis, LOS is caused by persistent aberrations of expression patterns of developmentally important genes starting as early as at the preimplantation stages. The underlying mechanisms are widely unknown at present, but epigenetic modifications of embryonic and fetal gene expression patterns, primarily caused by alterations in DNA methylation are thought to be involved in this syndrome. Appropriate DNA methylation is essential for regular transcription during mammalian development and differentiation. Sensitive reverse transcription polymerase chain reaction assays allow the study of messenger RNA (mRNA) expression levels of specific genes in single embryos. The methylation status of a specific gene can be assessed by bisulfite sequencing. Studies to unravel mRNA expression patterns from IVP- and NT-derived embryos have revealed numerous aberrations ranging from suppression of expression to de novo overexpression or more frequently to a significant upregulation or downregulation of a specific gene. mRNA expression patterns from in vivo-derived embryos are essential as the "physiological standard" against which the findings for IVP and NT-derived embryos are to be compared. Unraveling the underlying molecular mechanisms will contribute to the production of viable embryos and aid to improve biotechnologies applied to early mammalian embryos. PMID:16988388

Wrenzycki, Christine; Herrmann, Doris; Gebert, Claudia; Carnwath, Joseph W; Niemann, Heiner

2006-01-01

131

Aberrant Apolipoprotein E Expression and Cognitive Dysfunction in Patients with Poststroke Depression  

PubMed Central

Background: Apolipoprotein E (ApoE) is associated with some diseases with cognitive function defect. Aims: The purpose of this study was to examine the influence of ApoE on poststroke depression (PSD) risk and to define objective markers for diagnosis. Methods: The cognitive function, serum ApoE, and peripheral mononuclear blood cell ApoE mRNA expression of patients with PSD were compared to age-matched control patients with stroke and healthy volunteers. Sixty-seven patients with stroke were selected according to the cerebral infarction diagnosis standard of the Fourth National Cerebrovascular Disease Conference and divided into a PSD group (28 patients, 43–76 years old) or a control stroke group (39 patients, 43–78 years old) using the Hamilton Rating Scale for Depression, and compared to 40 healthy volunteers (42–78 years old). Cognitive function was evaluated by analysis of event-related potentials (ERPs), while expression of ApoE mRNA was determined by quantitative reverse transcription–polymerase chain reaction and serum ApoE by ELISA. Results: The latencies of ERP components N2 and P3 were prolonged, and the P3 amplitude was lower in the PSD group compared to the control stroke group and healthy controls (p<0.01). There were no significant group differences in N1 and P2 latencies (all p>0.05). The latency of N2 was positively correlated to the P3 latency in the PSD group (p<0.05). No associations were detected between P3 amplitude, expression of ApoE mRNA, and serum ApoE in the PSD group (all p>0.05). The ERP results indicated that patients with PSD were significantly slower at identifying a target stimulus, suggesting deficits in perception and/or cognitive processing. Peripheral expression of ApoE mRNA was lower in the PSD group than the control stroke group (p<0.701) while serum ApoE was higher than in the control stroke group (p<0.05), possibly reflecting a feedback reduction in expression. Conclusion: We suggest that aberrant serum ApoE together with abnormalities in some ERP components may be useful markers for assessment of PSD risk and clinical diagnosis.

Zhang, Zhaohui; Mu, Junlin; Li, Jing

2013-01-01

132

Ontogeny of erythroid gene expression.  

PubMed

Erythroid ontogeny is characterized by overlapping waves of primitive and definitive erythroid lineages that share many morphologic features during terminal maturation but have marked differences in cell size and globin expression. In the present study, we compared global gene expression in primitive, fetal definitive, and adult definitive erythroid cells at morphologically equivalent stages of maturation purified from embryonic, fetal, and adult mice. Surprisingly, most transcriptional complexity in erythroid precursors is already present by the proerythroblast stage. Transcript levels are markedly modulated during terminal erythroid maturation, but housekeeping genes are not preferentially lost. Although primitive and definitive erythroid lineages share a large set of nonhousekeeping genes, annotation of lineage-restricted genes shows that alternate gene usage occurs within shared functional categories, as exemplified by the selective expression of aquaporins 3 and 8 in primitive erythroblasts and aquaporins 1 and 9 in adult definitive erythroblasts. Consistent with the known functions of Aqp3 and Aqp8 as H2O2 transporters, primitive, but not definitive, erythroblasts preferentially accumulate reactive oxygen species after exogenous H2O2 exposure. We have created a user-friendly Web site (http://www.cbil.upenn.edu/ErythronDB) to make these global expression data readily accessible and amenable to complex search strategies by the scientific community. PMID:23243273

Kingsley, Paul D; Greenfest-Allen, Emily; Frame, Jenna M; Bushnell, Timothy P; Malik, Jeffrey; McGrath, Kathleen E; Stoeckert, Christian J; Palis, James

2012-12-12

133

Aberrant Expression of p63 in Adenocarcinoma of the Prostate: A Radical Prostatectomy Study.  

PubMed

Prostatic adenocarcinoma with aberrant diffuse expression of p63 (p63-PCa) is a recently described variant of prostatic adenocarcinoma. The aim of this study was to investigate the clinical and pathologic features of p63-PCa at radical prostatectomy (RP). We reviewed 21 cases of p63-PCa diagnosed on needle biopsy at subsequent RP. Immunohistochemical analysis for PIN4 and Ki-67 was performed in all RP cases. p63-PCa showed a distinctive morphology consisting of atrophic, poorly formed glands, with multilayered and often spindled nuclei. Gleason grading was 3+3=6 in 28.5%, 3+5=8 in 38%, 3+4=7 in 14.3%, and 4+3=7, 5+3=8, and 5+4=9 in 9.5%. Usual-type acinar carcinoma coexisted in 85.7% with only p63-PCa present in the remaining cases. The usual-type carcinoma was Gleason grade 3+2=5 in 4.7%, 3+3=6 in 57%, 3+4=7 in 19%, and 4+3=7 in 4.3%. Overall, p63-PCa represented 65% of the total cancer volume (median 80%). The tumor was organ-confined in 16 cases (76.2%). In the remaining 5 cases, 2 had p63-PCa extending to the margin in areas of intraprostatic incisions, 2 had usual-type acinar adenocarcinoma extending to the margin and extraprostatic tissue, respectively, and 1 had p63-PCa with an unusual cribriform morphology involving the bladder neck. Ki-67 was low, <5% in all cases of p63-PCa, with similar expression in the coexisting acinar-type carcinoma. In summary, it is recommended that these tumors not be assigned a Gleason score and their favorable findings at RP be noted. PMID:23774168

Giannico, Giovanna A; Ross, Hillary M; Lotan, Tamara; Epstein, Jonathan I

2013-09-01

134

Population genomics of human gene expression  

Microsoft Academic Search

Genetic variation influences gene expression, and this variation in gene expression can be efficiently mapped to specific genomic regions and variants. Here we have used gene expression profiling of Epstein-Barr virus–transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find that gene expression

Barbara E Stranger; Alexandra C Nica; Matthew S Forrest; Antigone Dimas; Christine P Bird; Claude Beazley; Catherine E Ingle; Mark Dunning; Paul Flicek; Daphne Koller; Stephen Montgomery; Simon Tavare ´; Panos Deloukas; Emmanouil T Dermitzakis

2007-01-01

135

Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease  

Microsoft Academic Search

The aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, is a diagnostic feature of sporadic Alzheimer's disease (AD). We found PS2V is hypoxia-inducible in human neuroblastoma SK-N-SH cells. We purified a responsible trans-acting factor based on its binding to an exon 5 fragment. The factor was identified as the high mobility group A1a

T Manabe; T Katayama; N Sato; F Gomi; J Hitomi; T Yanagita; T Kudo; A Honda; Y Mori; S Matsuzaki; K Imaizumi; A Mayeda; M Tohyama

2003-01-01

136

Gene Expression Profiling in Familial Adenomatous Polyposis Adenomas and Desmoid Disease  

PubMed Central

Gene expression profiling is a powerful method by which alterations in gene expression can be interrogated in a single experiment. The disease familial adenomatous polyposis (FAP) is associated with germline mutations in the APC gene, which result in aberrant ?-catenin control. The molecular mechanisms underlying colorectal cancer development in FAP are being characterised but limited information is available about other symptoms that occur in this disorder. Although extremely rare in the general population, desmoid tumours in approximately 10% of FAP patients. The aim of this study was to determine the similarities and differences in gene expression profiles in adenomas and compare them to those observed in desmoid tumours. Illumina whole genome gene expression BeadChips were used to measure gene expression in FAP adenomas and desmoid tumours. Similarities between gene expression profiles and mechanisms important in regulating formation of FAP adenomas and desmoid tumours were identified. This study furthers our understanding of the mechanisms underlying FAP and desmoid tumour formation.

Bowden, Nikola A; Croft, Amanda; Scott, Rodney J

2007-01-01

137

Expression Trend of Selected Ribosomal Protein Genes in Nasopharyngeal Carcinoma  

PubMed Central

Background: Ribosomal proteins are traditionally associated with protein biosynthesis until recent studies that implicated their extraribosomal functions in human diseases and cancers. Our previous studies using GeneFishing™ DEG method and microarray revealed underexpression of three ribosomal protein genes, RPS26, RPS27, and RPL32 in cancer of the nasopharynx. Herein, we investigated the expression pattern and nucleotide sequence integrity of these genes in nasopharyngeal carcinoma to further delineate their involvement in tumourigenesis. The relationship of expression level with clinicopathologic factors was also statistically studied. Methods: Quantitative Polymerase Chain Reaction was performed on nasopharyngeal carcinoma and their paired normal tissues. Expression and sequence of these three genes were analysed. Results: All three ribosomal protein genes showed no significant difference in transcript expressions and no association could be established with clinicopathologic factors studied. No nucleotide aberrancy was detected in the coding regions of these genes. Conclusion: There is no early evidence to substantiate possible involvement of RPS26, RPS27, and RPL32 genes in NPC tumourigenesis.

Ma, Xiang-Ru; Sim, Edmund Ui-Hang; Ling, Teck-Yee; Tiong, Thung-Sing; Subramaniam, Selva Kumar; Khoo, Alan Soo-Beng

2012-01-01

138

Method for Expressing Clinical and Statistical Significance of Ocular and Corneal Wavefront Error Aberrations  

PubMed Central

Purpose The significance of ocular or corneal aberrations may be subject to misinterpretation whenever eyes with different pupil sizes or the application of different Zernike expansion orders are compared. A method is shown that uses simple mathematical interpolation techniques based on normal data to rapidly determine the clinical significance of aberrations, without concern for pupil and expansion order. Methods Corneal topography (Tomey, Inc.; Nagoya, Japan) from 30 normal corneas was collected and the corneal wavefront error analyzed by Zernike polynomial decomposition into specific aberration types for pupil diameters of 3, 5, 7, and 10 mm and Zernike expansion orders of 6, 8, 10 and 12. Using this 4×4 matrix of pupil sizes and fitting orders, best-fitting 3-dimensional functions were determined for the mean and standard deviation of the RMS error for specific aberrations. The functions were encoded into software to determine the significance of data acquired from non-normal cases. Results The best-fitting functions for 6 types of aberrations were determined: defocus, astigmatism, prism, coma, spherical aberration, and all higher-order aberrations. A clinical screening method of color-coding the significance of aberrations in normal, postoperative LASIK, and keratoconus cases having different pupil sizes and different expansion orders is demonstrated. Conclusions A method to calibrate wavefront aberrometry devices by using a standard sample of normal cases was devised. This method could be potentially useful in clinical studies involving patients with uncontrolled pupil sizes or in studies that compare data from aberrometers that use different Zernike fitting-order algorithms.

Smolek, Michael K.

2011-01-01

139

Gene expression regulation in trypanosomatids.  

PubMed

Trypanosomatids are protozoan micro-organisms that cause serious health problems in humans and domestic animals. In addition to their medical relevance, these pathogens have novel biological structures and processes. From nuclear DNA transcription to mRNA translation, trypanosomes use unusual mechanisms to control gene expression. For example, transcription by RNAPII (RNA polymerase II) is polycistronic, and only a few transcription initiation sites have been identified so far. The sequences present in the polycistronic units code for proteins having unrelated functions, that is, not involved in a similar metabolic pathway. Owing to these biological constraints, these micro-organisms regulate gene expression mostly by post-transcriptional events. Consequently, the function of proteins that recognize RNA elements preferentially at the 3' UTR (untranslated region) of transcripts is central. It was recently shown that mRNP (messenger ribonucleoprotein) complexes are organized within post-transcriptional operons to co-ordinately regulate gene expression of functionally linked transcripts. In the present chapter we will focus on particular characteristics of gene expression in the so-called TriTryp parasites: Trypanosoma cruzi, Trypanosoma brucei and Leishmania major. PMID:22023440

De Gaudenzi, Javier G; Noé, Griselda; Campo, Vanina A; Frasch, Alberto C; Cassola, Alejandro

2011-01-01

140

Genetics of global gene expression  

Microsoft Academic Search

A new field of genetic analysis of global gene expression has emerged in recent years, driven by the realization that traditional techniques of linkage and association analysis can be applied to thousands of transcript levels measured by microarrays. Genetic dissection of transcript abundance has shed light on the architecture of quantitative traits, provided a new approach for connecting DNA sequence

Matthew V. Rockman; Leonid Kruglyak

2006-01-01

141

Downregulation of anti-oncomirs miR-143/145 cluster occurs before APC gene aberration in the development of colorectal tumors.  

PubMed

Accumulating data indicate that some microRNAs (miRNAs or miRs) can function as tumor suppressors or oncogenes and as such are important in cancer development. We previously reported that miR-143 and -145 are frequently downregulated in colon adenomas and cancers, acting as tumor suppressors. In this present study, we investigated the relationship between the downregulation of the miR-143/145 cluster and genetic aberrations of adenomatous polyposis coli (APC), which are early genetic events in the development of colorectal tumors. The expression levels of both miRs were determined by performing real-time PCR on tissue samples of familial adenomatous polyposis (FAP), colorectal adenoma, colorectal cancer, and paired non-tumorous tissues. Also, the expression of C- or N-terminus of the APC protein and that of the p53 protein in these tissues were examined immunohistochemically. Our data clearly indicated that the decreased expression of miR-143 and -145 frequently occurred before APC gene aberrations. The downregulation of miR-143 and -145 is thus an important genetic event for the initiation step in colorectal tumor development. PMID:23397547

Kamatani, Akemi; Nakagawa, Yoshihito; Akao, Yukihiro; Maruyama, Naoko; Nagasaka, Mitsuo; Shibata, Tomoyuki; Tahara, Tomomitsu; Hirata, Ichiro

2013-02-09

142

Vascular gene expression: a hypothesis  

PubMed Central

The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a “primitive” vascular tissue (a lycophyte), as well as from others that lack a true vascular tissue (a bryophyte), and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non-vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT, and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.

Martinez-Navarro, Angelica C.; Galvan-Gordillo, Santiago V.; Xoconostle-Cazares, Beatriz; Ruiz-Medrano, Roberto

2013-01-01

143

Vascular gene expression: a hypothesis.  

PubMed

The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a "primitive" vascular tissue (a lycophyte), as well as from others that lack a true vascular tissue (a bryophyte), and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non-vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT, and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants. PMID:23882276

Martínez-Navarro, Angélica C; Galván-Gordillo, Santiago V; Xoconostle-Cázares, Beatriz; Ruiz-Medrano, Roberto

2013-07-17

144

Aberrant O-GlcNAc-modified proteins expressed in primary colorectal cancer.  

PubMed

O-GlcNAcylation is a post-translational modification of serine and threonine residues which is dynamically regulated by 2 enzymes; O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that catalyze the addition and removal of a single N-acetylglucosamine (GlcNAc) molecule, respectively. This modification is thought to be a nutrient sensor in highly proliferating cells via the hexosamine biosynthesis pathway, a minor branch of glycolysis. Although emerging evidence suggests that O-GlcNAc modification is associated with many types of cancer, identification of O-GlcNAc?modified proteins and their role in cancer remain unexplored. In the present study, we demonstrated that O-GlcNAcylation is increased in primary colorectal cancer tissues, and that this augmentation is associated with an increased expression of OGT levels. Using 2-dimensional O-GlcNAc immunoblotting and LC-MS/MS analysis, 16 proteins were successfully identified and 8 proteins showed an increase in O-GlcNAcylation, including cytokeratin 18, heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1), hnRNP H, annexin A2, annexin A7, laminin-binding protein, ?-tubulin and protein DJ-1. Among these identified proteins, annexin A2 was further confirmed to show overexpression of O-GlcNAc in all cancer samples. The results, therefore, indicate that aberrant O-GlcNAcylation of proteins is associated with colorectal cancer and that identification of O-GlcNAc-modified proteins may provide novel biomarkers of cancer. PMID:24126823

Phueaouan, Thanong; Chaiyawat, Parunya; Netsirisawan, Pukkavadee; Chokchaichamnankit, Daranee; Punyarit, Phaibul; Srisomsap, Chantragan; Svasti, Jisnuson; Champattanachai, Voraratt

2013-10-11

145

Whole Transcriptome Sequencing Reveals Gene Expression and Splicing Differences in Brain Regions Affected by Alzheimer's Disease  

Microsoft Academic Search

Recent studies strongly indicate that aberrations in the control of gene expression might contribute to the initiation and progression of Alzheimer's disease (AD). In particular, alternative splicing has been suggested to play a role in spontaneous cases of AD. Previous transcriptome profiling of AD models and patient samples using microarrays delivered conflicting results. This study provides, for the first time,

Natalie A. Twine; Karolina Janitz; Marc R. Wilkins; Michal Janitz

2011-01-01

146

MicroRNA Expression Aberration as Potential Peripheral Blood Biomarkers for Schizophrenia  

PubMed Central

Since brain tissue is not readily accessible, a new focus in search of biomarkers for schizophrenia is blood-based expression profiling of non-protein coding genes such as microRNAs (miRNAs), which regulate gene expression by inhibiting the translation of messenger RNAs. This study aimed to identify potential miRNA signature for schizophrenia by comparing genome-wide miRNA expression profiles in patients with schizophrenia vs. healthy controls. A genome-wide miRNA expression profiling was performed using a Taqman array of 365 human miRNAs in the mononuclear leukocytes of a learning set of 30 cases and 30 controls. The discriminating performance of potential biomarkers was validated in an independent testing set of 60 cases and 30 controls. The expression levels of the miRNA signature were then evaluated for their correlation with the patients' clinical symptoms, neurocognitive performances, and neurophysiological functions. A seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) was derived from a supervised classification with internal cross-validation, with an area under the curve (AUC) of receiver operating characteristics of 93%. The putative signature was then validated in the testing set, with an AUC of 85%. Among these miRNAs, miR-34a was differentially expressed between cases and controls in both the learning (P?=?0.005) and the testing set (P?=?0.002). These miRNAs were differentially correlated with patients' negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the mononuclear leukocyte-based miRNA profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-miRNA signature warrants further investigation.

Lai, Chi-Yu; Yu, Sung-Liang; Hsieh, Ming H.; Chen, Chun-Houh; Chen, Hsuan-Yu; Wen, Chun-Chiang; Huang, Yung-Hsiang; Hsiao, Po-Chang; Hsiao, Chuhsing Kate; Liu, Chih-Min; Yang, Pan-Chyr; Hwu, Hai-Gwo; Chen, Wei J.

2011-01-01

147

Control of Stochasticity in Eukaryotic Gene Expression  

Microsoft Academic Search

Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which

Jonathan M. Raser; Erin K. O'Shea

2004-01-01

148

Aberrant SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas.  

PubMed

Sarco (endo)plasmic reticulum Ca(2+)-ATPase (SERCAs) 3 is involved in calcium mobilization from endoplasmic reticulum into cytosol and closely links to metabolism, neuronal plasticity, gene transcription, cell growth, differentiation, apoptosis, protein folding, and carcinogenesis. To clarify the role of SERCA3 in gastric carcinogenesis and subsequent progression, its expression was examined by immunohistochemistry and in situ hybridization (ISH) on tissue microarrays containing gastric carcinomas, adjacent non-neoplastic mucosa (NNM), and metastatic lymph node. SERCA3 expression was studied in gastric carcinoma tissue and cell lines by Western blot, reverse transcriptase-polymerase chain reaction, or immunofluorescence. The results demonstrated that SERCA3 was distinctively expressed in GES-1, AGS, BGC-823, GT-3TKB, HGC-27, KATO-III, MGC-803, MKN28, MKN45, SCH, SGC-7901, and STKM-2 at both mRNA and protein levels. The carcinomas showed higher SERCA3 mRNA expression than the matched NNM by real-time PCR and ISH (P > 0.05). Immunohistochemically, SERCA3 expression was decreased from gastric NNM, primary to metastatic carcinoma (P > 0.05). SERCA3 expression was negatively related to depth of invasion, distant metastasis, and tumor node metastasis (TNM) staging (P > 0.05), but not to age, sex, lymphatic or venous invasion, or lymph node metastasis (P > 0.05). Kaplan-Meier analysis indicated that SERCA3 expression was positively associated with favorable prognosis of the patients with gastric carcinoma (P > 0.05). Cox's proportional hazard model indicated that venous invasion, distant metastasis and TNM staging (P > 0.05) were independent prognostic factors for gastric carcinomas. It was suggested that downregulated SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas. It might be employed to indicate the pathobiological behaviors and prognosis of gastric carcinomas. PMID:22948776

Xu, Xiao-yan; Gou, Wen-feng; Yang, Xue; Wang, Guo-li; Takahashi, Hiroyuki; Yu, Miao; Mao, Xiao-yun; Takano, Yasuo; Zheng, Hua-chuan

2012-09-05

149

Heat-responsive gene expression for gene therapy  

Microsoft Academic Search

Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. By this approach, combination of chemotherapy, radiation or hyperthermia with gene therapy can result in considerable, additive or synergistic improvement of therapeutic efficacy. This concept has been successfully tested in particular for gene therapy

Wolfgang Walther; Ulrike Stein

2009-01-01

150

Hypoxia targeting gene expression for breast cancer gene therapy  

Microsoft Academic Search

Gene therapy is a promising strategy to treat various inherited and acquired diseases. However, targeting gene expression to specific tissue is required to minimize side effects of gene therapy. Hypoxia is present in the microenvironment of solid tumors such as breast tumors. A hypoxic tumor targeting gene expression system has been developed for cancer gene therapy. In hypoxic tissues, hypoxia

Minhyung Lee

2009-01-01

151

Alternative splicing in the human cytochrome P450IIB6 gene generates a high level of aberrant messages.  

PubMed Central

Polymorphisms within the human cytochrome P450 system can have severe clinical consequences and have been associated with adverse drug side effects and susceptibility to environmentally linked diseases such as cancer. Aberrant splicing of cytochrome P450 mRNA has been proposed as a potential mechanism for these polymorphisms. We have isolated aberrantly, as well as normally, spliced mRNAs (cDNAs) from the human P450IIB6 gene which either contain part of intron 5 and lack exon 8 or which contain a 58-bp fragment (exon 8A) instead of exon 8. Sequence analysis of the P450IIB6 gene demonstrates the presence of cryptic splice sites in intron 8 which will account for the generation of exon 8A. The mRNAs were therefore generated by alternative splicing. These data gain significance as the mRNAs will not encode a functional P450 enzyme and appear to represent a high proportion of the P450IIB6 mRNA population. Analysis of mRNA from fifteen individual human livers and cDNA libraries constructed from a variety of human tissues using the polymerase chain reaction shows that the aberrant splicing occurs in all cells and all individuals tested. This suggests a high level of infidelity in the processing of P450IIB6 mRNAs and demonstrates that the presence of abnormal transcripts does not imply the presence of a functionally inactive gene. Images

Miles, J S; McLaren, A W; Wolf, C R

1989-01-01

152

Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-alpha converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma.  

PubMed

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-alpha, was inhibited by TNF-alpha protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G2-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process. PMID:16982746

Ringel, Jörg; Jesnowski, Ralf; Moniaux, Nicolas; Lüttges, Jutta; Ringel, Jens; Choudhury, Amit; Batra, Surinder K; Klöppel, Günter; Löhr, Matthias

2006-09-15

153

Gene expression throughout a vertebrate's embryogenesis  

PubMed Central

Background Describing the patterns of gene expression during embryonic development has broadened our understanding of the processes and patterns that define morphogenesis. Yet gene expression patterns have not been described throughout vertebrate embryogenesis. This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Results Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (> 200 genes) relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16, (pre-mid-gastrulation) the largest number of genes has peak expression. This stage has an over representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases). Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. Conclusions These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development.

2011-01-01

154

ABERRATIONS OF A PUTATIVE TUMOR SUPPRESSOR GENE SEL1L IN PANCREATIC DUCTAL ADENOCARCINOMA  

Microsoft Academic Search

Introduction: Pancreatic cancer is the fourth leading cause of cancer-related death among males and females in the United States. Sel-1-like (SEL1L) is a putative tumor suppressor gene that is downregulated in a significant proportion of human pancreatic ductal adenocarcinoma (PDAC). It was hypothesized that SEL1L expression could be down-modulated by somatic mutation, loss of heterozygosity (LOH), CpG island hypermethylation and\\/or

Qian Liu

2011-01-01

155

A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia.  

PubMed

Many mutations in the skeletal-muscle sodium-channel gene SCN4A have been associated with myotonia and/or periodic paralysis, but so far all of these mutations are located in exons. We found a patient with myotonia caused by a deletion/insertion located in intron 21 of SCN4A, which is an AT-AC type II intron. This is a rare class of introns that, despite having AT-AC boundaries, are spliced by the major or U2-type spliceosome. The patient's skeletal muscle expressed aberrantly spliced SCN4A mRNA isoforms generated by activation of cryptic splice sites. In addition, genetic suppression experiments using an SCN4A minigene showed that the mutant 5' splice site has impaired binding to the U1 and U6 snRNPs, which are the cognate factors for recognition of U2-type 5' splice sites. One of the aberrantly spliced isoforms encodes a channel with a 35-amino acid insertion in the cytoplasmic loop between domains III and IV of Nav1.4. The mutant channel exhibited a marked disruption of fast inactivation, and a simulation in silico showed that the channel defect is consistent with the patient's myotonic symptoms. This is the first report of a disease-associated mutation in an AT-AC type II intron, and also the first intronic mutation in a voltage-gated ion channel gene showing a gain-of-function defect. PMID:21412952

Kubota, Tomoya; Roca, Xavier; Kimura, Takashi; Kokunai, Yosuke; Nishino, Ichizo; Sakoda, Saburo; Krainer, Adrian R; Takahashi, Masanori P

2011-04-28

156

Interactive Fly: Early Zygotic Gene Expression Images  

NSDL National Science Digital Library

In situ images from an award-winning and comprehensive site, The Interactive Fly. Entering through an expression pattern, this site thoroughly discusses each genes and shows its expression relative to other genes at this stage.

PhD Thomas B Brody (NIH Laboratory of Neurochemistry)

2006-12-12

157

Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma  

PubMed Central

Osteosarcoma (OS) is the eighth most common form of childhood and adolescence cancer. Approximately 10%–20% of patients present metastatic disease at diagnosis and the 5-year overall survival remains around 70% for nonmetastatic patients and around 30% for metastatic patients. Metastatic disease at diagnosis and the necrosis grade induced by preoperative treatment are the only well-established prognostic factors for osteosarcoma. The DNA aberrant methylation is a frequent epigenetic alteration in humans and has been described as a molecular marker in different tumor types. This study evaluated the DNA aberrant methylation status of 18 genes in 34 OS samples without previous chemotherapy treatment and in four normal bone specimens and compared the methylation profile with clinicopathological characteristics of the patients. We were able to define a three-gene panel (AIM1, p14ARF, and ESR1) in which methylation was correlated with OS cases. The hypermethylation of p14ARF showed a significant association with the absence of metastases at diagnoses, while ESR1 hypermethylation was marginally associated with worse overall survival. This study demonstrated that aberrant promoter methylation is a common event in OS and provides evidence that p14ARF and ESR1 hypermethylation could be useful as a prognostic indicator for this disease.

Sonaglio, Viviane; de Carvalho, Ana C; Toledo, Silvia R C; Salinas-Souza, Carolina; Carvalho, Andre L; Petrilli, Antonio S; de Camargo, Beatriz; Vettore, Andre L

2013-01-01

158

Characterization of a Cis-Acting Regulatory Element which Silences Expression of the Class II-A ~ Gene in Epithelium  

Microsoft Academic Search

Summary Class II major histocompatibility complex (MHC) genes encode for oe\\/13 chain pairs that are constitutively expressed principally on mature B cells and dendritic cells in mice. These gene products are easily induced on macrophages with cytokines, and may also aberrantly appear on the surface of epithelium during immune injury. The appearance of class II determinants in parenchymal tissue potentially

Shelley E. Albert; Frank Strutz; Kathleen Shelton; Thomas Haverty; Mac Jane Sun; Shao-ran Li; Amy Denham; Richard A. Maki; Eric G. Neilson

159

Correlation between ECT2 gene expression and methylation change of ECT2 promoter region in pancreatic cancer  

Microsoft Academic Search

BACKGROUND: Pancreatic cancer is closely related to epigenetic abnormality. The epithelial cell transforming sequence 2 gene (ECT2) plays a critical role in Rho activation during cytokinesis, and thus may play a role in the pathogenesis of pancreatic cancer. In this study, we investigated the relationships between aberrant expression and epigenetic changes of the ECT2 gene in pancreatic cancer. METHODS: Four

Mang-Li Zhang; Sen Lu; Lin Zhou; Shu-Sen Zheng

2008-01-01

160

Aberrant cerebellar granule cell-specific GABAA receptor expression in the epileptic and ataxic mouse mutant, Tottering.  

PubMed

The Tottering (cacna1a(tg)) mouse arose as a consequence of a spontaneous mutation in cacna1a, the gene encoding the pore-forming subunit of the pre-synaptic P/Q-type voltage-gated calcium channel (VGCC, Ca(V)2.1). The mouse phenotype includes ataxia and intermittent myoclonic seizures which have been attributed to impaired excitatory neurotransmission at cerebellar granule cell (CGC) parallel fiber-Purkinje cell (PF-PC) synapses [Zhou YD, Turner TJ, Dunlap K (2003) Enhanced G-protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca(2+)-channel mutant mouse, tottering. J Physiol 547:497-507]. We hypothesized that the expression of cerebellar GABA(A) receptors may be affected by the mutation. Indeed, abnormal GABA(A) receptor function and expression in the cacna1a(tg) forebrain has been reported previously [Tehrani MH, Barnes EM Jr (1995) Reduced function of gamma-aminobutyric acid A receptors in tottering mouse brain: role of cAMP-dependent protein kinase. Epilepsy Res 22:13-21; Tehrani MH, Baumgartner BJ, Liu SC, Barnes EM Jr (1997) Aberrant expression of GABA(A) receptor subunits in the tottering mouse: an animal model for absence seizures. Epilepsy Res 28:213-223]. Here we show a deficit of 40.2+/-3.6% in the total number of cerebellar GABA(A) receptors expressed (gamma2+delta subtypes) in adult cacna1a(tg) relative to controls. [(3)H]Muscimol autoradiography identified that this was partly due to a significant loss of CGC-specific alpha6 subunit-containing GABA(A) receptor subtypes. A large proportion of this loss of alpha6 receptors was attributable to a significantly reduced expression of the CGC-specific benzodiazepine-insensitive Ro15-4513 (BZ-IS) binding subtype, alpha6betagamma2 subunit-containing receptors. BZ-IS binding was reduced by 36.6+/-2.6% relative to controls in cerebellar membrane homogenates and by 37.2+/-3.7% in cerebellar sections. Quantitative immunoblotting revealed that the steady-state expression level of alpha6 and gamma2 subunits was selectively reduced relative to controls by 30.2+/-8.2% and 38.8+/-13.1%, respectively, alpha1, beta3 and delta were unaffected. Immunohistochemically probed control and cacna1a(tg) cerebellar sections verified that alpha6 and gamma2 subunit expression was reduced and that this deficit was restricted to the CGC layer. Thus, we have shown that abnormal cerebellar P/Q-type VGCC activity results in a deficit of CGC-specific subtype(s) of GABA(A) receptors which may contribute to, or may be a consequence of the impaired cerebellar network signaling that occurs in cacna1a(tg) mice. PMID:17614209

Kaja, S; Hann, V; Payne, H L; Thompson, C L

2007-07-05

161

Tissue classification with gene expression profiles  

Microsoft Academic Search

Constantly improving gene expression profiling technologies are expected to provide understanding and insight into cancer related cellular processes. Gene expression data is also expected to significantly and in the development of efficient cancer diagnosis and classification platforms. In this work we examine two sets of gene expression data measured across sets of tumor and normal clinical samples One set consists

Amir Ben-Dor; Laurakay Bruhn; Nir Friedman; Iftach Nachman; Michèl Schummer; Zohar Yakhini

2000-01-01

162

Challenges of Translating Gene Expression Microarray Data ...  

Center for Biologics Evaluation and Research (CBER)

Text Version... Low power under stringent multiple testing corrections ? Co-regulation of genes 12 Beyond Gene Lists: ... 14 Gene Expression Profile ... More results from www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials

163

Aberrant expression of adaptation to phenobarbital may cause selective growth of foci of altered cells in rat liver.  

PubMed

According to the multistage concept of carcinogenesis, promoters induce selective or preferential multiplication of initiated cells, thereby accelerating one of the rate-limiting steps in cancer formation. The driving force for this selective growth of initiated cells is not known. In normal liver, various liver tumour promoters induce expression of adaptive programmes. One such programme, induced by phenobarbital, consists of organ growth and an increase in the activity of various enzymes involved in the metabolism of lipophilic substrates. In foci of altered rat liver cells (the putative progeny of initiated cells), expression of the programme is still possible and is coupled to certain regulatory defects (excessive, unbalanced proliferation; independence from position-specific restrictions within the hepatic acinus; autonomous expression of some adaptive changes). Promoters seem to switch on this aberrant expression of the programme of adaptation, thereby leading to preferential growth of foci. PMID:6152623

Schulte-Hermann, R; Timmermann-Trosiener, I; Schuppler, J

1984-01-01

164

Identification of four soybean reference genes for gene expression normalization  

Technology Transfer Automated Retrieval System (TEKTRAN)

Gene expression analysis requires the use of reference genes stably expressed independently of specific tissues or environmental conditions. Housekeeping genes (e.g., actin, tubulin, ribosomal, polyubiquitin and elongation factor 1-alpha) are commonly used as reference genes with the assumption tha...

165

Modulation of Gene Expression Made Easy  

Microsoft Academic Search

A new approach for modulating gene expression, based on randomization of promoter (spacer) sequences, was developed. The method was applied to chromosomal genes in Lactococcus lactis and shown to generate libraries of clones with broad ranges of expression levels of target genes. In one example, overexpression was achieved by introducing an additional gene copy into a phage attachment site on

Christian Solem; Peter Ruhdal Jensen

2002-01-01

166

DNA Methylation and Gene Expression Profiling of Ewing Sarcoma Primary Tumors Reveal Genes That Are Potential Targets of Epigenetic Inactivation  

PubMed Central

The role of aberrant DNA methylation in Ewing sarcoma is not completely understood. The methylation status of 503 genes in 52 formalin-fixed paraffin-embedded EWS tumors and 3 EWS cell lines was compared to human mesenchymal stem cell primary cultures (hMSCs) using bead chip methylation analysis. Relative expression of methylated genes was assessed in 5-Aza-2-deoxycytidine-(5-AZA)-treated EWS cell lines and in a cohort of primary EWS samples and hMSCs by gene expression and quantitative RT-PCR. 129 genes demonstrated statistically significant hypermethylation in EWS tumors compared to hMSCs. Thirty-six genes were profoundly methylated in EWS and unmethylated in hMSCs. 5-AZA treatment of EWS cell lines resulted in upregulation of expression of hundreds of genes including 162 that were increased by at least 2-fold. The expression of 19 of 36 candidate hypermethylated genes was increased following 5-AZA. Analysis of gene expression from an independent cohort of tumors confirmed decreased expression of six of nineteen hypermethylated genes (AXL, COL1A1, CYP1B1, LYN, SERPINE1,) and VCAN. Comparing gene expression and DNA methylation analyses proved to be an effective way to identify genes epigenetically regulated in EWS. Further investigation is ongoing to elucidate the role of these epigenetic alterations in EWS pathogenesis.

Patel, Nikul; Black, Jennifer; Chen, Xi; Marcondes, A. Mario; Grady, William M.; Lawlor, Elizabeth R.; Borinstein, Scott C.

2012-01-01

167

Aberrant expression of MUC1 mucin in ductal hyperplasia and ductal carcinoma In situ of the breast.  

PubMed

MUC1 mucin is a high molecular weight transmembrane glycoprotein expressed on the apical cell surface of normal glandular epithelia. In many human adenocarcinomas, this protein is up-regulated and/or underglycosylated, and its expression changes from apical to the entire cell membrane. It is thought that entire cell membrane expression of MUC1 reduces cell-cell and cell-extracellular matrix interactions and therefore may facilitate invasive growth and development of metastases. In this study, we determined immunohistochemically the expression of normal and underglycosylated MUC1 in normal breast tissue (n = 8) and in a spectrum of breast lesions, including usual ductal hyperplasia (n = 23), atypical ductal hyperplasia (n = 7), and ductal carcinoma in situ (DCIS) (n = 22). We used 4 monoclonal antibodies; 115D8 is directed to a glycopeptide, the other 3 to the peptide core of the molecule, of which 139H2 is not affected by the degree of glycosylation of MUC1, whereas SM3 and VU-4-H5 stain only underglycosylated forms. All cases showed apical positivity for 115D8 and 139H2. Entire cell membrane expression of fully (normal) glycosylated MUC1 was mainly found in DCIS lesions. Apical staining of SM3 was found in 38% of normal cases and 60% of the ductal lesions with no difference between the different subgroups. Apical staining of VU-4-H5 was found more often in DCIS (27%) than in normal tissue or ductal hyperplasia (3%). Membrane expression of underglycosylated MUC1 was found only in poorly differentiated DCIS. In conclusion, aberrant expression of MUC1, i.e., on the entire cell membrane and/or underglycosylated forms, can be found in ductal hyperplasia with atypia and especially in DCIS of the breast. This finding implies that these lesions with aberrant expression are at higher risk for developing subsequent invasive breast carcinoma. PMID:10502721

Mommers, E C; Leonhart, A M; von Mensdorff-Pouilly, S; Schol, D J; Hilgers, J; Meijer, C J; Baak, J P; van Diest, P J

1999-10-22

168

High-resolution gene copy number and expression profiling of human chromosome 22 in ovarian carcinomas  

Microsoft Academic Search

Previous low-resolution studies of chromosome 22 in ovarian carcinoma have suggested its involvement in the development of the disease. We report a high-resolution analysis of DNA copy number and gene expression of 22q in 18 ovarian carcinomas using a 22q-specific genomic microarray. We identified aberrations in 67% of the studied tumors, which displayed 3 distinct gene copy number profiles. The

Magdalena Benetkiewicz; Yun Wang; Marci Schaner; Pei Wang; Kiran K. Mantripragada; Patrick G. Buckley; Gunnar Kristensen; Jan P. Dumanski

2005-01-01

169

Gene Expression Patterns in Human Liver Cancers  

Microsoft Academic Search

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression

Xin Chen; Siu Tim Cheung; Samuel So; Sheung Tat Fan; Christopher Barry; John Higgins; Kin-Man Lai; Jiafu Ji; Sandrine Dudoit; Irene O. L. Ng; Matt van de Rijn; David Botstein; Patrick O. Brown

2002-01-01

170

The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia.  

PubMed

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and remains incurable with conventional chemotherapy treatment approaches. CLL as a disease entity is defined by a relatively parsimonious set of diagnostic criteria and therefore likely constitutes an umbrella term for multiple related illnesses. Of the enduring fundamental biological processes that affect the biology and clinical behavior of CLL, few are as central to the pathogenesis of CLL as recurrent acquired genomic copy number aberrations (aCNA) and recurrent gene mutations. Here, a state-of-the-art overview of the pathological anatomy of the CLL genome is presented, including detailed descriptions of the anatomy of aCNA and gene mutations. Data from SNP array profiling and large-scale sequencing of large CLL cohorts, as well as stimulated karyotyping, are discussed. This review is organized by discussions of the anatomy, underlying pathomechanisms and clinical significance of individual genomic lesions and recurrent gene mutations. Finally, gaps in knowledge regarding the biological and clinical effects of recurrent genomic aberrations or gene mutations on CLL are outlined to provide critical stimuli for future research. PMID:23001040

Malek, S N

2012-09-24

171

Gene Expression and Mitotic Exit Induced by Microtubule-Stabilizing Drugs  

Microsoft Academic Search

To explore the molecular mechanisms underlying the actions of Taxol and the functionally related molecule epothilone B (EpoB), we have ana- lyzed the gene expression profiles in A549 cells in response to increasing concentrations of these microtubule-stabilizing drugs. An almost identical expression pattern was observed in cells treated with either Taxol or EpoB. Low concentrations of the drugs induced aberrant

Jie-Guang Chen; Chia-Ping Huang Yang; Michael Cammer; Susan Band Horwitz

2003-01-01

172

Gender differences in the induction of chromosomal aberrations and gene mutations in rodent germ cells  

SciTech Connect

Germ cell mutagenicity testing provides experimental data to quantify genetic risk for exposed human populations. The majority of tests are performed with exposure of males, and female data are relatively rare. The reason for this paucity lies in the differences between male and female germ cell biology. Male germ cells are produced throughout reproductive life and all developmental stages can be ascertained by appropriate breeding schemes. In contrast, the female germ cell pool is limited, meiosis begins during embryogenesis and oocytes are arrested over long periods of time until maturation processes start for small numbers of oocytes during the oestrus cycle in mature females. The literature data are reviewed to point out possible gender differences of germ cells to exogenous agents such as chemicals or ionizing radiation. From the limited information, it can be concluded that male germ cells are more sensitive than female germ cells to the induction of chromosomal aberrations and gene mutations. However, exceptions are described which shed doubt on the extrapolation of experimental data from male rodents to the genetic risk of the human population. Furthermore, the female genome may be more sensitive to mutation induction during peri-conceptional stages compared to the male genome of the zygote. With few exceptions, germ cell experiments have been carried out under high acute exposure to optimize the effects and to compensate for the limited sample size in animal experiments. Human exposure to environmental agents, on the other hand, is usually chronic and involves low doses. Under these conditions, gender differences may become apparent that have not been studied so far. Additionally, data are reviewed that suggest a false impression of safety when responses are negative under high acute exposure of male rodents while a mutational response is induced by low chronic exposure. The classical (morphological) germ cell mutation tests are not performed anymore because they are animal and time consuming. Nevertheless, information is needed to place genetic risk extrapolations on more solid grounds and thereby to prevent an increased genetic burden to future generations. It is pointed out that modern molecular methodologies are available now to experimentally address the open questions.

Adler, Ilse-Dore [GSF-Institute of Experimental Genetics, Neuherberg D-85758 (Germany); Carere, Angelo [Istituto Superiore di Sanita, Viale Regina Elena 299, Rome 00161 (Italy); Eichenlaub-Ritter, Ursula [Institute of Genetechnology/Microbiology, University of Bielefeld, Bielefeld D-33501 (Germany)]. E-mail: EiRi@uni-bielefeld.de; Pacchierotti, Francesca [Section of Toxicology and Biomedical Sciences, ENEA, CR Casaccia, Via Anguillarese 301, Rome 00060 (Italy)

2007-05-15

173

Cytoskeleton alterations in melanoma: aberrant expression of cortactin, an actin-binding adapter protein, correlates with melanocytic tumor progression  

PubMed Central

Cortactin is a multidomain actin-binding protein important for the functions of cytoskeleton by regulating cortical actin dynamics. It is involved in a diverse array of basic cellular functions. Tumorigenesis and tumor progression involves alterations in actin cytoskeleton proteins. We sought to study the role of cortactin in melanocytic tumor progression using immunohistochemistry on human tissues. The results reveal quantitative differences between benign and malignant lesions. Significantly higher cortactin expression is found in melanomas than in nevi (P<0.0001), with levels greater in metastatic than in invasive melanomas (P<0.05). Qualitatively, tumor tissues often show aberrant cortactin localization at the cell periphery, corresponding to its colocalization with filamentous actin in cell cortex of cultured melanoma cells. This suggests an additional level of protein dysregulation. Furthermore, in patients with metastatic disease, high-level cortactin expression correlates with poor disease-specific survival. Our data, in conjunction with outcome data on several other types of human cancers and experimental data from melanoma cell lines, supports a potential role of aberrant cortactin expression in melanoma tumor progression and a rational for targeting key elements of actin-signaling pathway for developmental therapeutics in melanomas.

Xu, Xu-Zhi; Garcia, Marileila Varella; Li, Tian-yu; Khor, Li-Yan; Gajapathy, R Sujatha; Spittle, Cindy; Weed, Scott; Lessin, Stuart R; Wu, Hong

2010-01-01

174

Dynamic agglomerative clustering of gene expression profiles  

Microsoft Academic Search

The increasing use of microarray technologies is generating a large amount of data that must be processed to extract underlying gene expression patterns. Existing clustering methods could suffer from certain drawbacks. Most methods cannot automatically separate scat- tered, singleton and mini-cluster genes from other genes. Inclusion of these types of genes into regular clustering processes can impede identification of gene

Faming Liang; Naisyin Wang

2007-01-01

175

Aberrant methylation of the M-type phospholipase A2 receptor gene in leukemic cells  

PubMed Central

Background The M-type phospholipase A2 receptor (PLA2R1) plays a crucial role in several signaling pathways and may act as tumor-suppressor. This study examined the expression and methylation of the PLA2R1 gene in Jurkat and U937 leukemic cell lines and its methylation in patients with myelodysplastic syndrome (MDS) or acute leukemia. Methods Sites of methylation of the PLA2R1 locus were identified by sequencing bisulfite-modified DNA fragments. Methylation specific-high resolution melting (MS-HRM) analysis was then carried out to quantify PLA2R1 methylation at 5`-CpG sites identified with differences in methylation between healthy control subjects and leukemic patients using sequencing of bisulfite-modified genomic DNA. Results Expression of PLA2R1 was found to be completely down-regulated in Jurkat and U937 cells, accompanied by complete methylation of PLA2R1 promoter and down-stream regions; PLA2R1 was re-expressed after exposure of cells to 5-aza-2´-deoxycytidine. MS-HRM analysis of the PLA2R1 locus in patients with different types of leukemia indicated an average methylation of 28.9%?±?17.8%, compared to less than 9% in control subjects. In MDS patients the extent of PLA2R1 methylation significantly increased with disease risk. Furthermore, measurements of PLA2R1 methylation appeared useful for predicting responsiveness to the methyltransferase inhibitor, azacitidine, as a pre-emptive treatment to avoid hematological relapse in patients with high-risk MDS or acute myeloid leukemia. Conclusions The study shows for the first time that PLA2R1 gene sequences are a target of hypermethylation in leukemia, which may have pathophysiological relevance for disease evolution in MDS and leukemogenesis.

2012-01-01

176

Aberrant splicing and transcription termination caused by P element insertion into the intron of a Drosophila gene  

SciTech Connect

Insertional mutagenesis screens using the P[lacZ, rosy{sup +}] (PZ) transposable element have provided thousands of mutant lines for analyzing genes of varied function in the fruitfly, Drosophila melanogaster. As has been observed with other P elements, many of the PZ-induced mutations result from insertion of the P element into the promoter or 5{prime} untranslated regions of the affected gene. We document here a novel mechanism for mutagenesis by this element. We show that sequences present within the element direct aberrant splicing and termination events that produce an mRNA composed of 5{prime} sequences from the mutated gene (in this case, pipsqueak) and 3{prime} sequences from within the P[lacZ, rosy{sup +}] element. These truncated RNAs could yield proteins with dominant mutant effects. 43 refs., 4 figs.

Horowitz, H.; Berg, C.A. [Univ. of Washington, Seattle, WA (United States)

1995-01-01

177

Mechanoregulation of gene expression in fibroblasts  

PubMed Central

Mechanical loads placed on connective tissues alter gene expression in fibroblasts through mechanotransduction mechanisms by which cells convert mechanical signals into cellular biological events, such as gene expression of extracellular matrix components (e.g., collagen). This mechanical regulation of ECM gene expression affords maintenance of connective tissue homeostasis. However, mechanical loads can also interfere with homeostatic cellular gene expression and consequently cause the pathogenesis of connective tissue diseases such as tendinopathy and osteoarthritis. Therefore, the regulation of gene expression by mechanical loads is closely related to connective tissue physiology and pathology. This article reviews the effects of various mechanical loading conditions on gene regulation in fibroblasts and discusses several mechanotransduction mechanisms. Future research directions in mechanoregulation of gene expression are also suggested.

Wang, James H.-C.; Thampatty, Bhavani P.; Lin, Jeen-Shang; Im, Hee-Jeong

2010-01-01

178

Lack of a phenotype in transgenic mice aberrantly expressing COL2A1 mRNA because of highly selective post-transcriptional down-regulation.  

PubMed Central

We reported previously that a 1.9-kb 5'-fragment from the human COL1A1 gene drove transcription of a promoterless human COL2A1 gene in tissues of transgenic mice that normally express the COL1A1 but not the COL2A1 gene. In the present study, we have established that the aberrant transcription of the COL2A1 gene did not produce any gross or microscopic phenotype, because the transcripts were not efficiently translated in cells that do not normally express the COL2A1 gene. In two lines of transgenic mice, the mRNA levels from the transgene were 30% to 45% of the mRNA for the proalpha1(I) chain of type I procollagen, the most abundant mRNA in the same tissues. Analysis of collagens extracted from skin of the transgenic mice indicated that triple-helical type II collagen, with the normal pattern of cyanogen bromide peptides, was synthesized from the transgene. However, the level of type II collagen in skin was less than 2% of the level of type I collagen. Hybridization in situ indicated the presence of mRNA for both COL2A1 and COL1A1 in the same cells. Immunofluorescence staining for type II collagen, however, was negative in the same tissues. The results, therefore, indicated that many mesenchymal cells in the transgenic mice had high steady-state levels of the homologous mRNAs for type I and type II procollagen, but only the mRNAs for type I procollagen were efficiently translated.

Yuan, C M; Ala-Kokko, L; Le Guellec, D; Franc, S; Fertala, A; Khillan, J S; Sokolov, B P; Prockop, D J

2000-01-01

179

Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma  

PubMed Central

Purpose The goal of this study was to comprehensively identify CpG island methylation alterations between pancreatic cancers and normal pancreata and their associated gene expression alterations. Experimental Design We employed Methylated CpG island Amplification followed by CpG island Microarray, a method previously validated for its accuracy and reproducibility, to analyze the methylation profile of 27800 CpG islands covering 21MB of the human genome in nine pairs of pancreatic cancer versus normal pancreatic epithelial tissues as well as in three matched pairs of pancreatic cancer versus lymphoid tissues from the same individual. Results This analysis identified 1658 known loci that were commonly differentially methylated in pancreatic cancer compared to normal pancreas. By integrating the pancreatic DNA methylation status with the gene expression profiles of the same samples before and after treatment with the DNA methyltransferase inhibitor 5-aza-2?-deoxycytidine, and the Histone Deacetylase inhibitor, Trichostatin A, we identified dozens of aberrantly methylated and differentially expressed genes in pancreatic cancers including a more comprehensive list of hypermethylated and silenced genes that have not been previously described as targets for aberrant methylation in cancer. Conclusion We expect that the identification of aberrantly hypermethylated and silenced genes will have diagnostic, prognostic and therapeutic applications.

Vincent, Audrey; Omura, Noriyuki; Hong, Seung-Mo; Jaffe, Andrew; Eshleman, James; Goggins, Michael

2011-01-01

180

Widespread ectopic expression of olfactory receptor genes  

Microsoft Academic Search

BACKGROUND: Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication

Ester Feldmesser; Tsviya Olender; Miriam Khen; Itai Yanai; Ron Ophir; Doron Lancet

2006-01-01

181

Predicting Gene Ontology Biological Process From Temporal Gene Expression Patterns  

PubMed Central

The aim of the present study was to generate hypotheses on the involvement of uncharacterized genes in biological processes. To this end, supervised learning was used to analyze microarray-derived time-series gene expression data. Our method was objectively evaluated on known genes using cross-validation and provided high-precision Gene Ontology biological process classifications for 211 of the 213 uncharacterized genes in the data set used. In addition, new roles in biological process were hypothesized for known genes. Our method uses biological knowledge expressed by Gene Ontology and generates a rule model associating this knowledge with minimal characteristic features of temporal gene expression profiles. This model allows learning and classification of multiple biological process roles for each gene and can predict participation of genes in a biological process even though the genes of this class exhibit a wide variety of gene expression profiles including inverse coregulation. A considerable number of the hypothesized new roles for known genes were confirmed by literature search. In addition, many biological process roles hypothesized for uncharacterized genes were found to agree with assumptions based on homology information. To our knowledge, a gene classifier of similar scope and functionality has not been reported earlier. [Supplemental material is available online at www.genome.org. All annotations, reclassifications of known genes, and classifications of uncharacterized genes are available online at http://www.lcb.uu.se/?hvidsten/fibroblast.

Laegreid, Astrid; Hvidsten, Torgeir R.; Midelfart, Herman; Komorowski, Jan; Sandvik, Arne K.

2003-01-01

182

Chromosomal aberrations in environmentally exposed population in relation to metabolic and DNA repair genes polymorphisms  

Microsoft Academic Search

The capital city of Prague is one of the most polluted localities of the Czech Republic. Therefore, the effect of exposure to carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) adsorbed onto respirable air particles (<2.5?m) on chromosomal aberrations was studied in a group of policemen (males, aged 22–50 years) working in the downtown area of Prague and spending daily >8h outdoors (N=53).

Radim J. Sram; Olena Beskid; Blanka Binkova; Irena Chvatalova; Zdena Lnenickova; Alena Milcova; Ivo Solansky; Elena Tulupova; Hana Bavorova; Dana Ocadlikova; Peter B. Farmer

2007-01-01

183

Decreased expression of RIZ1 and its clinicopathological significance in epithelial ovarian carcinoma: correlation with epigenetic inactivation by aberrant DNA methylation.  

PubMed

The retinoblastoma protein-interacting zinc finger gene (RIZ1) is considered a tumor suppressor gene. The purpose of the present study was to examine the expression of RIZ1 and evaluate its clinicopathological significance in ovarian carcinoma. Immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed for RIZ1 and its clinicopathological significance was examined. DNA methylation status of RIZ1 was also studied. All (6/6) of the normal, 5/9 of benign, and 4/9 of borderline tissues were positive for RIZ1 protein. In ovarian cancer tissues 32.9% (54/164) were positive for RIZ1. Decreased expression of RIZ1 was significantly correlated with histological subtypes (P < 0.0001), high tumor grade (P = 0.0153) and advanced clinical stage (P = 0.0345), and high Ki67 index (P = 0.0117) but was not associated with the overall prognoses of the patients (P = 0.519). The presence of methylated band was detected in 2/9 cell lines, and 5/69 ovarian cancer tissues. Median values of relative RIZ1 expression in cell lines with methylation were significantly lower than those without methylation (P = 0.0404), and treatment of 5-aza-2'deoxycitidine resulted in demethylation and re-expression of RIZ1. Reduced expression of RIZ1 may play an important role in the pathogenesis and/or development of epithelial ovarian carcinoma, and is considered to be caused in part by aberrant DNA methylation. PMID:17922684

Akahira, Jun-Ichi; Suzuki, Fumihiko; Suzuki, Takashi; Miura, Ikumi; Kamogawa, Noriko; Miki, Yasuhiro; Ito, Kiyoshi; Yaegashi, Nobuo; Sasano, Hironobu

2007-11-01

184

Differential gene detection incorporating common expression patterns  

NASA Astrophysics Data System (ADS)

In detection of differentially expressed (DE) genes between different groups of samples based on a high-throughput expression measurement system, we often use a classical statistical testing based on a simple assumption that the expression of a certain DE gene in one group is higher or lower in average than that in the other group. Based on this simple assumption, the theory of optimal discovery procedure (ODP) (Storey, 2005) provided an optimal thresholding function for DE gene detection. However, expression patterns of DE genes over samples may have such a structure that is not exactly consistent with group labels assigned to the samples. Appropriate treatment of such a structure can increase the detection ability. Namely, genes showing similar expression patterns to other biologically meaningful genes can be regarded as statistically more significant than those showing expression patterns independent of other genes, even if differences in mean expression levels are comparable. In this study, we propose a new statistical thresholding function based on a latent variable model incorporating expression patterns together with the ODP theory. The latent variable model assumes hidden common signals behind expression patterns over samples and the ODP theory is extended to involve the latent variables. When applied to several gene expression data matrices which include cluster structures or 'cancer outlier' structures, the newly-proposed thresholding functions showed prominently better detection performance of DE genes than the original ODP thresholding function did. We also demonstrate how the proposed methods behave through analyses of real breast cancer and lymphoma datasets.

Oba, Shigeyuki; Ishii, Shin

2009-12-01

185

Chromosome Aberrations and Cancer  

Microsoft Academic Search

Cancer may be defined as a progressive series of genetic events that occur in a single clone of cells because of alterations in a limited number of specific genes: the oncogenes and tumor suppressor genes. The association of consistent chromosome aberrations with particular types of cancer has led to the identification of some of these genes and the elucidation of

Ellen Solomon; Julian Borrow; Audrey D. Goddard

1991-01-01

186

Gene–Environment Interaction in Yeast Gene Expression  

Microsoft Academic Search

The effects of genetic variants on phenotypic traits often depend on environmental and physiological conditions, but such gene-environment interactions are poorly understood. Recently developed approaches that treat transcript abundances of thousands of genes as quantitative traits offer the opportunity to broadly characterize the architecture of gene-environment interactions. We examined the genetic and molecular basis of variation in gene expression between

Erin N. Smith; Leonid Kruglyak

2008-01-01

187

Gene Expression after Bacteriophage T7 Infection.  

National Technical Information Service (NTIS)

Bacteriophage T7 and its host, E. coli, have provided a simple system in which to analyze the organization and expression of a viral genome. T7 genes are clustered in three groups in the T7 DNA: early genes, genes involved in DNA metabolism, and genes inv...

F. W. Studier

1975-01-01

188

Methods for monitoring multiple gene expression  

SciTech Connect

The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

Berka, Randy (Davis, CA); Bachkirova, Elena (Davis, CA); Rey, Michael (Davis, CA)

2012-05-01

189

Methods for monitoring multiple gene expression  

DOEpatents

The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

Berka, Randy (Davis, CA); Bachkirova, Elena (Davis, CA); Rey, Michael (Davis, CA)

2008-06-01

190

Development of a novel approach, the epigenome-based outlier approach, to identify tumor-suppressor genes silenced by aberrant DNA methylation.  

PubMed

Identification of tumor-suppressor genes (TSGs) silenced by aberrant methylation of promoter CpG islands (CGIs) is important, but hampered by a large number of genes methylated as passengers of carcinogenesis. To overcome this issue, we here took advantage of the fact that the vast majority of genes methylated in cancers lack, in normal cells, RNA polymerase II (Pol II) and have trimethylation of histone H3 lysine 27 (H3K27me3) in their promoter CGIs. First, we demonstrated that three of six known TSGs in breast cancer and two of three in colon cancer had Pol II and lacked H3K27me3 in normal cells, being outliers to the general rule. BRCA1, HOXA5, MLH1, and RASSF1A had high Pol II, but were expressed only at low levels in normal cells, and were unlikely to be identified as outliers by their expression statuses in normal cells. Then, using epigenome statuses (Pol II binding and H3K27me3) in normal cells, we made a genome-wide search for outliers in breast cancers, and identified 14 outlier promoter CGIs. Among these, DZIP1, FBN2, HOXA5, and HOXC9 were confirmed to be methylated in primary breast cancer samples. Knockdown of DZIP1 in breast cancer cell lines led to increases of their growth, suggesting it to be a novel TSG. The outliers based on their epigenome statuses contained unique TSGs, including DZIP1, compared with those identified by the expression microarray data. These results showed that the epigenome-based outlier approach is capable of identifying a different set of TSGs, compared to the expression-based outlier approach. PMID:22433712

Kikuyama, Mizuho; Takeshima, Hideyuki; Kinoshita, Takayuki; Okochi-Takada, Eriko; Wakabayashi, Mika; Akashi-Tanaka, Sadako; Ogawa, Toshihisa; Seto, Yasuyuki; Ushijima, Toshikazu

2012-03-17

191

Imprinted gene expression in the brain  

Microsoft Academic Search

In normal mammals, autosomal genes are present in duplicate (i.e. two alleles), one inherited from the father, and one from the mother. For the majority of genes both alleles are transcribed (or expressed) equally. However, for a small subset of genes, known as imprinted genes, only one allele is expressed in a parent-of-origin dependent manner (note that the ‘imprint’ here

William Davies; Anthony R. Isles; Lawrence S. Wilkinson

2005-01-01

192

Normalization and quantification of differential expression in gene expression microarrays  

Microsoft Academic Search

Array-based gene expression studies frequently serve to identify genes that are expressed differently under two or more conditions. The actual analysis of the data, however, may be hampered by a number of technical and statistical problems. Possible remedies on the level of computational analysis lie in appropriate preprocessing steps, proper normalization of the data and application of statistical testing procedures

Christine Steinhoff; Martin Vingron

2006-01-01

193

A glucocorticoid-inducible gene expression system can cause growth defects in tobacco.  

PubMed

We find that an expression system widely used to chemically induce transgenes of interest in tobacco (Nicotiana tabacum Petit Havana SR1) can cause severe growth defects in this species. This gene expression system has been shown to cause non-specific effects (including growth retardation) in other plant species, but has until now been largely accepted to be a relatively problem-free system for use in tobacco. The expression system is based on the ability of the glucocorticoid dexamethasone (DEX) to activate a non-plant chimeric transcription factor (GVG), which then activates expression of a transgene of interest. The aberrant growth phenotype only manifests itself after DEX application and only occurs in plants in which the constitutive levels of GVG expression are higher than average. We found that approximately 30% of all transgenic plants produced showed some level of growth retardation under our standard growth conditions. However, by modulating irradiance levels following DEX application, we also showed that the manifestation and severity of the aberrant phenotype is highly dependent upon growth conditions, highlighting that such conditions are a critical parameter to consider during all stages of using this gene expression system. We also identified an increase in ACC oxidase gene expression as an early, sensitive and robust molecular marker for the aberrant phenotype. This molecular marker should be valuable to investigators wishing to readily identify transgenic plants in which GVG expression levels are beyond a threshold that begins to produce non-specific effects of the gene expression system under a defined set of growth conditions. PMID:17333253

Amirsadeghi, Sasan; McDonald, Allison E; Vanlerberghe, Greg C

2007-03-01

194

Aberrant Alternative Splicing Is Another Hallmark of Cancer  

PubMed Central

The vast majority of human genes are alternatively spliced. Not surprisingly, aberrant alternative splicing is increasingly linked to cancer. Splice isoforms often encode proteins that have distinct and even antagonistic properties. The abnormal expression of splice factors and splice factor kinases in cancer changes the alternative splicing of critically important pre-mRNAs. Aberrant alternative splicing should be added to the growing list of cancer hallmarks.

Ladomery, Michael

2013-01-01

195

Control of Stochasticity in Eukaryotic Gene Expression  

NASA Astrophysics Data System (ADS)

Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which the balance between promoter activation and transcription influences the variability in messenger RNA levels. To confirm the predictions of our model, we identified both cis- and trans-acting mutations that alter the noise of gene expression. These mutations suggest that noise is an evolvable trait that can be optimized to balance fidelity and diversity in eukaryotic gene expression.

Raser, Jonathan M.; O'Shea, Erin K.

2004-06-01

196

Mapping of sex-linked genes onto the genome sequence using various aberrations of the Z chromosome in Bombyx mori.  

PubMed

Many strains of Bombyx mori carry chromosomal aberrations, and they are useful resources for integration between phenotypes and genomic sequences. We compared the molecular structures of three kinds of Z chromosomes, i.e., two strains with chromosome deletions and one strain with translocation involving the Z chromosome. Using polymerase chain reaction markers, we showed that: (1) the Z(1) chromosome lacks more than 6Mb, including the proximal end; (2) the Z(Vg) chromosome lacks 1.5Mb in the interstitial portion; and (3) the +(od)p(Sa)+(p)W carries a 0.6-Mb Z-derived fragment surrounding the +(od) gene. The breakpoint junctions of these deletions and a translocation were precisely determined. Through deletion mapping, we narrowed down the regions where distinct oily (od), vestigial (Vg), and muscle dystrophy (Md) are located and identified a candidate gene for od. A retroposon-mediated deletion in BmBLOS2--the Bombyx gene homologous to human "biogenesis of lysosome-related organelles complex-1, subunit 2''--was detected in the od mutant. Although the genes responsible for Vg and Md were not definitively identified, we propose the candidate genes on the basis of their locations and phenotypes. PMID:19216995

Fujii, Tsuguru; Abe, Hiroaki; Katsuma, Susumu; Mita, Kazuei; Shimada, Toru

2008-03-21

197

Widespread ectopic expression of olfactory receptor genes  

PubMed Central

Background Olfactory receptors (ORs) are the largest gene family in the human genome. Although they are expected to be expressed specifically in olfactory tissues, some ectopic expression has been reported, with special emphasis on sperm and testis. The present study systematically explores the expression patterns of OR genes in a large number of tissues and assesses the potential functional implication of such ectopic expression. Results We analyzed the expression of hundreds of human and mouse OR transcripts, via EST and microarray data, in several dozens of human and mouse tissues. Different tissues had specific, relatively small OR gene subsets which had particularly high expression levels. In testis, average expression was not particularly high, and very few highly expressed genes were found, none corresponding to ORs previously implicated in sperm chemotaxis. Higher expression levels were more common for genes with a non-OR genomic neighbor. Importantly, no correlation in expression levels was detected for human-mouse orthologous pairs. Also, no significant difference in expression levels was seen between intact and pseudogenized ORs, except for the pseudogenes of subfamily 7E which has undergone a human-specific expansion. Conclusion The OR superfamily as a whole, show widespread, locus-dependent and heterogeneous expression, in agreement with a neutral or near neutral evolutionary model for transcription control. These results cannot reject the possibility that small OR subsets might play functional roles in different tissues, however considerable care should be exerted when offering a functional interpretation for ectopic OR expression based only on transcription information.

Feldmesser, Ester; Olender, Tsviya; Khen, Miriam; Yanai, Itai; Ophir, Ron; Lancet, Doron

2006-01-01

198

Chlamydia pneumoniae Expresses Genes Required for DNA Replication but Not Cytokinesis during Persistent Infection of HEp2 Cells  

Microsoft Academic Search

Chlamydia pneumoniae causes community-acquired pneumonia and is associated with several chronic dis- eases, including asthma and atherosclerosis. The intracellular growth rate of C. pneumoniae slows dramatically during chronic infection, and such persistence leads to attenuated production of new elementary bodies, appearance of morphologically aberrant reticulate bodies, and altered expression of several chlamydial genes. We used an in vitro system to

GERALD I. BYRNE; SCOT P. OUELLETTE; ZHAO WANG; J. P. Rao; LIN LU; WANDY L. BEATTY; ALAN P. HUDSON

2001-01-01

199

Inducible gene expression: diverse regulatory mechanisms  

Microsoft Academic Search

The rapid activation of gene expression in response to stimuli occurs largely through the regulation of RNA polymerase II-dependent transcription. In this Review, we discuss events that occur during the transcription cycle in eukaryotes that are important for the rapid and specific activation of gene expression in response to external stimuli. In addition to regulated recruitment of the transcription machinery

Vikki M. Weake; Jerry L. Workman

2010-01-01

200

Multivariate search for differentially expressed gene combinations  

Microsoft Academic Search

Background: To identify differentially expressed genes, it is standard practice to test a two- sample hypothesis for each gene with a proper adjustment for multiple testing. Such tests are essentially univariate and disregard the multidimensional structure of microarray data. A more general two-sample hypothesis is formulated in terms of the joint distribution of any sub-vector of expression signals. Results: By

Yuanhui Xiao; Robert D. Frisina; Alexander Gordon; Lev Klebanov; Andrei Yakovlev

2004-01-01

201

Peripheral gene expression biomarkers for autism  

US Patent & Trademark Office Database

The disclosed invention comprises methods and materials for screening cells for genetic profiles associated with autism spectrum disorders. The methods typically involve isolating a cell from an individual and then observing the expression profile of one or more genes in the cell, wherein certain expression patterns of the genes observed are associated with autism spectrum disorders.

2012-05-08

202

Expression of a truncated tomato polygalacturonase gene inhibits expression of the endogenous gene in transgenic plants  

Microsoft Academic Search

Tomato plants were transformed with a chimaeric polygalacturonase (PG) gene, designed to produce a truncated PG transcript constitutively. In these plants expression of the endogenous PG gene was inhibited during ripening, resulting in a substantial reduction in PG mRNA and enzyme accumulation. This inhibition was comparable to that achieved previously using antisense genes. The expression of the truncated gene in

C. J. S. Smith; C. F. Watson; C. R. Bird; J. Ray; W. Schuch; D. Grierson

1990-01-01

203

Arabidopsis gene expression patterns during spaceflight  

NASA Astrophysics Data System (ADS)

The exposure of Arabidopsis thaliana (Arabidopsis) plants to spaceflight environments resulted in the differential expression of hundreds of genes. A 5 day mission on orbiter Columbia in 1999 (STS-93) carried transgenic Arabidopsis plants engineered with a transgene composed of the alcohol dehydrogenase (Adh) gene promoter linked to the ? -Glucuronidase (GUS) reporter gene. The plants were used to evaluate the effects of spaceflight on two fronts. First, expression patterns visualized with the Adh/GUS transgene were used to address specifically the possibility that spaceflight induces a hypoxic stress response, and to assess whether any spaceflight response was similar to control terrestrial hypoxia-induced gene expression patterns. (Paul et al., Plant Physiol. 2001, 126:613). Second, genome-wide patterns of native gene expression were evaluated utilizing the Affymetrix ATH1 GeneChip? array of 8,000 Arabidopsis genes. As a control for the veracity of the array analyses, a selection of genes identified with the arrays was further characterized with quantitative Real-Time RT PCR (ABI - TaqmanTM). Comparison of the patterns of expression for arrays of hybridized with RNA isolated from plants exposed to spaceflight compared to the control arrays revealed hundreds of genes that were differentially expressed in response to spaceflight, yet most genes that are hallmarks of hypoxic stress were unaffected. These results will be discussed in light of current models for plant responses to the spaceflight environment, and with regard to potential future flight opportunities.

Paul, A.-L.; Ferl, R. J.

204

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway  

PubMed Central

Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase–protein kinase B/AKT–mammalian target of rapamycin (PI3K/AKT–mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K–AKT–mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor/neuron-restrictive silencing factor (REST/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids.

Varghese, Binny V.; Koohestani, Faezeh; McWilliams, Michelle; Colvin, Arlene; Gunewardena, Sumedha; Kinsey, William H.; Nowak, Romana A.; Nothnick, Warren B.; Chennathukuzhi, Vargheese M.

2013-01-01

205

Apoptosis and gene expression after TBI.  

PubMed

Proper CNS function depends on concerted expression of thousands of genes in a controlled and timely manner. Traumatic brain injury (TBI) in humans results in neuronal death and neurological dysfunction, which might be mediated by altered expression of several genes. By employing a CNS-specific GeneChip and real time polymerase chain reaction (PCR), the study analyzed the gene expression changes. The findings of necrosis and apoptosis can help to improve the wound age estimation after TBI in legal medicine. PMID:19282216

Dressler, Jan; Vemuganti, Raghu

2009-03-17

206

Genetics of human gene expression: mapping DNA variants that influence gene expression  

PubMed Central

There is extensive natural variation in human gene expression. As quantitative phenotypes, expression levels of genes are heritable. Genetic linkage and association mapping have identified cis- and trans-acting DNA variants that influence expression levels of human genes. New insights into human gene regulation are emerging from genetic analyses of gene expression in cells at rest and following exposure to stimuli. The integration of these genetic mapping results with data from co-expression networks is leading to a better understanding of how expression levels of individual genes are regulated and how genes interact with each other. These findings are important for basic understanding of gene regulation and of diseases that result from disruption of normal gene regulation.

Cheung, Vivian G.; Spielman, Richard S.

2010-01-01

207

Bioinformatic screening of human ESTs for differentially expressed genes in normal and tumor tissues  

PubMed Central

Background Owing to the explosion of information generated by human genomics, analysis of publicly available databases can help identify potential candidate genes relevant to the cancerous phenotype. The aim of this study was to scan for such genes by whole-genome in silico subtraction using Expressed Sequence Tag (EST) data. Methods Genes differentially expressed in normal versus tumor tissues were identified using a computer-based differential display strategy. Bcl-xL, an anti-apoptotic member of the Bcl-2 family, was selected for confirmation by western blot analysis. Results Our genome-wide expression analysis identified a set of genes whose differential expression may be attributed to the genetic alterations associated with tumor formation and malignant growth. We propose complete lists of genes that may serve as targets for projects seeking novel candidates for cancer diagnosis and therapy. Our validation result showed increased protein levels of Bcl-xL in two different liver cancer specimens compared to normal liver. Notably, our EST-based data mining procedure indicated that most of the changes in gene expression observed in cancer cells corresponded to gene inactivation patterns. Chromosomes and chromosomal regions most frequently associated with aberrant expression changes in cancer libraries were also determined. Conclusion Through the description of several candidates (including genes encoding extracellular matrix and ribosomal components, cytoskeletal proteins, apoptotic regulators, and novel tissue-specific biomarkers), our study illustrates the utility of in silico transcriptomics to identify tumor cell signatures, tumor-related genes and chromosomal regions frequently associated with aberrant expression in cancer.

Aouacheria, Abdel; Navratil, Vincent; Barthelaix, Audrey; Mouchiroud, Dominique; Gautier, Christian

2006-01-01

208

Gene expression drives local adaptation in humans.  

PubMed

The molecular basis of adaptation--and, in particular, the relative roles of protein-coding versus gene expression changes--has long been the subject of speculation and debate. Recently, the genotyping of diverse human populations has led to the identification of many putative "local adaptations" that differ between populations. Here I show that these local adaptations are over 10-fold more likely to affect gene expression than amino acid sequence. In addition, a novel framework for identifying polygenic local adaptations detects recent positive selection on the expression levels of genes involved in UV radiation response, immune cell proliferation, and diabetes-related pathways. These results provide the first examples of polygenic gene expression adaptation in humans, as well as the first genome-scale support for the hypothesis that changes in gene expression have driven human adaptation. PMID:23539138

Fraser, Hunter B

2013-03-28

209

Gene set analysis for longitudinal gene expression data  

PubMed Central

Background Gene set analysis (GSA) has become a successful tool to interpret gene expression profiles in terms of biological functions, molecular pathways, or genomic locations. GSA performs statistical tests for independent microarray samples at the level of gene sets rather than individual genes. Nowadays, an increasing number of microarray studies are conducted to explore the dynamic changes of gene expression in a variety of species and biological scenarios. In these longitudinal studies, gene expression is repeatedly measured over time such that a GSA needs to take into account the within-gene correlations in addition to possible between-gene correlations. Results We provide a robust nonparametric approach to compare the expressions of longitudinally measured sets of genes under multiple treatments or experimental conditions. The limiting distributions of our statistics are derived when the number of genes goes to infinity while the number of replications can be small. When the number of genes in a gene set is small, we recommend permutation tests based on our nonparametric test statistics to achieve reliable type I error and better power while incorporating unknown correlations between and within-genes. Simulation results demonstrate that the proposed method has a greater power than other methods for various data distributions and heteroscedastic correlation structures. This method was used for an IL-2 stimulation study and significantly altered gene sets were identified. Conclusions The simulation study and the real data application showed that the proposed gene set analysis provides a promising tool for longitudinal microarray analysis. R scripts for simulating longitudinal data and calculating the nonparametric statistics are posted on the North Dakota INBRE website http://ndinbre.org/programs/bioinformatics.php. Raw microarray data is available in Gene Expression Omnibus (National Center for Biotechnology Information) with accession number GSE6085.

2011-01-01

210

Gene expression patterns – a tool for bioanalysis  

Microsoft Academic Search

Gene expression patterns are efficient tools to elucidate responses to hormones as well as endocrine disruptors at the molecular level. Male zebrafish (Danio rerio) were exposed to 17?-estradiol (E2). Transcriptome analysis was first carried out by quantitative polymerase chain reaction (PCR) of the gene coding for vitellogenin (vtg1) in relation to the housekeeping gene ef1?. A significant increase in the

Martin Alberti; Ulf Kausch; Stefanie Haindl; Robert Leibiger; Jan Budczies; Martin Seifert; Bertold Hock

2005-01-01

211

Relational Descriptive Analysis of Gene Expression Data  

Microsoft Academic Search

This paper presents a method that uses gene ontologies, to- gether with the paradigm of relational subgroup discovery, to help nd description of groups of genes dieren tialy expressed in specic can- cers. The descriptions are represented by means of relational features, extracted from publicly available gene ontology information, and are straightforwardly interpretable by medical\\/biology researchers. We ap- plied the

Igor Trajkovski; Filip Zelezný; Nada Lavrac; Jakub Tolar

2006-01-01

212

Social regulation of human gene expression  

PubMed Central

Relationships between genes and social behavior have historically been construed as a one-way street, with genes in control. Recent analyses have challenged this view by discovering broad alterations in the expression of human genes as a function of differing socio-environmental conditions. The emerging field of social genomics has begun to identity the types of genes subject to social regulation, the biological signaling pathways mediating those effects, and the genetic polymorphisms that moderate socio-environmental influences on human gene expression.

Cole, Steve W.

2010-01-01

213

Immune-dependent and independent antitumor activity of GM-CSF aberrantly expressed by mouse and human colorectal tumors.  

PubMed

Granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) is a cytokine produced in the hematologic compartment that may enhance antitumor immune responses, mainly by activation of dendritic cells. Here, we show that more than one-third of human colorectal tumors exhibit aberrant DNA demethylation of the GM-CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune-associated antitumor effect. Unexpectedly, an immune-independent antitumor effect was observed that depended on the ectopic expression of GM-CSF receptor subunits by tumors. Cancer cells expressing GM-CSF and its receptor did not develop into tumors when autografted into immunocompetent mice. Similarly, 100% of the patients with human colon tumors that overexpressed GM-CSF and its receptor subunits survived at least 5 years after diagnosis. These data suggest that expression of GM-CSF and its receptor subunits by colon tumors may be a useful marker for prognosis as well as for patient stratification in cancer immunotherapy. PMID:23108143

Urdinguio, Rocio G; Fernandez, Agustin F; Moncada-Pazos, Angela; Huidobro, Covadonga; Rodriguez, Ramon M; Ferrero, Cecilia; Martinez-Camblor, Pablo; Obaya, Alvaro J; Bernal, Teresa; Parra-Blanco, Adolfo; Rodrigo, Luis; Santacana, Maria; Matias-Guiu, Xavier; Soldevilla, Beatriz; Dominguez, Gemma; Bonilla, Felix; Cal, Santiago; Lopez-Otin, Carlos; Fraga, Mario F

2012-10-29

214

Regulatory Protein Coordinating Gene Expression  

NSDL National Science Digital Library

The action of the glucocorticoid receptor is illustrated. On the left is shown a series of genes, each of which has various gene activator proteins bound to its regulatory region. However, these bound proteins are not sufficient on their own to activate transcription efficiently. On the right is shown the effects of adding an additional gene regulatory protein

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter

1998-07-01

215

Epigenetic Histone Methylation Modulates Fibrotic Gene Expression  

PubMed Central

TGF-?1–induced expression of extracellular matrix (ECM) genes plays a major role in the development of chronic renal diseases such as diabetic nephropathy. Although many key transcription factors are known, mechanisms involving the nuclear chromatin that modulate ECM gene expression remain unclear. Here, we examined the role of epigenetic chromatin marks such as histone H3 lysine methylation (H3Kme) in TGF-?1–induced gene expression in rat mesangial cells under normal and high-glucose (HG) conditions. TGF-?1 increased the expression of the ECM-associated genes connective tissue growth factor, collagen-?1[?], and plasminogen activator inhibitor-1. Increased levels of chromatin marks associated with active genes (H3K4me1, H3K4me2, and H3K4me3), and decreased levels of repressive marks (H3K9me2 and H3K9me3) at these gene promoters accompanied these changes in expression. TGF-?1 also increased expression of the H3K4 methyltransferase SET7/9 and recruitment to these promoters. SET7/9 gene silencing with siRNAs significantly attenuated TGF-?1–induced ECM gene expression. Furthermore, a TGF-?1 antibody not only blocked HG-induced ECM gene expression but also reversed HG-induced changes in promoter H3Kme levels and SET7/9 occupancy. Taken together, these results show the functional role of epigenetic chromatin histone H3Kme in TGF-?1–mediated ECM gene expression in mesangial cells under normal and HG conditions. Pharmacologic and other therapies that reverse these modifications could have potential renoprotective effects for diabetic nephropathy.

Sun, Guangdong; Reddy, Marpadga A.; Yuan, Hang; Lanting, Linda; Kato, Mitsuo

2010-01-01

216

Down-regulation and aberrant cytoplasmic expression of GLTSCR2 in prostatic adenocarcinomas.  

PubMed

GLTSCR2 is a nuclear/nucleolar protein that translocates to the nucleoplasm, suppressed and mutated in human cancers. Our aim in this study was to investigate whether downregulation or cytoplasmic expression of GLTSCR2 has any pathological significance in prostatic cancer development or progression. In this study we show that GLTSCR2 is suppressed in prostatic cancers and its expression is significantly associated with Gleason's scores. Furthermore, we investigated the pathogenetic mechanism of downregulation and cytoplasmic expression of GLTSCR2 in development or progression of prostatic cancers. Taken together, our results indicate that GLTSCR2 functions as a tumor suppressor in prostatic adenocarcinomas. PMID:23920125

Kim, Jee-Youn; Cho, Young-Eun; Kim, Gou Young; Lee, Hyung-Lae; Lee, Sun; Park, Jae-Hoon

2013-08-03

217

Identifying gene functions using functional expression profiles obtained by voxelation  

Microsoft Academic Search

Gene expression profiles have been widely used in functional genomic studies. However, not much work in traditional gene expression profiling takes into account the location information of a gene's expressions in the brain. Gene expression maps, which contain spatial information regarding the expression of genes in mice's brain, are obtained by combining voxelation and microarrays. Based on the idea that

Li An; Desmond J. Smith; Hongbo Xie; Vasileios Megalooikonomou; Zoran Obradovic

2010-01-01

218

Aberrant expression of microRNAs in T cells from patients with ankylosing spondylitis contributes to the immunopathogenesis.  

PubMed

Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by dysregulated T cells. We hypothesized that the aberrant expression of microRNAs (miRNAs) in AS T cells involved in the pathogenesis of AS. The expression profile of 270 miRNAs in T cells from five AS patients and five healthy controls were analysed by real-time polymerase chain reaction (PCR). Thirteen miRNAs were found potentially differential expression. After validation, we confirmed that miR-16, miR-221 and let-7i were over-expressed in AS T cells and the expression of miR-221 and let-7i were correlated positively with the Bath Ankylosing Spondylitis Radiology Index (BASRI) of lumbar spine in AS patients. The protein molecules regulated by miR-16, miR-221 and let-7i were measured by Western blotting. We found that the protein levels of Toll-like receptor-4 (TLR-4), a target of let-7i, in T cells from AS patients were decreased. In addition, the mRNA expression of interferon (IFN)-? was elevated in AS T cells. Lipopolysaccharide (LPS), a TLR-4 agonist, inhibited IFN-? secretion by anti-CD3(+) anti-CD28 antibodies-stimulated normal T cells but not AS T cells. In the transfection studies, we found the increased expression of let-7i enhanced IFN-? production by anti-CD3(+) anti-CD28(+) lipopolysaccharide (LPS)-stimulated normal T cells. In contrast, the decreased expression of let-7i suppressed IFN-? production by anti-CD3(+) anti-CD28(+) LPS-stimulated AS T cells. In conclusion, we found that miR-16, miR-221 and let-7i were over-expressed in AS T cells, but only miR-221 and let-7i were associated with BASRI of lumbar spine. In the functional studies, the increased let-7i expression facilitated the T helper type 1 (IFN-?) immune response in T cells. PMID:23607629

Lai, N-S; Yu, H-C; Chen, H-C; Yu, C-L; Huang, H-B; Lu, M-C

2013-07-01

219

Aberrant expression of Eag1 potassium channels in gastric cancer patients and cell lines  

Microsoft Academic Search

Recently, an interesting relationship between potassium channels and cancer has evolved. The aim of this study is to investigate\\u000a expression of Eag1 potassium channel in gastric cancer and its role in cancer cells growth.The expression of Eag1 for gasric\\u000a cancer patients and cell lines as well as gastric adenoma was investigated by immunohistochemistry and reverse transcription\\u000a polymerase chain reaction. In

Xiang-wu Ding; He-sheng Luo; Xiong Jin; Juan-juan Yan; Yao-wei Ai

2007-01-01

220

Using Gene Expression Noise to Understand Gene Regulation  

PubMed Central

Phenotypic variation is ubiquitous in biology and is often traceable to underlying genetic and environmental variation. However, even genetically identical cells in identical environments display variable phenotypes. Stochastic gene expression, or gene expression ‘noise’, has been suggested as a major source of this variability, and its physiological consequences have been topics of intense research for the last decade. Several recent studies have measured variability in protein and mRNA levels, and have discovered strong connections between noise and gene regulation mechanisms. When integrated with discrete stochastic models, measurements of cell-to-cell variability provide a sensitive ‘fingerprint’ with which to explore fundamental questions on gene regulation. In this review, we highlight several studies that used gene expression variability to develop a quantitative understanding of the mechanisms and dynamics of gene regulation.

Munsky, Brian; Neuert, Gregor; van Oudenaarden, Alexander

2012-01-01

221

Gene Expression Profiling of Solitary Fibrous Tumors  

PubMed Central

Background Solitary fibrous tumors (SFTs) are rare spindle-cell tumors. Their cell-of-origin and molecular basis are poorly known. They raise several clinical problems. Differential diagnosis may be difficult, prognosis is poorly apprehended by histoclinical features, and no effective therapy exists for advanced stages. Methods We profiled 16 SFT samples using whole-genome DNA microarrays and analyzed their expression profiles with publicly available profiles of 36 additional SFTs and 212 soft tissue sarcomas (STSs). Immunohistochemistry was applied to validate the expression of some discriminating genes. Results SFTs displayed whole-genome expression profiles more homogeneous and different from STSs, but closer to genetically-simple than genetically-complex STSs. The SFTs/STSs comparison identified a high percentage (?30%) of genes as differentially expressed, most of them without any DNA copy number alteration. One of the genes most overexpressed in SFTs encoded the ALDH1 stem cell marker. Several upregulated genes and associated ontologies were also related to progenitor/stem cells. SFTs also overexpressed genes encoding therapeutic targets such as kinases (EGFR, ERBB2, FGFR1, JAK2), histone deacetylases, or retinoic acid receptors. Their overexpression was found in all SFTs, regardless the anatomical location. Finally, we identified a 31-gene signature associated with the mitotic count, containing many genes related to cell cycle/mitosis, including AURKA. Conclusion We established a robust repertoire of genes differentially expressed in SFTs. Certain overexpressed genes could provide new diagnostic (ALDH1A1), prognostic (AURKA) and/or therapeutic targets.

Bertucci, Francois; Bouvier-Labit, Corinne; Finetti, Pascal; Metellus, Philippe; Adelaide, Jose; Mokhtari, Karima; Figarella-Branger, Dominique; Decouvelaere, Anne-Valerie; Miquel, Catherine; Coindre, Jean-Michel; Birnbaum, Daniel

2013-01-01

222

Expression of the DISC1 Gene  

NSDL National Science Digital Library

Gene expression is the process of converting genetic information encoded in the brain into a final product (a protein or RNA). Uncovering where a given gene's protein is most commonly expressed in the body can yield vital clues as to the purpose of that gene. DISC1 expression has been traced to neurons in a number of areas in the brain, particularly the hippocampus. It is associated with synaptic function, suggesting that one of its adult functions may be synaptic plasticity, a process that underlines learning and memory.

2009-04-14

223

Histone Modifications Depict an Aberrantly Heterochromatinized FMR1 Gene in Fragile X Syndrome  

Microsoft Academic Search

histones, and chromatin condensation, all characteristics of a transcriptionally inactive gene. Here, we show that there is a graded spectrum of histone H4 acetylation that is proportional to CGG repeat length and that correlates with responsiveness of the gene to DNA demethylation but not with chromatin condensation. We also identify alterations in patient cells of two recently identified histone H3

Fuping Zhang; Stephanie Ceman; Stephen T. Warren; Daniel Reines

2002-01-01

224

Gene expression profiling of metastatic brain cancer.  

PubMed

Gene expression profiling of metastatic brain tumors from primary lung adenocarcinoma, using a 17k-expression array, revealed that 1561 genes were consistently altered. Further functional classification placed the genes into seven categories: cell cycle and DNA damage repair, apoptosis, signal transduction molecules, transcription factors, invasion and metastasis, adhesion, and angiogenesis. Genes involved in apoptosis, such as caspase 2 (CASP2), transforming growth factor-beta inducible early gene (TIEG), and neuroprotective heat shock protein 70 (Hsp70) were underexpressed in metastatic brain tumors. Alterations in Rho GTPases (ARHGAP26, ARHGAP1), as well as down-regulation of the metastasis suppressor gene KiSS-1 were noted, which may contribute to tumor aggression. Overexpression of the invasion-related gene neurofibromatosis 1 (NF1), and angiogenesis-related genes vascular endothelial growth factor-B (VEGF-B) and placental growth factor (PGF) was also evidenced. Brain-specific angiogenesis inhibitors 1 and 3 (BAI1 and BAI3) were underexpressed as well. Examination of cell-adhesion and migration-related genes revealed an increased expression of integrins and extracellular matrices collagen and laminin. The study also showed alterations in p53 protein-associated genes, among these increased gene expression of p53, up-regulation of Reprimo or candidate mediator of the p53-dependent G2-arrest, down-regulation of p53-regulated apoptosis-inducing protein 1 (p53AIP1), decreased expression of tumor protein inducible nuclear protein 1 (p53DINP1), and down-regulation of Mdm4 (MDMX). The results demonstrated that genes involved in adhesion, motility, and angiogenesis were consistently up-regulated in metastatic brain tumors, while genes involved in apoptosis, neuroprotection, and suppression of angiogenesis were markedly down-regulated, collectively making these cancer cells prone to metastasis. PMID:17611651

Zohrabian, Vahe Michael; Nandu, Hari; Gulati, Nicholas; Khitrov, Greg; Zhao, Connie; Mohan, Avinash; Demattia, Joseph; Braun, Alex; Das, Kaushik; Murali, Raj; Jhanwar-Uniyal, Meena

2007-08-01

225

Splicing aberrations caused by constitutional RB1 gene mutations in retinoblastoma.  

PubMed

Analysis of RB1 mRNA from blood leukocytes of patients with retinoblastoma identified the effects of mutations involving consensus splice site, exonic substitution and whole-exon deletions identified in genomic DNA of these patients. In addition, this study identified mutations in cases in which no mutations were detectable in the genomic DNA. One proband had mutation at the canonical splice site at +5 position of IVS22, and analysis of the transcripts in this family revealed skipping of exon 22 in three members of this family. In one proband, a missense substitution of c.652T greater than G (g.56897T greater than G; Leu218Val) in exon 7 led to splicing aberrations involving deletions of exons 7 and 8, suggesting the formation of a cryptic splice site. In two probands with no detectable changes in the genomic DNA upon screening of RB1 exons and flanking intronic sequences, transcripts were found to have deletions of exon 6 in one, and exons 21 and 22 in another family. In two probands, RNA analysis confirmed genomic deletions involving one or more exons. This study reveals novel effects of RB1 mutations on splicing and suggests the utility of RNA analysis as an adjunct to mutational screening of genomic DNA in retinoblastoma. PMID:21654082

Parsam, Vidya Latha; Ali, Mohammed Javed; Honavar, Santosh G; Vemuganti, Geeta K; Kannabiran, Chitra

2011-06-01

226

High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas  

Microsoft Academic Search

Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including

K Köchert; K Ullrich; S Kreher; J C Aster; M Kitagawa; K Jöhrens; I Anagnostopoulos; F Jundt; B Lamprecht; U Zimber-Strobl; H Stein; M Janz; B Dörken; S Mathas

2011-01-01

227

Network-enabled gene expression analysis  

PubMed Central

Background Although genome-scale expression experiments are performed routinely in biomedical research, methods of analysis remain simplistic and their interpretation challenging. The conventional approach is to compare the expression of each gene, one at a time, between treatment groups. This implicitly treats the gene expression levels as independent, but they are in fact highly interdependent, and exploiting this enables substantial power gains to be realized. Results We assume that information on the dependence structure between the expression levels of a set of genes is available in the form of a Bayesian network (directed acyclic graph), derived from external resources. We show how to analyze gene expression data conditional on this network. Genes whose expression is directly affected by treatment may be identified using tests for the independence of each gene and treatment, conditional on the parents of the gene in the network. We apply this approach to two datasets: one from a hepatotoxicity study in rats using a PPAR pathway, and the other from a study of the effects of smoking on the epithelial transcriptome, using a global transcription factor network. Conclusions The proposed method is straightforward, simple to implement, gives rise to substantial power gains, and may assist in relating the experimental results to the underlying biology.

2012-01-01

228

Neutral and adaptive variation in gene expression  

PubMed Central

Variation among populations in gene expression should be related to the accumulation of random-neutral changes and evolution by natural selection. The following evolutionary analysis has general applicability to biological and medical science because it accounts for genetic relatedness and identifies patterns of expression variation that are affected by natural selection. To identify genes evolving by natural selection, we allocate the maximum among-population variation to genetic distance and then examine the remaining variation relative to a hypothesized important ecological parameter (temperature). These analyses measure the expression of metabolic genes in common-gardened populations of the fish Fundulus heteroclitus whose habitat is distributed along a steep thermal gradient. Although much of the variation in gene expression fits a null model of neutral drift, the variation in expression for 22% of the genes that regress with habitat temperature was far greater than could be accounted for by genetic distance alone. The most parsimonious explanation for among-population variation for these genes is evolution by natural selection. In addition, many metabolic genes have patterns of variation incongruent with neutral evolution: They have too much or too little variation. These patterns of biological variation in expression may reflect important physiological or ecological functions.

Whitehead, Andrew; Crawford, Douglas L.

2006-01-01

229

Discovery of genes expressed in Hydra embryogenesis.  

PubMed

Hydra's remarkable capacity to regenerate, to proliferate asexually by budding, and to form a pattern de novo from aggregates allows studying complex cellular and molecular processes typical for embryonic development. The underlying assumption is that patterning in adult hydra tissue relies on factors and genes which are active also during early embryogenesis. Previously, we reported that in Hydra the timing of expression of conserved regulatory genes, known to be involved in adult patterning, differs greatly in adults and embryos (Fröbius, A.C., Genikhovich, G., Kürn, U., Anton-Erxleben, F. and Bosch, T.C.G., 2003. Expression of developmental genes during early embryogenesis of Hydra. Dev. Genes Evol. 213, 445-455). Here, we describe an unbiased screening strategy to identify genes that are relevant to Hydra vulgaris embryogenesis. The approach yielded two sets of differentially expressed genes: one set was expressed exclusively or nearly exclusively in the embryos, while the second set was upregulated in embryos in comparison to adult polyps. Many of the genes identified in hydra embryos had no matches in the database. Among the conserved genes upregulated in embryos is the Hydra orthologue of Embryonic Ectoderm Development (HyEED). The expression pattern of HyEED in developing embryos suggests that interstitial stem cells in Hydra originate in the endoderm. Importantly, the observations uncover previously unknown differences in genes expressed by embryos and polyps and indicate that not only the timing of expression of developmental genes but also the genetic context is different in Hydra embryos compared to adults. PMID:16337937

Genikhovich, Grigory; Kürn, Ulrich; Hemmrich, Georg; Bosch, Thomas C G

2005-12-09

230

Feedback control of gene expression  

Microsoft Academic Search

Although feedback regulation of photosynthesis by carbon metabolites has long been recognized and investigated, its underlying molecular mechanisms remain unclear. The recent discovery that glucose and acetate trigger global repression of maize photosynthetic gene transcription provides the first direct evidence that a fundamental mechanism is used for feedback regulation of photosynthesis in higher plants. The metabolic repression of photosynthetic genes

Jen Sheen

1994-01-01

231

Gene expression in periodontal tissues following treatment  

PubMed Central

Background In periodontitis, treatment aimed at controlling the periodontal biofilm infection results in a resolution of the clinical and histological signs of inflammation. Although the cell types found in periodontal tissues following treatment have been well described, information on gene expression is limited to few candidate genes. Therefore, the aim of the study was to determine the expression profiles of immune and inflammatory genes in periodontal tissues from sites with severe chronic periodontitis following periodontal therapy in order to identify genes involved in tissue homeostasis. Gingival biopsies from 12 patients with severe chronic periodontitis were taken six to eight weeks following non-surgical periodontal therapy, and from 11 healthy controls. As internal standard, RNA of an immortalized human keratinocyte line (HaCaT) was used. Total RNA was subjected to gene expression profiling using a commercially available microarray system focusing on inflammation-related genes. Post-hoc confirmation of selected genes was done by Realtime-PCR. Results Out of the 136 genes analyzed, the 5% most strongly expressed genes compared to healthy controls were Interleukin-12A (IL-12A), Versican (CSPG-2), Matrixmetalloproteinase-1 (MMP-1), Down syndrome critical region protein-1 (DSCR-1), Macrophage inflammatory protein-2? (Cxcl-3), Inhibitor of apoptosis protein-1 (BIRC-1), Cluster of differentiation antigen 38 (CD38), Regulator of G-protein signalling-1 (RGS-1), and Finkel-Biskis-Jinkins murine osteosarcoma virus oncogene (C-FOS); the 5% least strongly expressed genes were Receptor-interacting Serine/Threonine Kinase-2 (RIP-2), Complement component 3 (C3), Prostaglandin-endoperoxide synthase-2 (COX-2), Interleukin-8 (IL-8), Endothelin-1 (EDN-1), Plasminogen activator inhibitor type-2 (PAI-2), Matrix-metalloproteinase-14 (MMP-14), and Interferon regulating factor-7 (IRF-7). Conclusion Gene expression profiles found in periodontal tissues following therapy indicate activation of pathways that regulate tissue damage and repair.

Beikler, Thomas; Peters, Ulrike; Prior, Karola; Eisenacher, Martin; Flemmig, Thomas F

2008-01-01

232

Age-Dependent Brain Gene Expression and Copy Number Anomalies in Autism Suggest Distinct Pathological Processes at Young Versus Mature Ages  

Microsoft Academic Search

Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings of the disorder are largely unknown. Aberrant brain overgrowth is a well-replicated observation in the autism literature; but association, linkage, and expression studies have not identified genetic factors that explain this trajectory. Few studies have had sufficient statistical power to investigate whole-genome gene expression and genotypic variation in the

Maggie L. Chow; Tiziano Pramparo; Mary E. Winn; Cynthia Carter Barnes; Hai-Ri Li; Lauren Weiss; Jian-Bing Fan; Sarah Murray; Craig April; Haim Belinson; Xiang-Dong Fu; Anthony Wynshaw-Boris; Nicholas J. Schork; Eric Courchesne

2012-01-01

233

Gene expression profiling using DNA microarrays.  

PubMed

In Arabidopsis research, microarrays have typically been employed for the measurement of gene expression under different conditions. Microarray analysis is often used to analyze the effects of the expression of wild-type genes (control) versus mutants, the effects of varying environmental conditions, and the effects of hormones. In addition, microarray analysis is used to analyze differences in gene expression between growth stages and tissues. Other array applications include comparative genomic hybridization, chromatin immunoprecipitation, mutation detection, and genotyping. This chapter focuses on gene expression profiling, which is typically performed by the competitive hybridization of two samples, each labeled with a fluorescent dye such as cyanine 3-CTP or cyanine 5-CTP. We describe the steps, from RNA purification to data analysis, that are involved in obtaining data from DNA microarrays. PMID:24057377

Maruyama, Kyonoshin; Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo

2014-01-01

234

Exertional Heat Illness and Human Gene Expression.  

National Technical Information Service (NTIS)

Microarray analysis of gene expression at the level of RNA has generated new insights into the relationship between cellular responses to acute heat shock in vitro, exercise, and exertional heat illness. Here we discuss the systemic physiology of exertion...

C. M. Lilly L. Sonna M. N. Sawka

2007-01-01

235

Epigenetic genes regulated by the BRAFV600E signaling are associated with alterations in the methylation and expression of tumor suppressor genes and patient survival in melanoma  

PubMed Central

We have previously reported that the BRAFV600E signaling causes genome-wide aberrations in gene methylation in melanoma cells. To explore the potential molecular mechanisms for this epigenetic effect of BRAFV600E, in this in silico study we analyzed 11 microarray datasets retrieved from NCBI GEO database and examined the relationship of the expression of the epigenetic genes (genes involved in epigenetic regulation) with BRAFV600E signaling, methylation and expression of tumor-suppressor genes (TSGs) in melanoma, and patient survival with this cancer. Among 273 epigenetic genes examined, 12 genes were down-regulated (named DD genes) and 16 were up-regulated (UU genes) by suppression of the BRAFV600E signaling using inhibitors. While the expression of 245 non-DD/UU genes overall had no correlation with the expression and methylation of a set of potential TSGs, the expression of DD genes was significantly correlated negatively with the TSG expression and positively with TSG methylation. Expression of UU genes was positively, albeit weakly, associated with the TSG expression. Overall, no correlation was found between UU gene expression and TSG methylation. Importantly, the expression of DD genes, but not UU genes, was significantly associated with decreased survival of patients with melanoma. Interestingly, the promoters of DD genes contain more binding motifs of c-fos and myc, two BRAFV600E signaling-related transcription factors, than those of UU and non-DD/UU genes. Thus, these results link epigenetic genes to methylation and suppression of tumor suppressor genes as a mechanism involved in BRAFV600E-promoted melanoma tumorigenesis and uncover a novel molecular signature that predicts a poor prognosis of melanoma.

Liu, Dingxie; Liu, Xuan; Xing, Mingzhao

2012-01-01

236

Polyunsaturated fatty acid regulation of gene expression  

Microsoft Academic Search

Polyunsaturated fatty acids (PUFAs), specifically the n-3 and n-6 series, play a key role in the progression or prevention\\u000a of human diseases such as obesity, diabetes, cancer, neurological and heart disease, mainly by affecting cellular membrane\\u000a lipid composition, metabolism, signal-transduction pathways, and by direct control of gene expression. PUFAs show regulation\\u000a of gene expression in several tissues, including brain, liver,

James M. Ntambi; Henry Bené

2001-01-01

237

The functional landscape of mouse gene expression  

Microsoft Academic Search

ABSTRACT: BACKGROUND: Large-scale quantitative analysis of transcriptional co-expression has been used to dissect regulatory networks and to predict the functions of new genes discovered by genome sequencing in model organisms such as yeast. Although the idea that tissue-specific expression is indicative of gene function in mammals is widely accepted, it has not been objectively tested nor compared with the related

Wen Zhang; Quaid D Morris; Richard Chang; Ofer Shai; Malina A Bakowski; Nicholas Mitsakakis; Naveed Mohammad; Mark D Robinson; Ralph Zirngibl; Eszter Somogyi; Nancy Laurin; Eftekhar Eftekharpour; Eric Sat; Jörg Grigull; Qun Pan; Wen-Tao Peng; Nevan Krogan; Jack Greenblatt; Michael Fehlings; Derek van der Kooy; Jane Aubin; Benoit G Bruneau; Janet Rossant; Benjamin J Blencowe; Brendan J Frey; Timothy R Hughes

2004-01-01

238

Deciphering Development: Quantifying Gene Expression through Imaging  

NSDL National Science Digital Library

This article from BioScience provides information on genetic tagging and how it can provide imaging in live animals. Scientists can now visualize developmental gene expression quantitatively in three dimensions and at single-cell resolution. Recent advances in optical microscopy and fluorescent genetic tags allow imaging of gene expression in live animals, as well. Eventually, researchers hope to construct virtual atlases of animal development.

Melissa Lee Philips (;)

2007-08-01

239

Genes expressed in sugarcane maturing internodal tissue  

Microsoft Academic Search

To explore gene expression during sugarcane culm maturation, we performed a partial sequence analysis of random clones from maturing culm total and subtracted cDNA libraries. Database comparisons revealed that of the 337 cDNA sequences analysed, 167 showed sequence homology to gene products in the protein databases, while 111 matched uncharacterised plant expressed sequence tags (ESTs) only. The remaining cDNAs showed

D. L. Carson; F. C. Botha

2002-01-01

240

Sugarcane genes differentially expressed during water deficit  

Microsoft Academic Search

To identify genes that are up and down-regulated by water deficit in sugarcane we used the macroarray methodology and the\\u000a expression level of 3 575 independent sugarcane cDNAs was measured by hybridization with RNA extracted from plants submitted\\u000a to mild, moderate and severe water deficit. We identified approximately 1 670 differentially expressed genes from which 62\\u000a % were up-regulated by

F. A. Rodrigues; J. P. Da Graça; M. L. De Laia; A. Nhani-Jr; J. A. Galbiati; M. I. T. Ferro; J. A. Ferro; S. M. Zingaretti

2011-01-01

241

Comparative gene expression between two yeast species  

PubMed Central

Background Comparative genomics brings insight into sequence evolution, but even more may be learned by coupling sequence analyses with experimental tests of gene function and regulation. However, the reliability of such comparisons is often limited by biased sampling of expression conditions and incomplete knowledge of gene functions across species. To address these challenges, we previously systematically generated expression profiles in Saccharomyces bayanus to maximize functional coverage as compared to an existing Saccharomyces cerevisiae data repository. Results In this paper, we take advantage of these two data repositories to compare patterns of ortholog expression in a wide variety of conditions. First, we developed a scalable metric for expression divergence that enabled us to detect a significant correlation between sequence and expression conservation on the global level, which previous smaller-scale expression studies failed to detect. Despite this global conservation trend, between-species gene expression neighborhoods were less well-conserved than within-species comparisons across different environmental perturbations, and approximately 4% of orthologs exhibited a significant change in co-expression partners. Furthermore, our analysis of matched perturbations collected in both species (such as diauxic shift and cell cycle synchrony) demonstrated that approximately a quarter of orthologs exhibit condition-specific expression pattern differences. Conclusions Taken together, these analyses provide a global view of gene expression patterns between two species, both in terms of the conditions and timing of a gene's expression as well as co-expression partners. Our results provide testable hypotheses that will direct future experiments to determine how these changes may be specified in the genome.

2013-01-01

242

A switch region inversion contributes to the aberrant rearrangement of a mu immunoglobulin heavy chain gene in MPC-11 cells.  

PubMed Central

We describe the unique features of an aberrantly rearranged mu immunoglobulin heavy chain gene isolated from MPC-11 cells (a gamma 2b producing Balb/c plasmacytoma). A novel rearrangement has occurred 1.5 Kb 5' of the MPC-11 mu gene (denoted 18b mu) resulting in the deletion of the majority of the repetitive switch region (S mu) and 5' flanking DNA including the Joining (JH) sequences. The remainder (275 bp) of the S mu repeat has undergone a complete sequence inversion. DNA sequences 5' of the inverted S mu sequence do not resemble Variable (VH), Diversity (D), JH or their conserved flanking sequences. A DNA sequence localized 5' of the inverted S mu sequence, (p18b mu-1.4) detects a small family of homologous sequences in Balb/c DNA. The 18b mu-1.4 like sequences lack homology to S mu, exhibit flanking sequence polymorphisms in 5 out of 6 inbred mouse strains and undergo partial or complete deletion in 5 out of 10 plasmacytomas tested. Two 18b mu-1.4 homologous sequences display a higher copy number in C57Bl/6, AL/N and CAL9 mouse strains. Images

Greenberg, R; Lang, R B; Diamond, M S; Marcu, K B

1982-01-01

243

Candidate genes for panhypopituitarism identified by gene expression profiling  

PubMed Central

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease.

Mortensen, Amanda H.; MacDonald, James W.; Ghosh, Debashis

2011-01-01

244

Differential gene expression during terminal erythroid differentiation  

PubMed Central

Terminal erythroid differentiation in mammals is the process whereby nucleated precursor cells accumulate erythroid-specific proteins, such as hemoglobin, undergo extensive cellular and nuclear remodeling, and ultimately shed their nuclei to form reticulocytes, which then become mature erythrocytes in the circulation. Little is known about the mechanisms that enable erythroblasts to undergo such a transformation. We hypothesized that genes involved in these mechanisms were likely expressed at restricted times during the differentiation process and used differential display reverse transcriptase polymerase chain reaction (DDRT-PCR) as a first step in identifying such genes. We identified 3 differentially expressed genes that we termed late erythroblast (LEB) 1-3. None of these genes were previously identified as being expressed in erythroblasts and their pattern of expression indicated they are likely to be involved in the differentiation process. LEB-1, which shares homology with members of the apolipoprotein L family in humans, and LEB-3 represented novel genes with no known function, whereas LEB-2 corresponded to ranBP16, a nuclear exportin. LEB-3 mRNA was also strongly expressed in the testis and was localized to a region of the seminiferous tubule where secondary spermatocytes and early spermatids are found, suggesting a role for LEB-3 in spermatogenesis as well as terminal erythroid differentiation. We have thus identified three genes not previously described as being expressed in erythroblasts that could be relevant in elucidating mechanisms involved in terminal erythroid differentiation.

Koury, S.; Yarlagadda, S.; Moskalik-Liermo, K.; Popli, N.; Kim, N.; Apolito, C.; Peterson, A.; Zhang, X.; Zu, P.; Tamburlin, J.; Bofinger, D.

2008-01-01

245

A Gene Expression Map of the Arabidopsis Root  

Microsoft Academic Search

A global map of gene expression within an organ can identify genes with coordi- nated expression in localized domains, thereby relating gene activity to cell fate and tissue specialization. Here, we present localization of expression of more than 22,000 genes in the Arabidopsis root. Gene expression was mapped to 15 different zones of the root that correspond to cell types

Kenneth Birnbaum; Dennis E. Shasha; Jean Y. Wang; Jee W. Jung; Georgina M. Lambert; Philip N. Benfey

2003-01-01

246

Gene expression profiling: can we identify the right target genes?  

Microsoft Academic Search

Gene expression profiling allows the simultaneous monitoring of the transcriptional behaviour of thousands of genes, which may potentially be involved in disease development. Several studies have been performed in idiopathic pulmonary fibrosis (IPF), which aim to define genetic links to the disease in an attempt to improve the current understanding of the underlying pathogenesis of the disease and target pathways

J. E. Loyd

2008-01-01

247

Transcription factories: gene expression in unions?  

Microsoft Academic Search

Transcription is a fundamental step in gene expression, yet it remains poorly understood at a cellular level. Visualization of transcription sites and active genes has led to the suggestion that transcription occurs at discrete sites in the nucleus, termed transcription factories, where multiple active RNA polymerases are concentrated and anchored to a nuclear substructure. However, this concept is not universally

Heidi Sutherland; Wendy A. Bickmore

2009-01-01

248

REGULATION OF BACTERIAL GENE EXPRESSION BY RIBOSWITCHES  

Microsoft Academic Search

Riboswitches are structured domains that usually reside in the non- coding regions of mRNAs, where they bind metabolites and control gene expression. Like their protein counterparts, these RNA gene control elements form highly specific binding pockets for the target metabolite and undergo allosteric changes in structure. Numerous classes of riboswitches are present in bacteria and they comprise a common and

Wade C. Winkler; Ronald R. Breaker

2005-01-01

249

Polyunsaturated fatty acids and gene expression  

Technology Transfer Automated Retrieval System (TEKTRAN)

Purpose of review. This review focuses on the effect(s) of n-3 polyunsaturated fatty acids (PUFA) on gene transcription as determined from data generated using cDNA microarrays. Introduced within the past decade, this methodology allows detection of the expression of thousands of genes simultaneo...

250

The TRANSFAC system on gene expression regulation  

Microsoft Academic Search

The TRANSFAC database on transcription factors and their DNA-binding sites and profiles (http:\\/\\/ www.gene-regulation.de\\/) has been quantitatively extended and supplemented by a number of modules. These modules give information about pathologically relevant mutations in regulatory regions and transcription factor genes (PathoDB), scaffold\\/matrix attached regions (S\\/MARt DB), signal transduction (TRANSPATH) and gene expression sources (CYTOMER). Altogether, these distinct data- base modules

Edgar Wingender; Xin Chen; Ellen Fricke; R. Geffers; R. Hehl; Ines Liebich; Mathias Krull; V. Matys; Holger Michael; R. Ohnhäuser; M. Prüß; Frank Schacherer; S. Thiele; S. Urbach

2001-01-01

251

Aberrant TTF-1 expression in papillary high-grade urothelial neoplasm: case report and literature review.  

PubMed

We herein report the case of a 48-year-old man who developed synchronous advanced tumors in the lung and the bladder. The most striking feature of our case is that the otherwise typical bladder urothelial carcinoma showed focal areas (comprising less than 5% of the tumor mass) of nuclear positivity for TTF-1 (thyroid transcription factor-1). The different pattern of cytokeratin expression led us to consider them two independent primary tumors. Several recent reports have indicated that the type of clone used can influence the results of TTF-1 staining and can explain positivity in extrapulmonary and extrathyroid tumors. PMID:21424050

Fernández-Aceñero, Maria J; Córdova, S; Santonja, C

2011-01-01

252

Distance-enhanced association rules for gene expression  

Microsoft Academic Search

We introduce a novel data mining technique for the analysis of gene expression. Gene expression is the effective production of the protein that a gene encodes. We focus on the characterization of the expression patterns of genes based on their promoter regions. The promoter region of a gene contains short sequences called motifs to which gene regulatory proteins may bind,

Aleksandar Icev; Carolina Ruiz; Elizabeth F. Ryder

2003-01-01

253

Bayesian assignment of gene ontology terms to gene expression experiments  

PubMed Central

Motivation: Gene expression assays allow for genome scale analyses of molecular biological mechanisms. State-of-the-art data analysis provides lists of involved genes, either by calculating significance levels of mRNA abundance or by Bayesian assessments of gene activity. A common problem of such approaches is the difficulty of interpreting the biological implication of the resulting gene lists. This lead to an increased interest in methods for inferring high-level biological information. A common approach for representing high level information is by inferring gene ontology (GO) terms which may be attributed to the expression data experiment. Results: This article proposes a probabilistic model for GO term inference. Modelling assumes that gene annotations to GO terms are available and gene involvement in an experiment is represented by a posterior probabilities over gene-specific indicator variables. Such probability measures result from many Bayesian approaches for expression data analysis. The proposed model combines these indicator probabilities in a probabilistic fashion and provides a probabilistic GO term assignment as a result. Experiments on synthetic and microarray data suggest that advantages of the proposed probabilistic GO term inference over statistical test-based approaches are in particular evident for sparsely annotated GO terms and in situations of large uncertainty about gene activity. Provided that appropriate annotations exist, the proposed approach is easily applied to inferring other high level assignments like pathways. Availability: Source code under GPL license is available from the author. Contact: peter.sykacek@boku.ac.at

Sykacek, P.

2012-01-01

254

The Implication of Aberrant GM-CSF Expression in Decidual Cells in the Pathogenesis of Preeclampsia  

PubMed Central

Preeclampsia is characterized by an exaggerated systemic inflammatory state as well as shallow placentation. In the decidual implantation site, preeclampsia is accompanied by an excessive number of both macrophages and dendritic cells as well as their recruiting chemokines, which have been implicated in the impairment of endovascular trophoblast invasion. Granulocyte-macrophage colony–stimulating factor is known to regulate the differentiation of both macrophages and dendritic cells, prompting both in vivo and in vitro evaluation of granulocyte-macrophage colony-stimulating factor expression in human decidua as well as in a mouse model of preeclampsia. This study revealed increased granulocyte-macrophage colony–stimulating factor expression levels in preeclamptic decidua. Moreover, both tumor necrosis factor-? and interleukin-1 ?, cytokines that are implicated in the genesis of preeclampsia, markedly up-regulated granulocyte-macrophage colony-stimulating factor production in cultured first-trimester human decidual cells. The conditioned media of these cultures promoted the differentiation of both macrophages and dendritic cells from a monocyte precursor. Evaluation of a murine model of preeclampsia revealed that the decidua of affected animals displayed higher levels of immunoreactive granulocyte-macrophage colony–stimulating factor as well as increased numbers of both macrophages and dendritic cells when compared to control animals. Because granulocyte-macrophage colony–stimulating factor is a potent inducer of differentiation and activation of both macrophages and dendritic cells, these findings suggest that this factor plays a crucial role in the pathogenesis of preeclampsia.

Huang, S. Joseph; Zenclussen, Ana C.; Chen, Chie-Pein; Basar, Murat; Yang, Hui; Arcuri, Felice; Li, Min; Kocamaz, Erdogan; Buchwalder, Lynn; Rahman, Mizanur; Kayisli, Umit; Schatz, Frederick; Toti, Paolo; Lockwood, Charles J.

2010-01-01

255

Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour  

Microsoft Academic Search

The human DOC-2\\/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumour-suppressor gene inactivated by methylation in several cancers. In this study, we analysed the methylation and expression status of hDAB2IP in gastrointestinal tumours. The promoter region of hDAB2IP was divided into two regions (m2a and m2b) based

H Dote; S Toyooka; K Tsukuda; M Yano; T Ota; M Murakami; M Naito; M Toyota; A F Gazdar; N Shimizu

2005-01-01

256

An integrative characterization of recurrent molecular aberrations in glioblastoma genomes.  

PubMed

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between 'effector' molecular aberrations and 'target' gene expressions in GBMs. A rich collection of prior studies attempted to combine copy number variation (CNV) and mRNA expression data. However, systematic methods to integrate multiple types of cancer genomic data-gene mutations, single nucleotide polymorphisms, CNVs, DNA methylations, mRNA and microRNA expressions and clinical information-are relatively scarce. We proposed an algorithm to build 'association modules' linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets. The inferred association modules were validated by six tests using external information and datasets of central nervous system tumors: (i) indication of prognostic effects among patients; (ii) coherence of target gene expressions; (iii) retention of effector-target associations in external data sets; (iv) recurrence of effector molecular aberrations in GBM; (v) functional enrichment of target genes; and (vi) co-citations between effectors and targets. Modules associated with well-known molecular aberrations of GBM-such as chromosome 7 amplifications, chromosome 10 deletions, EGFR and NF1 mutations-passed the majority of the validation tests. Furthermore, several modules associated with less well-reported molecular aberrations-such as chromosome 11 CNVs, CD40, PLXNB1 and GSTM1 methylations, and mir-21 expressions-were also validated by external information. In particular, modules constituting trans-acting effects with chromosome 11 CNVs and cis-acting effects with chromosome 10 CNVs manifested strong negative and positive associations with survival times in brain tumors. By aligning the information of association modules with the established GBM subclasses based on transcription or methylation levels, we found each subclass possessed multiple concurrent molecular aberrations. Furthermore, the joint molecular characteristics derived from 16 association modules had prognostic power not explained away by the strong biomarker of CpG island methylator phenotypes. Functional and survival analyses indicated that immune/inflammatory responses and epithelial-mesenchymal transitions were among the most important determining processes of prognosis. Finally, we demonstrated that certain molecular aberrations uniquely recurred in GBM but were relatively rare in non-GBM glioma cells. These results justify the utility of an integrative analysis on cancer genomes and provide testable characterizations of driver aberration events in GBM. PMID:23907387

Sintupisut, Nardnisa; Liu, Pei-Ling; Yeang, Chen-Hsiang

2013-07-31

257

An integrative characterization of recurrent molecular aberrations in glioblastoma genomes  

PubMed Central

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor in adults. Decades of investigations and the recent effort of the Cancer Genome Atlas (TCGA) project have mapped many molecular alterations in GBM cells. Alterations on DNAs may dysregulate gene expressions and drive malignancy of tumors. It is thus important to uncover causal and statistical dependency between ‘effector’ molecular aberrations and ‘target’ gene expressions in GBMs. A rich collection of prior studies attempted to combine copy number variation (CNV) and mRNA expression data. However, systematic methods to integrate multiple types of cancer genomic data—gene mutations, single nucleotide polymorphisms, CNVs, DNA methylations, mRNA and microRNA expressions and clinical information—are relatively scarce. We proposed an algorithm to build ‘association modules’ linking effector molecular aberrations and target gene expressions and applied the module-finding algorithm to the integrated TCGA GBM data sets. The inferred association modules were validated by six tests using external information and datasets of central nervous system tumors: (i) indication of prognostic effects among patients; (ii) coherence of target gene expressions; (iii) retention of effector–target associations in external data sets; (iv) recurrence of effector molecular aberrations in GBM; (v) functional enrichment of target genes; and (vi) co-citations between effectors and targets. Modules associated with well-known molecular aberrations of GBM—such as chromosome 7 amplifications, chromosome 10 deletions, EGFR and NF1 mutations—passed the majority of the validation tests. Furthermore, several modules associated with less well-reported molecular aberrations—such as chromosome 11 CNVs, CD40, PLXNB1 and GSTM1 methylations, and mir-21 expressions—were also validated by external information. In particular, modules constituting trans-acting effects with chromosome 11 CNVs and cis-acting effects with chromosome 10 CNVs manifested strong negative and positive associations with survival times in brain tumors. By aligning the information of association modules with the established GBM subclasses based on transcription or methylation levels, we found each subclass possessed multiple concurrent molecular aberrations. Furthermore, the joint molecular characteristics derived from 16 association modules had prognostic power not explained away by the strong biomarker of CpG island methylator phenotypes. Functional and survival analyses indicated that immune/inflammatory responses and epithelial-mesenchymal transitions were among the most important determining processes of prognosis. Finally, we demonstrated that certain molecular aberrations uniquely recurred in GBM but were relatively rare in non-GBM glioma cells. These results justify the utility of an integrative analysis on cancer genomes and provide testable characterizations of driver aberration events in GBM.

Sintupisut, Nardnisa; Liu, Pei-Ling; Yeang, Chen-Hsiang

2013-01-01

258

Inducible gene expression systems and plant biotechnology  

Microsoft Academic Search

Plant biotechnology relies heavily on the genetic manipulation of crops. Almost invariantly, the gene of interest is expressed in a constitutive fashion, although this may not be strictly necessary for several applications. Currently, there are several regulatable expression systems for the temporal, spatial and quantitative control of transgene activity. These molecular switches are based on components derived from different organisms,

Giandomenico Corrado; Marianthi Karali

2009-01-01

259

SAGEmap: A Public Gene Expression Resource  

PubMed Central

We have constructed a public gene expression data repository and online data access and analysis, WWW and FTP sites for serial analysis of gene expression (SAGE) data. The WWW and FTP components of this resource, SAGEmap, are located at http://www.ncbi.nlm.nih.gov/sage and ftp://ncbi.nlm.nih.gov/pub/sage, respectively. We herein describe SAGE data submission procedures, the construction and characteristics of SAGE tags to gene assignments, the derivation and use of a novel statistical test designed specifically for differential-type analyses of SAGE data, and the organization and use of this resource.

Lash, Alex E.; Tolstoshev, Carolyn M.; Wagner, Lukas; Schuler, Gregory D.; Strausberg, Robert L.; Riggins, Gregory J.; Altschul, Stephen F.

2000-01-01

260

[Aberrant over-expression of adenosine deaminase and its significance on rheumatoid arthritis].  

PubMed

Adenosine deaminase (ADA; EC 3.5.4.4) activity is elevated in the synovial fluid (SF) of rheumatoid arthritis (RA) patients. Since the anti-inflammatory effect of methotrexate is reportedly associated with increased levels of extracellular adenosine, the study was undertaken to clarify the role of two ADA isozymes (ADA1 and ADA2) in the pathogenesis of RA. The activities of ADA1 and ADA2 were measured in SF from RA and osteoarthritis (OA) patients, sera from RA patients, and lysates prepared from mononuclear and polymorphonuclear cells from RA-SF, peripheral blood from RA patients, and fibroblast-like synoviocytes (FLS) from RA and OA patients. Also investigated were the effects of proinflammatory cytokines on ADA1 activity and ADA mRNA expression in RA-FLS by the real-time PCR assay. The adenosine concentration in RA-SF was determined using a radioimmunoassay. The adenosine concentration in RA-SF ranged from 0.027 microM to 0.508 microM (mean+/-SD, 0.156+/-0.132). At these concentrations, ADA1 is expected to be functionally dominant due to its higher affinity for adenosine. ADA1 activity in RA-SF (14.4+/- 8.5 IU/l) was significantly higher than in OA-SF(3.0+/- 1.1 IU/l) or RA-sera (3.0+/-0.6 IU/l), suggesting they are the major source of ADA1 in RA-SF. Proinflammatory cytokines failed to affect ADA1 activity or ADA mRNA expression in RA-FLS. Taken together, these findings suggest that the elevated ADA1 activity is an intrinsic characteristic of RA-FLS, which likely contributes to the pathogenesis of RA by neutralizing the anti-rheumatic properties of endogenous adenosine. PMID:16190361

Koshiba, Masahiro; Nakamachi, Yuji; Kumagai, Shunichi

2005-08-01

261

Gene Expression Profiles of Mesenchymal Stem Cells  

Microsoft Academic Search

Past studies profiling gene expression in MSCs have typically revealed a preponderance of expressed transcripts encoding structural\\u000a proteins common in skeletal tissue and secreted factors that regulate hematopoiesis. Our SAGE analysis of the MSC transcriptome\\u000a corroborated many of these previous findings, but also revealed that the cells express a plethora of transcripts encoding\\u000a proteins involved in cell communication, motility, neural

D. G. PHINNEY

262

Exploration of Global Gene Expression Patterns in Pancreatic Adenocarcinoma Using cDNA Microarrays  

PubMed Central

Pancreatic cancer is the fifth leading cause of cancer death in the United States. We used cDNA microarrays to analyze global gene expression patterns in 14 pancreatic cancer cell lines, 17 resected infiltrating pancreatic cancer tissues, and 5 samples of normal pancreas to identify genes that are differentially expressed in pancreatic cancer. We found more than 400 cDNAs corresponding to genes that were differentially expressed in the pancreatic cancer tissues and cell lines as compared to normal pancreas. These genes that tended to be expressed at higher levels in pancreatic cancers were associated with a variety of processes, including cell-cell and cell-matrix interactions, cytoskeletal remodeling, proteolytic activity, and Ca++ homeostasis. Two prominent clusters of genes were related to the high rates of cellular proliferation in pancreatic cancer cell lines and the host desmoplastic response in the resected pancreatic cancer tissues. Of 149 genes identified as more highly expressed in the pancreatic cancers compared with normal pancreas, 103 genes have not been previously reported in association with pancreatic cancer. The expression patterns of 14 of these highly expressed genes were validated by either immunohistochemistry or reverse transcriptase-polymerase chain reaction as being expressed in pancreatic cancer. The overexpression of one gene in particular, 14-3-3?, was found to be associated with aberrant hypomethylation in the majority of pancreatic cancers analyzed. The genes and expressed sequence tags presented in this study provide clues to the pathobiology of pancreatic cancer and implicate a large number of potentially new molecular markers for the detection and treatment of pancreatic cancer.

Iacobuzio-Donahue, Christine A.; Maitra, Anirban; Olsen, Mari; Lowe, Anson W.; Van Heek, N. Tjarda; Rosty, Christophe; Walter, Kim; Sato, Norihiro; Parker, Antony; Ashfaq, Raheela; Jaffee, Elizabeth; Ryu, Byungwoo; Jones, Jessa; Eshleman, James R.; Yeo, Charles J.; Cameron, John L.; Kern, Scott E.; Hruban, Ralph H.; Brown, Patrick O.; Goggins, Michael

2003-01-01

263

Gene expression profile analysis: an emerging approach to investigate mechanisms of genotoxicity.  

PubMed

The response to stress triggers transcriptional activation of genes involved in cell survival and/or cell death. Thus, the monitoring of gene expression levels in large gene sets or whole genomes in response to various agents (toxicogenomics) has been proposed as a tool for investigating mechanisms of toxicity. Although standard in vitro genetic toxicity testing provides relatively simple and accurate hazard detection, interpretation of positive findings, i.e., in vitro chromosome aberrations, in terms of relevant risk to humans is difficult, due to the limited insight into the underlying mechanisms. Therefore, the development of experimental approaches capable of differentiating a wide range of genotoxic mechanisms is expected to significantly improve risk assessment. The goal of this review is to summarize current developments in toxicogenomic analysis of genotoxic stress, and to provide a perspective on the application of gene expression profile analysis in genetic toxicology. PMID:16004560

Aubrecht, Jiri; Caba, Ebru

2005-06-01

264

Lineage specificity of gene expression patterns  

PubMed Central

The hematopoietic system offers many advantages as a model for understanding general aspects of lineage choice and specification. Using oligonucleotide microarrays, we compared gene expression patterns of multiple purified hematopoietic cell populations, including neutrophils, monocytes, macrophages, resting, centrocytic, and centroblastic B lymphocytes, dendritic cells, and hematopoietic stem cells. Some of these cells were studied under both resting and stimulated conditions. We studied the collective behavior of subsets of genes derived from the Biocarta database of functional pathways, hand-tuned groupings of genes into broad functional categories based on the Gene Ontology database, and the metabolic pathways in the Kyoto Encyclopedia of Genes and Genomes database. Principal component analysis revealed strikingly pervasive differences in relative levels of gene expression among cell lineages that involve most of the subsets examined. These results indicate that many processes in these cells behave differently in different lineages. Much of the variation among lineages was captured by the first few principal components. Principal components biplots were found to provide a convenient visual display of the contributions of the various genes within the subsets in lineage discrimination. Moreover, by applying tree-constructing methodologies borrowed from phylogenetics to the expression data from differentiated cells and stem cells, we reconstructed a tree of relationships that resembled the established hematopoietic program of lineage development. Thus, the mRNA expression data implicitly contained information about developmental relationships among cell types.

Kluger, Yuval; Tuck, David P.; Chang, Joseph T.; Nakayama, Yasuhiro; Poddar, Ranjana; Kohya, Naohiko; Lian, Zheng; Nasr, Abdelhakim Ben; Halaban, H. Ruth; Krause, Diane S.; Zhang, Xueqing; Newburger, Peter E.; Weissman, Sherman M.

2004-01-01

265

Microarray analysis of gene expression in lupus.  

PubMed

Recent advances in the study of global patterns of gene expression with the use of microarray technology, coupled with data analysis using sophisticated statistical algorithms, have provided new insights into pathogenic mechanisms of disease. Complementary and reproducible data from multiple laboratories have documented the feasibility of analysis of heterogeneous populations of peripheral blood mononuclear cells from patients with rheumatic diseases through use of this powerful technology. Although some patterns of gene expression, including increased expression of immune system cell surface activation molecules, confirm previous data obtained with other techniques, some novel genes that are differentially expressed have been identified. Most interesting is the dominant pattern of interferon-induced gene expression detected among blood mononuclear cells from patients with systemic lupus erythematosus and juvenile dermatomyositis. These data are consistent with longstanding observations indicating increased circulating interferon-alpha in the blood of patients with active lupus, but draw attention to the dominance of the interferon pathway in the hierarchy of gene expression pathways implicated in systemic autoimmunity. PMID:14680503

Crow, Mary K; Wohlgemuth, Jay

2003-10-13

266

MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder  

PubMed Central

The purpose of this study was to determine the relationship between methylation status of the insulin-like growth factor 2 (IGF-2) gene and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in bladder transitional cell carcinoma tissues in a Chinese population. The polymorphisms of the folate metabolism enzyme gene MTHFR were studied by restrictive fragment length polymorphism (RFLP). PCR-based methods of DNA methylation analysis were used to detect the CpG island methylation status of the IGF-2 gene. The association between the methylation status of the IGF-2 gene and clinical characteristics, as well as MTHFR C677T polymorphisms, was analyzed. Aberrant hypomethylation of the IGF-2 gene was found in 68.3% bladder cancer tissues and 12.4% normal bladder tissues, respectively, while hypomethylation was not detected in almost all normal bladder tissues. The hypomethylation rate of the IGF-2 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables the variant allele of MTHFR C677T was found to be associated with hypomethylation of the IGF-2 gene. Compared with wildtype CC, the odds ratio was 4.33 (95% CI=1.06-10.59) for CT and 4.95 (95% CI=1.18-12.74) for TT. MTHFR 677 CC and CT genotypes might be one of the reasons that cause abnormal hypomethylation of the IGF-2 gene, and the aberrant CpG island hypomethylation of the IGF-2 gene may contribute to the genesis and progression of bladder transitional cell carcinoma.

Cheng, Huan; Deng, Zhonglei; Wang, Zengjun; Zhang, Wei; Su, Jiantang

2012-01-01

267

Loss of membrane localization and aberrant nuclear E-cadherin expression correlates with invasion in pancreatic endocrine tumors.  

PubMed

Decrease in E-cadherin is considered a molecular event in dysfunction of the cell-cell adhesion system, triggering invasion and metastasis in many malignancies, including those of endocrine origin. In addition, alterations in the cadherin-catenin system may also be involved in tumorigenesis. E-cadherin and beta-catenin, components of the Wnt signal transduction pathway, may serve as a common switch in central processes that regulate cellular differentiation and growth. The purpose of this study was to examine if abnormalities of the Wnt signaling pathway, specifically, E-cadherin and beta-catenin, occur in pancreatic endocrine tumors (PETs) and correlate these with clinicopathologic parameters. Tissue microarrays were constructed from 57 cases with 4 to 14 cores measuring 1.0 mm from each case. Size of tumor, presence or absences of necrosis, gross invasiveness/demarcation, lymphovascular invasion, and lymph node involvement and liver metastasis were recorded. The mitotic count, expressed per 50 high power fields (HPF) and MIB-1 index of the entire tumor were assessed. All the tissue microarray blocks were stained with commercially available antibodies to E-cadherin (cytoplasmic and extracellular domains), beta-catenin, APC, and GSK-3beta. Twenty-seven were male patients and 30 female, ranging in age from 23 to 80 years (mean, 51.7 y). Six patients had MEN1 syndrome and 1 von Hippel Lindau disease. The tumors ranged in size from 0.8 to 9.8 cm with a mean of 3.4 cm. Sixteen patients had lymph node spread and 7 had liver metastasis. The Ki-67 labeling index ranged from 1% to 30% and the mitotic counts from 0 to 27 per 50 HPF. Thirty of 57 cases (52.6%) cases showed abnormal beta-catenin expression. Thirteen of the 16 cases with lymph node metastasis and all 7 cases with liver spread showed abnormalities of beta-catenin immunostaining. Only 2 cases showed nuclear beta-catenin. The average size of tumors with beta-catenin abnormalities was 4.8 cm. Thirty-four of the 57 (59.6%) cases showed loss of normal membranous immunoreactivity for both antibodies E-cadherin, including nuclear localization in 18 cases with the antibody that recognizes the cytoplasmic domain. E-cadherin decrease and/or loss was identical to beta-catenin with the same 13 cases showing nodal involvement and all 7 cases with liver metastasis displaying aberrant E-cadherin staining. Seven of the 18 cases with nuclear E-cadherin had lymph node spread and 3 liver metastases. The mean size of the 34 cases with abnormal E-cadherin expression was 4.4 cm, compared to the series mean of 3.4 cm. Interestingly, cases with nuclear E-cadherin had a mean size of 5.2 cm. beta-catenin and E-cadherin abnormalities did not correlate with other clinicopathological parameters. All 57 cases showed cytoplasmic immunoreactivity for APC, and cytoplasmic and nuclear positivity for GSK-3beta. APC and GSK-3beta did not show any correlation with beta-catenin or E-cadherin staining. Abnormalities of beta-catenin and E-cadherin immunoexpression are seen in the majority of PETs. Nuclear beta-catenin is rare in PET but nuclear E-cadherin, a previously unrecognized staining pattern in PETs was seen 18 of 57 cases with the antibody detecting the cytoplasmic fragment of E-cadherin. Aberrant expression of both beta-catenin and E-cadherin correlated strongly with lymph node spread and liver metastases. PMID:18300809

Chetty, Runjan; Serra, Stefano; Asa, Sylvia L

2008-03-01

268

Differential gene expression during multistage carcinogenesis.  

PubMed Central

The use of the mouse skin multistage model of carcinogenesis has aided our understanding of critical target genes in chemical carcinogenesis. The mutagenic activation of the Harvey-ras proto-oncogene has been found to be an early event associated with the initiation of mouse skin tumors by the polycyclic aromatic hydrocarbon 7,12 dimethylbenz[alpha]anthracene and the pure initiator ethyl carbamate (urethane). In contrast to chemical initiation of mouse skin tumors, ionizing radiation-initiated malignant skin tumors have been shown to possess distinct non-ras transforming gene(s). Differential screening of cDNA libraries made from chemically initiated malignant skin tumors has been used to identify a number of cellular gene transcripts that are overexpressed during mouse skin tumor progression. These differentially expressed genes include beta-actin, ubiquitin, a hyperproliferative keratin (K6), a gene whose product is a member of a fatty acid or lipid-binding protein family, and a gene called transin or stromelysin. The overexpression of the stromelysin gene, which encodes a metalloproteinase that degrades proteins in the basement membrane, is hypothesized to play a functional role in malignant tumor cell invasion and metastasis. We believe that the cloning, identification, and characterization of gene sequences that are differentially expressed during tumor progression could lead to the discovery of gene products that either play functional roles in skin tumor progression or in the maintenance of various progressive tumor phenotypes.

Bowden, G T; Krieg, P

1991-01-01

269

Gene expression regulating blastocyst formation  

Microsoft Academic Search

Development of embryos to the blastocyst stage is a critical event in the early lives of all eutherian mammalian species. Blastocyst formation is essential for implantation and is the principal morphological determinant of embryo quality prior to embryo transfer. The physiological events and roles of specific gene families that regulate blastocyst formation are subjects of intense research. Recent findings have

A. J Watson; M. E Westhusin; P. A De Sousa; D. H Betts; L. C Barcroft

1999-01-01

270

Phytochrome-regulated Gene Expression  

Technology Transfer Automated Retrieval System (TEKTRAN)

Identification of all genes involved in the phytochrome (phy)- mediated responses of plants to their light environment is an important goal in providing an overall understanding of light-regulated growth and development. This article highlights and integrates the central findings of two recent compr...

271

Regulation of gene expression in human tendinopathy  

PubMed Central

Background Chronic tendon injuries, also known as tendinopathies, are common among professional and recreational athletes. These injuries result in a significant amount of morbidity and health care expenditure, yet little is known about the molecular mechanisms leading to tendinopathy. Methods We have used histological evaluation and molecular profiling to determine gene expression changes in 23 human patients undergoing surgical procedures for the treatment of chronic tendinopathy. Results Diseased tendons exhibit altered extracellular matrix, fiber disorientation, increased cellular content and vasculature, and the absence of inflammatory cells. Global gene expression profiling identified 983 transcripts with significantly different expression patterns in the diseased tendons. Global pathway analysis further suggested altered expression of extracellular matrix proteins and the lack of an appreciable inflammatory response. Conclusions Identification of the pathways and genes that are differentially regulated in tendinopathy samples will contribute to our understanding of the disease and the development of novel therapeutics.

2011-01-01

272

Gene expression profiles in thyroid carcinomas  

PubMed Central

The gene expression profiles of human thyroid carcinomas were analysed by serial analysis of gene expression (SAGE) which allows quantitative and simultaneous analysis of a large number of transcripts. More than 29 000 transcripts derived from a normal thyroid tissue and four thyroid tumours were analysed. While extensive similarity was noted between the expression profiles of the normal thyroid tissue and three differentiated thyroid tumours, many transcripts, such as osteonectin, a-tubulin, glyceraldehyde-3-phosphate dehydrogenase, glutathione peroxidase, and thyroglobulin, were expressed at extremely different levels in differentiated and undifferentiated carcinomas. These data provide new information that might be used to identify genes useful for the diagnosis and treatment of thyroid carcinomas. © 2000 Cancer Research Campaign http://www.bjcancer.com

Takano, T; Hasegawa, Y; Matsuzuka, F; Miyauchi, A; Yoshida, H; Higashiyama, T; Kuma, K; Amino, N

2000-01-01

273

A Novel Aberrant Splicing Mutation of the PEX16 Gene in Two Patients with Zellweger Syndrome  

Microsoft Academic Search

Human Pex16p, a peroxisomal membrane protein composed of 336 amino acids, plays a central role in peroxisomal membrane biogenesis. A nonsense mutation (R176ter) in the PEX16 gene has been reported in the case of only one patient (D-01) belonging to complementation group D of the peroxisome biogenesis disorders. We have now identified two patients belonging to group D (D-02 and

Nobuyuki Shimozawa; Tomoko Nagase; Yasuhiko Takemoto; Yasuyuki Suzuki; Yukio Fujiki; Ronald J. A. Wanders; Naomi Kondo

2002-01-01

274

Heterelogous Expression of Plant Genes  

PubMed Central

Heterologous expression allows the production of plant proteins in an organism which is simpler than the natural source. This technology is widely used for large-scale purification of plant proteins from microorganisms for biochemical and biophysical analyses. Additionally expression in well-defined model organisms provides insights into the functions of proteins in complex pathways. The present review gives an overview of recombinant plant protein production methods using bacteria, yeast, insect cells, and Xenopus laevis oocytes and discusses the advantages of each system for functional studies and protein characterization.

Yesilirmak, Filiz; Sayers, Zehra

2009-01-01

275

Heterelogous expression of plant genes.  

PubMed

Heterologous expression allows the production of plant proteins in an organism which is simpler than the natural source. This technology is widely used for large-scale purification of plant proteins from microorganisms for biochemical and biophysical analyses. Additionally expression in well-defined model organisms provides insights into the functions of proteins in complex pathways. The present review gives an overview of recombinant plant protein production methods using bacteria, yeast, insect cells, and Xenopus laevis oocytes and discusses the advantages of each system for functional studies and protein characterization. PMID:19672459

Yesilirmak, Filiz; Sayers, Zehra

2009-08-06

276

Aberrant TRPV1 expression in heat hyperalgesia associated with trigeminal neuropathic pain.  

PubMed

Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model. PMID:23091405

Urano, Hiroko; Ara, Toshiaki; Fujinami, Yoshiaki; Hiraoka, B Yukihiro

2012-10-02

277

Immunophenotypic heterogeneity of primary sinonasal melanoma with aberrant expression of neuroendocrine markers and calponin.  

PubMed

Primary sinonasal melanoma is an aggressive tumor that often presents a diagnostic challenge owing to its rarity and variable morphology. Unusual immunophenotypic expression of sinonasal melanoma compounds the problem particularly in a limited tissue sample. We studied immunohistochemical patterns of 5 primary sinonasal melanoma using antibodies against pan-cytokeratin, S-100, HMB-45, Melan-A, chromogranin, synaptophysin, neurofilament protein, and calponin and correlated these patterns with histologic appearance. Sinus/nasal mucosa from non-neoplastic cases were stained for Melan-A to evaluate prevalence of melanocytes in the benign mucosa in comparison to the staining pattern of the mucosa adjacent to the tumor. Similar to previous report, small cell pattern appeared to be over represented in the sinonasal melanoma. Small cell population in 4 cases was almost devoid of pigment, and also was either completely negative or only focally positive for S-100. Three cases stained positive for neuroendocrine markers and neurofilament protein bringing olfactory neuroblastoma and small cell neuroendocrine carcinoma in as differential diagnosis. Three cases were focally positive for calponin without spindle cell morphology or desmoplastic reaction. Immunophenotypic heterogeneity along with the unconventional histomorphology of sinonasal melanoma compounds diagnostic problem and warrants a precautionary approach to avoid misinterpretation. It is necessary to apply a broad panel of immunohistochemistry for the purpose of screening when sinonasal melanoma is considered as a differential diagnosis. PMID:20881840

Lee, Hwajeong; Torres, Frank X; McLean, Scott A; Chen, Ruey; Lee, Min W

2011-01-01

278

Aberrant TRPV1 Expression in Heat Hyperalgesia Associated with Trigeminal Neuropathic Pain  

PubMed Central

Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

Urano, Hiroko; Ara, Toshiaki; Fujinami, Yoshiaki; Hiraoka, B. Yukihiro

2012-01-01

279

Early gene expression changes with rush immunotherapy  

PubMed Central

Background To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment. Methods For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry. Results In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ?1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1?, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints. Conclusions We observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin.

2011-01-01

280

Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome.  

PubMed

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5' untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology. PMID:22022567

Sheridan, Steven D; Theriault, Kraig M; Reis, Surya A; Zhou, Fen; Madison, Jon M; Daheron, Laurence; Loring, Jeanne F; Haggarty, Stephen J

2011-10-12

281

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome  

PubMed Central

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5? untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology.

Reis, Surya A.; Zhou, Fen; Madison, Jon M.; Daheron, Laurence; Loring, Jeanne F.; Haggarty, Stephen J.

2011-01-01

282

Adenoviral targeting of gene expression to tumors.  

PubMed

Using biochemical, imaging and histological methods, we employed transcriptional targeting to increase the specificity of tumor gene expression in vivo for intravenously administered recombinant adenovirus vectors. Surprisingly, the relative specificity of tumor expression in comparison with other tissues was increased for a constitutively expressing recombinant adenovirus, AdCMVLuc, by simply reducing the viral dose. Even at lower doses, however, the high frequency of viral infection and transgene expression in the liver using constitutive promoters still represents a substantial problem. To further augment tumor specificity, we constructed a series of adenoviruses expressing luciferase from several other promoters and tested their ability to selectively transcribe genes in tumor cells, both in vitro and in vivo. Constitutively active viral promoters (RSV, SRalpha) varied widely in their tumor selectivity, but hypoxia-responsive promoters (carbonic anhydrase 9, PAI-1, SOD2 and several chimeric constructs) showed the most tumor-selective expression. Our results show that tumor targeting to HT1080 fibrosarcomas was readily achieved using transcriptional targeting mechanisms. We attribute the relatively high level of gene transfer and expression in HT1080 tumors in vivo to increased viral access to the tumor, presumably due to discontinuities in tumor vasculature and augmented expression from stress-responsive promoters in the hypoxic and inflammatory tumor microenvironment. PMID:20139924

Hogg, R T; Garcia, J A; Gerard, R D

2010-02-05

283

Genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene  

PubMed Central

The promyelocytic leukemia zinc finger gene (PLZF) is involved in chromosomal translocation t(11;17) associated with acute promyelocytic leukemia. In this work, a 201-kilobase genomic DNA region containing the entire PLZF gene was sequenced. Repeated elements account for 19.83%, and no obvious coding information other than PLZF is present over this region. PLZF contains six exons and five introns, and the exon organization corresponds well with protein domains. There are at least four alternative splicings (AS-I, -II, -III, and -IV) within exon 1. AS-I could be detected in most tissues tested whereas AS-II, -III, and -IV were present in the stomach, testis, and heart, respectively. Although splicing donor and acceptor signals at exon–intron boundaries for AS-I and exons 1–6 were classical (gt–ag), AS-II, -III, and -IV had atypical splicing sites. These alternative splicings, nevertheless, maintained the ORF and may encode isoforms with absence of important functional domains. In mRNA species without AS-I, there is a relatively long 5? UTR of 6.0 kilobases. A TATA box and several transcription factor binding sites were found in the putative promoter region upstream of the transcription start site. PLZF is a well conserved gene from Caenorhabditis elegans to human. PLZF paralogous sequences are found in human genome. The presence of two MLL/PLZF-like alignments on human chromosome 11q23 and 19 suggests a syntenic replication during evolution. The chromosomal breakpoints and joining sites in the index acute promyelocytic leukemia case with t(11;17) also were characterized, which suggests the involvement of DNA damage-repair mechanism.

Zhang, T.; Xiong, H.; Kan, L.-X.; Zhang, C.-K.; Jiao, X.-F.; Fu, G.; Zhang, Q.-H.; Lu, L.; Tong, J.-H.; Gu, B.-W.; Yu, M.; Liu, J.-X.; Licht, J.; Waxman, S.; Zelent, A.; Chen, E.; Chen, S.-J.

1999-01-01

284

Extracting expression modules from perturbational gene expression compendia  

Microsoft Academic Search

Background  Compendia of gene expression profiles under chemical and genetic perturbations constitute an invaluable resource from a systems\\u000a biology perspective. However, the perturbational nature of such data imposes specific challenges on the computational methods\\u000a used to analyze them. In particular, traditional clustering algorithms have difficulties in handling one of the prominent\\u000a features of perturbational compendia, namely partial coexpression relationships between genes.

Steven Maere; Patrick Van Dijck; Martin Kuiper

2008-01-01

285

Mixture modeling of microarray gene expression data  

PubMed Central

About 28% of genes appear to have an expression pattern that follows a mixture distribution. We use first- and second-order partial correlation coefficients to identify trios and quartets of non-sex-linked genes that are highly associated and that are also mixtures. We identified 18 trio and 35 quartet mixtures and evaluated their mixture distribution concordance. Concordance was defined as the proportion of observations that simultaneously fall in the component with the higher mean or simultaneously in the component with the lower mean based on their Bayesian posterior probabilities. These trios and quartets have a concordance rate greater than 80%. There are 33 genes involved in these trios and quartets. A factor analysis with varimax rotation identifies three gene groups based on their factor loadings. One group of 18 genes has a concordance rate of 56.7%, another group of 8 genes has a concordance rate of 60.8%, and a third group of 7 genes has a concordance rate of 69.6%. Each of these rates is highly significant, suggesting that there may be strong biological underpinnings for the mixture mechanisms of these genes. Bayesian factor screening confirms this hypothesis by identifying six single-nucleotide polymorphisms that are significantly associated with the expression phenotypes of the five most concordant genes in the first group.

Yang, Yang; Tashman, Adam P; Lee, Jung Yeon; Yoon, Seungtai; Mao, Wenyang; Ahn, Kwangmi; Kim, Wonkuk; Mendell, Nancy R; Gordon, Derek; Finch, Stephen J

2007-01-01

286

Emphysema lung tissue gene expression profiling.  

PubMed

Emphysema occurs in a subgroup of patients with chronic obstructive pulmonary disease and patients with the genetic defect of alpha(1)-antitrypsin deficiency who have a smoking history of many years' duration. Emphysema is generally the result of a chronic and progressive destruction of the alveolar structures, which is believed to be driven by chronic inflammation, infections, oxidative stress, and an imbalance of protease and antiprotease activity. Here, we use microarray technology to characterize the gene expression profile of lung tissue samples obtained from patients with advanced emphysema and that obtained from healthy subjects. We hypothesized that the gene expression profile of emphysema lung tissue is distinct when compared with the expression profile of normal lungs. We report that severely emphysematous tissue is characterized by a global decrease in gene expression and by an increased abundance of transcripts encoding proteins involved in inflammation, immune responses, and proteolysis. Whereas the gene expression profile is to some degree shared between "usual" emphysema and alpha(1)-antitrypsin deficiency-related emphysema, there are statistically significant differences in the modulation of groups of genes associated with protein and energy metabolism, and immune function, which allow distinction between these two emphysema types on the lung tissue level. PMID:15284076

Golpon, Heiko A; Coldren, Christopher D; Zamora, Martin R; Cosgrove, Gregory P; Moore, Mark D; Tuder, Rubin M; Geraci, Mark W; Voelkel, Norbert F

2004-07-29

287

Gene expression in human brown adipose tissue.  

PubMed

Brown adipose tissue (BAT) has profound effects on body weight and metabolism in rodents. Recent reports show that human adults have significant amounts of BAT. Our aim was to study the gene expression profile of human BAT. Biopsies of adipose tissue with brown-red color and subcutaneous white adipose tissue (WAT) were obtained from 24 patients undergoing surgery in the thyroid region. Intrascapular BAT and epididymal WAT biopsies were obtained from 10 mice. Expression was analyzed by DNA microarray, real-time PCR and immunohistochemistry. Using the expression of the brown adipocyte-specific gene uncoupling protein 1 (UCP1) as a marker, approximately half of the human brown-red adipose tissue biopsies taken in the thyroid region contained BAT, and the presence of cells with brown adipocyte morphology was also verified by histology. Microarray analysis of 9 paired human BAT and WAT samples showed that 17 genes had at least a 4-fold higher expression in BAT compared to WAT and five of them (CKMT1, KCNK3, COBL, HMGCS2, TGM2) were verified using real-time PCR (P<0.05 for all). In addition, immunohistochemistry showed that the UCP1, KCNK3 and CKMT1 proteins are expressed in brown adipocytes. Except for UCP1 and KCNK3, the genes overexpressed in human BAT were not overexpressed in mouse BAT compared to mouse WAT. Our analysis identified genes that are differentially expressed in human BAT compared to WAT. The results also show that there are species-specific differences in BAT gene expression and this emphasizes the need for further molecular characterization of human BAT to clarify the mechanisms involved in regulated heat production in humans. PMID:21125211

Svensson, Per-Arne; Jernås, Margareta; Sjöholm, Kajsa; Hoffmann, Jenny M; Nilsson, Bengt E; Hansson, Magnus; Carlsson, Lena M S

2010-12-01

288

EGFR Gene Variants Are Associated with Specific Somatic Aberrations in Glioma  

PubMed Central

A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

Wibom, Carl; Ghasimi, Soma; Van Loo, Peter; Brannstrom, Thomas; Trygg, Johan; Lau, Ching; Henriksson, Roger; Bergenheim, Tommy; Andersson, Ulrika; Ryden, Patrik; Melin, Beatrice

2012-01-01

289

ATYPICAL HEMOLYTIC UREMIC SYNDROME AND GENETIC ABERRATIONS IN THE COMPLEMENT FACTOR H RELATED 5 GENE  

PubMed Central

Atypical HUS (aHUS) is a severe renal disorder that is associated with mutations in the genes encoding proteins of the complement alternative pathway. Previously, we identified pathogenic variations in genes encoding complement regulators (CFH, CFI, and MCP) in our aHUS cohort. In this study, we screened for mutations in the alternative pathway regulator CFHR5 in 65 aHUS patients by means of PCR on genomic DNA and sequence analysis. Potential pathogenicity of genetic alterations was determined by published data on CFHR5 variants, evolutionary conservation, and in silico mutation prediction programs. Detection of serum CFHR5 was performed by western blot analysis and ELISA. A potentially pathogenic sequence variation was found in CFHR5 in three patients (4.6%). All variations were located in SCRs that might be involved in binding to C3b, heparin, or CRP. The identified CFHR5 mutations require functional studies to determine their relevance to aHUS, but they might be candidates for an altered genetic profile predisposing to the disease.

Westra, Dineke; Vernon, Katherine A.; Volokhina, Elena B.; Pickering, Matthew C.; van de Kar, Nicole C.A.J.; van den Heuvel, Lambert P.

2012-01-01

290

Aberrant Expression of the Cell Cycle Associated Proteins TP53, MDM2, p21, p27, cdk4, Cyclin D1, RB, and EGFR in Cervical Carcinomas  

Microsoft Academic Search

Objective.The aims of this study were to study aberrant expression and coexpression of the cell cycle associated proteins TP53, p21, p27, cyclin D1, cdk4, RB, EGFR, and MDM2 in cervical carcinomas, to correlate protein alterations with histopathological and clinical parameters, and to evaluate whether these alterations provide prognostic information.Methods.Seventy-four cervical carcinomas and 10 cases of normal cervical epithelium from patients

Hanne Skomedal; Gunnar B. Kristensen; Agnes Kathrine Lie; Ruth Holm

1999-01-01

291

[Expression and regulation of the SOST gene].  

PubMed

Sclerostin(SOST), mainly expressed in osteocytes, is a negative regulator of bone formation. Hormones PTH and E2 inhibit the expression of the SOST gene. Transcription factors Osterix, Runx2, and Mef2c promote the SOST expression, while Sirt1 negatively regulates the SOST expression. In addition, the expression of the SOST gene is regulated by epigenetic mechanisms, such as DNA methylation and microRNA. Mutations in the SOST gene, which cause sclerosteosis and Van Buchem diseases, are associated with osteoporosis. Wnt and BMP are two important signaling pathways in bone metabolic regulation. SOST can regulate osteoblastic differentiation and bone formation by binding type I/II receptors and co-receptor LRP5/6 to inhibit BMP and Wnt signaling pathways. Suppression of SOST provides a new approach for osteoporosis treatment. This review covers the structure, function and expression regulation of the SOST gene, human disease association, mechanism in the regulation of bone metabolism and prospect in clinical application. PMID:23956082

Qin, Long-Juan; Ding, Da-Xia; Cui, Lu-Lu; Huang, Qing-Yang

2013-08-01

292

Large-Scale Serial Analysis of Gene Expression Reveals Genes Differentially Expressed in Ovarian Cancer1  

Microsoft Academic Search

Difficulties in the detection, diagnosis, and treatment of ovarian cancer result in an overall low survival rate of women with this disease. A better understanding of the pathways involved in ovarian tumorigenesis will likely provide new targets for early and effective intervention. Here, we have used serial analysis of gene expression (SAGE) to generate global gene expression profiles from various

Colleen D. Hough; Cheryl A. Sherman-Baust; Ellen S. Pizer; F. J. Montz; Dwight D. Im; Neil B. Rosenshein; Kathleen R. Cho; Gregory J. Riggins; Patrice J. Morin

2000-01-01

293

Virus-mediated reprogramming of gene expression in plants  

Microsoft Academic Search

Plant viruses have made many significant contributions to plant biology over the years: they have provided plant researchers with functional promoters, transient expression systems and, most recently, with critical insights into the phenomenon of posttranscriptional gene silencing. Plant virus expression vectors have the ability to either overexpress genes or suppress gene expression in plants. Whereas the ‘rules’ for gene expression

John A Lindbo; Wayne P Fitzmaurice; Guy della-Cioppa

2001-01-01

294

Structure and regulated expression of mammalian RUNX genes  

Microsoft Academic Search

The RUNX are key regulators of lineage-specific gene expression in major developmental pathways. The expression of RUNX genes is tightly regulated, leading to a highly specific spatio\\/temporal expression pattern and to distinct phenotypes of gene knockouts. This review highlights the extensive structural similarities between the three mammalian RUNX genes and delineates how regulation of their expression at the levels of

Ditsa Levanon; Yoram Groner

2004-01-01

295

Selective Gene Expression in Multigene Families from Yeast to Mammals  

NSDL National Science Digital Library

Cell identity is the direct consequence of the genes expressed. This STKE Review highlights the diverse mechanisms that cells use to achieve exclusive gene expression. The details of the molecular mechanism underlying yeast mating-type switching are compared and contrasted with the mechanisms involved in immunoglobulin gene expression and odorant receptor gene expression in mammals.

Jacob Z. Dalgaard (Marie Curie Research Institute; REV); Sonya Vengrova (Marie Curie Research Institute; REV)

2004-10-26

296

Gene-set approach for expression pattern analysis  

Microsoft Academic Search

Recently developed gene set analysis methods evaluate differential expression patterns of gene groups instead of those of individual genes. This approach especially targets gene groups whose constituents show subtle but coordi- nated expression changes, which might not be detected by the usual individual gene analysis. The approach has been quite successful in deriving new information from expression data, and a

Dougu Nam; Seon-young Kim

2008-01-01

297

Relationship of eukaryotic DNA replication to committed gene expression: general theory for gene control.  

PubMed Central

The historic arguments for the participation of eukaryotic DNA replication in the control of gene expression are reconsidered along with more recent evidence. An earlier view in which gene commitment was achieved with stable chromatin structures which required DNA replication to reset expression potential (D. D. Brown, Cell 37:359-365, 1984) is further considered. The participation of nonspecific stable repressor of gene activity (histones and other chromatin proteins), as previously proposed, is reexamined. The possible function of positive trans-acting factors is now further developed by considering evidence from DNA virus models. It is proposed that these positive factors act to control the initiation of replicon-specific DNA synthesis in the S phase (early or late replication timing). Stable chromatin assembles during replication into potentially active (early S) or inactive (late S) states with prevailing trans-acting factors (early) or repressing factors (late) and may asymmetrically commit daughter templates. This suggests logical schemes for programming differentiation based on replicons and trans-acting initiators. This proposal requires that DNA replication precede major changes in gene commitment. Prior evidence against a role for DNA replication during terminal differentiation is reexamined along with other results from terminal differentiation of lower eukaryotes. This leads to a proposal that DNA replication may yet underlie terminal gene commitment, but that for it to do so there must exist two distinct modes of replication control. In one mode (mitotic replication) replicon initiation is tightly linked to the cell cycle, whereas the other mode (terminal replication) initiation is not cell cycle restricted, is replicon specific, and can lead to a terminally differentiated state. Aberrant control of mitotic and terminal modes of DNA replication may underlie the transformed state. Implications of a replicon basis for chromatin structure-function and the evolution of metazoan organisms are considered. Images

Villarreal, L P

1991-01-01

298

Expression and methylation status of imprinted genes in placentas of deceased and live cloned transgenic calves.  

PubMed

Placental deficiencies are linked with developmental abnormalities in cattle produced by somatic cell nuclear transfer (SCNT). To investigate whether the aberrant expression of imprinted genes in placenta was responsible for fetal overgrowth and placental hypertrophy, quantitative expression analysis of six imprinted genes (H19, XIST, IGF2R, SNRPN, PEG3, and IGF2) was conducted in placentas of: 1) deceased (died during perinatal period) transgenic calves (D group, n = 4); 2) live transgenic calves (L group, n = 15); and 3) conventionally produced (control) female calves (N group, n = 4). In this study, XIST, PEG3 and IGF2 were significantly over-expressed in the D group, whereas expression of H19 and IGF2R was significantly reduced in the D group compared to controls. The DNA methylation patterns in the differentially methylated region (DMR) from H19, XIST, and IGF2R were compared using Bisulfite Sequencing PCR (BSP) and Combined Bisulfite Restriction Analysis (COBRA). In the D group, H19 DMR was significantly hypermethylated, but XIST DMR and IGF2R ICR were significantly hypomethylated compared to controls. In contrast, there were no noticeable differences in the expression and DNA methylation status of imprinted genes (except DNA methylation level of XIST DMR) in the L group compared to controls. In conclusion, altered DNA methylation levels in the DMRs of imprinted genes in placentas of deceased transgenic calves, presumably due to aberrant epigenetic nuclear reprogramming during SCNT, may have been associated with abnormal expression of these genes; perhaps this caused developmental insufficiencies and ultimately death in cloned transgenic calves. PMID:21295824

Su, Jian-min; Yang, Bo; Wang, Yong-sheng; Li, Yan-yan; Xiong, Xian-rong; Wang, Li-jun; Guo, Ze-kun; Zhang, Yong

2011-02-04

299

Effects of multidrug resistance gene expression in acute erythroleukemia.  

PubMed

Acute erythroleukemia is a relatively rare disorder of a multilineal nature. Patients with this type of leukemia traditionally have been treated with a standard myeloid protocol, with a wide variation in prognosis between M6a, which has a similar prognosis to acute myelogenous leukemias, and M6b, with an extremely poor outcome despite aggressive therapy. Forty-eight archival cases of acute erythroleukemia, subtypes M6a (the traditional FAB-M6), M6b (pure erythroleukemia), and M6c (>30% myeloblasts and >30% pronormoblasts by FAB exclusion criteria), were evaluated for multidrug resistance gene (MDR-1) status. Findings were correlated with clinical course and karyotypes. Immunohistochemical stain for the protein product of MDR-1, P-glycoprotein, was variably positive in 11 of 23 patients with M6a, as well as in all of the patients with M6b (strongly positive) and M6c (weakly positive). P-glycoprotein expression positively correlated with unfavorable cytogenetic aberrations, poor response to chemotherapeutic agents, and short survival. Most significant was that P-glycoprotein expression demonstrated a negative additive effect on response to treatment and prognosis with unfavorable cytogenetic anomalies. P-glycoprotein expression and multiple cytogenetic anomalies most probably contribute to the resistance to chemotherapy and poor survival characteristic of the patients with M6b (mean survival, 3.15 +/- 4.2 mo) and M6c (mean survival, 10.5 +/- 12.7 mo). Because patients with M6b and M6c have increased numbers of pronormoblasts in their bone marrow and past chemotherapeutic attempts have failed, chemotherapy directed at these cells is appropriate. Additional therapy directed toward the MDR-1 gene and its protein product seems indicated from our findings. PMID:10786807

Mazzella, F M; Kowal-Vern, A; Shrit, M A; Rector, J T; Cotelingam, J D; Schumacher, H R

2000-04-01

300

Extracting expression modules from perturbational gene expression compendia  

PubMed Central

Background Compendia of gene expression profiles under chemical and genetic perturbations constitute an invaluable resource from a systems biology perspective. However, the perturbational nature of such data imposes specific challenges on the computational methods used to analyze them. In particular, traditional clustering algorithms have difficulties in handling one of the prominent features of perturbational compendia, namely partial coexpression relationships between genes. Biclustering methods on the other hand are specifically designed to capture such partial coexpression patterns, but they show a variety of other drawbacks. For instance, some biclustering methods are less suited to identify overlapping biclusters, while others generate highly redundant biclusters. Also, none of the existing biclustering tools takes advantage of the staple of perturbational expression data analysis: the identification of differentially expressed genes. Results We introduce a novel method, called ENIGMA, that addresses some of these issues. ENIGMA leverages differential expression analysis results to extract expression modules from perturbational gene expression data. The core parameters of the ENIGMA clustering procedure are automatically optimized to reduce the redundancy between modules. In contrast to the biclusters produced by most other methods, ENIGMA modules may show internal substructure, i.e. subsets of genes with distinct but significantly related expression patterns. The grouping of these (often functionally) related patterns in one module greatly aids in the biological interpretation of the data. We show that ENIGMA outperforms other methods on artificial datasets, using a quality criterion that, unlike other criteria, can be used for algorithms that generate overlapping clusters and that can be modified to take redundancy between clusters into account. Finally, we apply ENIGMA to the Rosetta compendium of expression profiles for Saccharomyces cerevisiae and we analyze one pheromone response-related module in more detail, demonstrating the potential of ENIGMA to generate detailed predictions. Conclusion It is increasingly recognized that perturbational expression compendia are essential to identify the gene networks underlying cellular function, and efforts to build these for different organisms are currently underway. We show that ENIGMA constitutes a valuable addition to the repertoire of methods to analyze such data.

Maere, Steven; Van Dijck, Patrick; Kuiper, Martin

2008-01-01

301

Gene expression profiling in the developing prostate.  

PubMed

Gene expression profiling has proven to be an effective tool for characterizing genes and molecular pathways operative at key stages of organogenesis. Temporal profiling of RNA transcripts can provide valuable insights into mechanisms of differentiation and lay a foundation for characterizing molecular aspects of development. Descriptive and functional experiments have demonstrated critical roles for androgenic hormones and mesenchymal-epithelial interactions during prostate organogenesis. These studies have uncovered roles for members of several growth factor pathways--primarily using a candidate gene approach--but it is likely that critical molecular determinants of prostate organogenesis remain to be defined. Despite the potential for expression profiling to uncover novel genes and pathways, only a limited number of gene profiling studies have focused on the developing prostate. Among these are studies based on the generation of cDNA libraries and expressed sequence tags (ESTs) and other tag counting strategies such as serial analysis of gene expression (SAGE). Recently, microarray-based assays have provided more comprehensive time-course studies of molecular pathways associated with induction, branching morphogenesis, and secretory differentiation. Several profiling methods have also been used to characterize the influences of androgenic hormones on different tissue compartments including the urogenital sinus mesenchyme (UGM) and urogenital sinus epithelium (UGE) in order to define paracrine mediators operative in early morphogenesis. While hypothesis-driven candidate gene studies remain the gold standard for delineating cause-and-effect relationships dictating the complex biological regulators of the developing prostate, gene profiling provides a valuable adjunct, and is especially useful as an unbiased first step for generating new hypotheses. This review will focus on detailing the methods and results of profiling strategies in the context of normal prostate gland development, with implications for alterations in conserved pathways that may contribute to prostatic diseases. PMID:18462436

Pritchard, Colin C; Nelson, Peter S

2008-05-07

302

Bayesian Networks Learning for Gene Expression Datasets  

Microsoft Academic Search

\\u000a DNA arrays yield a global view of gene expression and can be used to build genetic networks models, in order to study relations\\u000a between genes. Literature proposes Bayesian network as an appropriate tool for develop similar models. In this paper, we exploit\\u000a the contribute of two Bayesian network learning algorithms to generate genetic networks from microarray datasets of experiments\\u000a performed

Giacomo Gamberoni; Evelina Lamma; Fabrizio Riguzzi; Sergio Storari; Stefano Volinia

2005-01-01

303

GATA transcription factors regulate LH? gene expression.  

PubMed

The GATA family of transcription factors are critical determinants of cell differentiation as well as regulation of adult gene expression throughout the reproductive axis. Within the anterior pituitary gland, GATA factors have been shown to increase glycoprotein ?-subunit gene promoter activity; however, nothing has been known about the impact of these factors on expression of the gonadotropin ?-subunits. In this study, we demonstrate expression of both GATA2 and GATA4 in primary mouse gonadotropes and the gonadotrope cell line, L?T2. Based on the transient transfection in fibroblast cells, GATA factors increase LH ?-subunit gene (LH?) promoter activity alone and in synergy with the orphan nuclear receptors steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1). The GATA response was localized to a DNA regulatory region at position -101 in the rat LH? gene promoter which overlaps with a previously described cis-element for pituitary homeobox-1 (Pitx1) and is flanked by two SF-1/LRH-1 regulatory sites. As determined by gel shift, GATA and Pitx1 can compete for binding to this element. Furthermore, mutation analysis revealed a requirement for both the GATA/Pitx1 and the SF-1/LRH-1 cis-elements in order to achieve synergy. These studies identify a novel role for GATA transcription factors in the pituitary and reveal additional molecular mechanisms by which precise modulation of LH? gene expression can be achieved. PMID:21571865

Lo, Ann; Zheng, Weiming; Gong, Yimei; Crochet, John R; Halvorson, Lisa M

2011-07-18

304

[Imprinting genes and it's expression in Arabidopsis].  

PubMed

Genomic imprinting refers to the phenomenon that the expression of a gene copy depends on its parent of origin. The Arabidopsis imprinted FIS (Fertilisation-independent seed) genes, mea, fis2, and fie, play essential roles in the repression of central cell and the regulation of early endosperm development. fis mutants display two phenotypes: autonomous diploid endosperm development when fertilization is absent and un-cellularised endosperm formation when fertilization occurs. The FIS Polycomb protein complex including the above three FIS proteins catalyzes histone H3 K27 tri-methylation on target loci. DME (DEMETER), a DNA glycosylase, and AtMET1 (Methyltransferase1), a DNA methyltransferase, are involved in the regulation of imprinted expression of both mea and fis2. This review summarizes the studies on the Arabidopsis imprinted FIS genes and other related genes. Recent works have shown that the insertion of transposons may affect nearby gene expression, which may be the main driving force behind the evolution of genomic imprinting. This summary covers the achievements on Arabidopsis imprinted genes will provide important information for studies on genomic imprinting in the important crops such as rice and maize. PMID:20650847

Zhang, Hong-Yu; Xu, Pei-Zhou; Yang, Hua; Wu, Xian-Jun

2010-07-01

305

Gene expression profiles relate to SS18/SSX fusion type in synovial sarcoma.  

PubMed

We applied 27k spotted cDNA microarray slides to assess gene expression profiles in 26 samples from 24 patients with synovial sarcomas (SS). The data were analyzed in relation to histopathologic type, cytogenetic aberrations, gene fusion type and development of distant metastases. Supervised analysis based on gene fusion type in 12 SS with SS18/SSX1 and 9 with SS18/SSX2 revealed significant differences in gene expression profiles. Among the discriminators were several genes that have previously been found to be upregulated in SS, including AXL, ZIC2, SPAG7, AGRN, FOXC1, NCAM1 and multiple metallothioneins. Histopathology and degree of cytogenetic complexity did not significantly influence expression, whereas a genetic signature that related to development of metastases could be discerned, albeit with a high false-positive rate. In conclusion, our findings demonstrate differentially expressed genes for the 2 major gene fusion variants in SS, SS18/SSX1 and SS18/SSX2, and thereby suggest that these result in different downstream effects. PMID:16152617

Fernebro, Josefin; Francis, Princy; Edén, Patrik; Borg, Ake; Panagopoulos, Ioannis; Mertens, Fredrik; Vallon-Christersson, Johan; Akerman, Måns; Rydholm, Anders; Bauer, Henrik C F; Mandahl, Nils; Nilbert, Mef

2006-03-01

306

Gene Expression Profiling in Multiple Sclerosis Brain  

PubMed Central

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. Microarray-based comparative gene profiling provides a snapshot of genes underlying a particular condition. Several large scale microarray studies have been conducted using brain tissue from MS patients. In this review, we summarize existing data from different gene expression profiling studies and how they relate to understanding the pathogenesis of MS.

Dutta, Ranjan; Trapp, Bruce D.

2010-01-01

307

Detecting Selective Expression of Genes and Proteins  

PubMed Central

Selective expression of a gene product (mRNA or protein) is a pattern in which the expression is markedly high, or markedly low, in one particular tissue compared with its level in other tissues or sources. We present a computational method for the identification of such patterns. The method combines assessments of the reliability of expression quantitation with a statistical test of expression distribution patterns. The method is applicable to small studies or to data mining of abundance data from expression databases, whether mRNA or protein. Though the method was developed originally for gene-expression analyses, the computational method is, in fact, rather general. It is well suited for the identification of exceptional values in many sorts of intensity data, even noisy data, for which assessments of confidences in the sources of the intensities are available. Moreover, the method is indifferent as to whether the intensities are experimentally or computationally derived. We show details of the general method and examples of computational results on gene abundance data.

Greller, Larry D.; Tobin, Frank L.

1999-01-01

308

Gene Discovery Methods from Large-Scale Gene Expression Data  

NASA Astrophysics Data System (ADS)

Microarrays provide genome-wide gene expression changes. In current analyses, the majority of genes on the array are frequently eliminated for further analysis just in order for computational effort to be affordable. This strategy risks failure to discover whole sets of genes related to a quantitative trait of interest, which is generally controlled by several loci that might be eliminated in current approaches. Here, we describe a high-throughput gene discovery method based on correspondence analysis with a new index for expression ratios [arctan (1/ratio)] and three artificial marker genes. This method allows us to quickly analyze the whole microarray dataset without elimination and discover up/down-regulated genes related to a trait of interest. We employed an example dataset to show the theoretical advantage of this method. We then used the method to identify 88 cancer-related genes from a published microarray data from patients with breast cancer. This method can be easily performed and the result is also visible in three-dimensional viewing software that we have developed. Our method is useful for revaluating the wealth of microarray data available from web-sites.

Shimizu, Akifumi; Yano, Kentaro

2010-01-01

309

Capturing changes in gene expression dynamics by gene set differential coordination analysis  

Microsoft Academic Search

Analyzing gene expression data at the gene set level greatly improves feature extraction and data interpretation. Currently most efforts in gene set analysis are focused on differential expression analysis — finding gene sets whose genes show first-order relationship with the clinical outcome. However the regulation of the biological system is complex, and much of the change in gene expression dynamics

Tianwei Yu; Yun Bai

310

Visualizing gene expression in situ  

NASA Astrophysics Data System (ADS)

Visualizing bacterial cells and describing their responses to the environment are difficult tasks. Their small size is the chief reason for the difficulty, which means that we must often use many millions of cells in a sample in order to determine what the average response of the bacteria is. However, an average response can sometimes mask important events in bacterial physiology, which means that our understanding of these organisms will suffer. We have used a variety of instruments to visualize bacterial cells, all of which tell us something different about the sample. We use a fluorescence activated cell sorter to sort cells based on the fluorescence provided by bioreporter genes, and these can be used to select for particular genetic mutations. Cells can be visualized by epifluorescent microscopy, and sensitive photodetectors can be added that allow us to find a single bacterial cell that is fluorescent or bioluminescent. We have also used standard photomultipliers to examine cell aggregates as field bioreporter microorganisms. Examples of each of these instruments show how our understanding of bacterial physiology has changed with the technology.

Burlage, Robert S.

1999-02-01

311

Visualizing Gene Expression In Situ  

SciTech Connect

Visualizing bacterial cells and describing their responses to the environment are difficult tasks. Their small size is the chief reason for the difficulty, which means that we must often use many millions of cells in a sample in order to determine what the average response of the bacteria is. However, an average response can sometimes mask important events in bacterial physiology, which means that our understanding of these organisms will suffer. We have used a variety of instruments to visualize bacterial cells, all of which tell us something different about the sample. We use a fluorescence activated cell sorter to sort cells based on the fluorescence provided by bioreporter genes, and these can be used to select for particular genetic mutations. Cells can be visualized by epifluorescent microscopy, and sensitive photodetectors can be added that allow us to find a single bacterial cell that is fluorescent or bioluminescent. We have also used standard photomultipliers to examine cell aggregates as field bioreporter microorganisms. Examples of each of these instruments show how our understanding of bacterial physiology has changed with the technology.

Burlage, R.S.

1998-11-02

312

Transgenic control of perforin gene expression  

SciTech Connect

Perforin is a pore-forming effector molecule of CTL and NK cells. To characterize perforin gene expression and its transcriptional control mechanisms in vivo, expression of a cell surface tag, i.e., human CD4, was driven by 5.1 kb of the murin perforin 5{prime} flanking and promoter region in transgenic mice. Six out of seven transgenic lines expressed the perforin-tag hybrid gene at low to intermediate levels, depending on the integration site. Transgene expression occurred in all cells that physiologically are able to express perforin. At the whole organ level, significant amounts of transgenic mRNA and endogenous perforin mRNA were co-expressed in the lymphoid organs, as well as in the lung, the ileum, the oviduct/uterus, and the bone marrow. At the single cell level, the perforin tag was present on NK cells and on CD8{sup +}, as well as on CD4{sup +} cells. Also targeted were Thy-1.2{sup +} {gamma}{delta} T cells, but not Thy-1.2{sup -} {gamma}{delta} T cells, B cells, nor monocytes. During thymic T cell development, transgene expression occurred in double negative (CD4{sup -}CD8{sup -}) thymocytes and was detected at all subsequent stages, but exceeded the expression levels of the endogenous gene in the thymus. In conclusion, the analyzed perforin 5{prime} flanking and promoter region contains important cis-acting sequences that restrict perforin expression to T cells and NK cells, and therefore provides a unique tool for manipulating T cell and/or Nk cell-mediated immune responses in transgenic mice. On the other hand, the normal control of perforin gene expression involves at least one additional negative control mechanism that was not mediated by the transgenic promoter and upstream region. This control restricts perforin gene expression in thymically developing T cells and in most resting peripheral T cells, but can be released upon T cell activation. 43 refs., 7 figs., 1 tab.

Lichtenheld, M.G.; Podack, E.R.; Levy, R.B. [Univ. of Miami, FL (United States)

1995-03-01

313

Structure and expression of fungal calmodulin gene.  

PubMed

I report on the isolation, structural analysis, and in vivo expression patterns of a fungal calmodulin gene. The gene is intronless and encodes a protein of 148 amino acid residues that is 92% homologous with vertebrate calmodulins. Through S1 nuclease transcript mapping, it was determined that the cloned gene (a) is transcribed in vivo, (b) has a 5'-untranslated region of about 400 nucleotides, and (c) has a 3'-untranslated end of about 300 nucleotides. Southern blot hybridization analysis of the genomic DNA and the cloned gene provide evidence for the existence of only one type of calmodulin gene in the organism. The amino acid sequence deduced from the DNA sequence shows that Achlya klebsiana calmodulin has amino acid substitutions that are a mix of those seen in calmodulins from invertebrates such as Drosophila and trypanosome when compared to mammalian calmodulins. Not surprisingly, it has less resemblance to calmodulins from Saccharomyces and Dictyostelium. PMID:2808429

LéJohn, H B

1989-11-15

314

Organization of regionally expressed silkmoth chorion genes.  

PubMed Central

We described the organization of two silkmoth chorion genes, called E1 and E2, whose expression is largely restricted in time to the very late period of choriogenesis and in space to one of two major subpopulations of follicle cells. Using E1 and E2 clone cDNAs as probes, we showed that gene copy numbers per haploid genome remain constant throughout silkmoth development despite major changes in total DNA content per nucleus. Furthermore, gene copy numbers are the same in both cellular regions of the choriogenic follicle despite differences in nuclear size and levels of E gene expression. Southern analysis indicated between two and four copies each for E1 and E2 genes. Analysis of chromosomal clones showed that single copies of E1 and E2 are separated by about 7.5 kilobases and are transcribed from the same DNA strand. Two distinct pairs of cloned E1 and E2 genes were characterized. No other chorion genes were in their immediate vicinity. Images

Hatzopoulos, A K; Regier, J C

1986-01-01

315

Cytogenetic responses to ionizing radiation exposure of human fibroblasts with knocked-down expressions of various DNA damage signaling genes  

NASA Astrophysics Data System (ADS)

Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have demonstrated that genes with up-regulated expression induced by IR may play important roles in DNA damage sensing, cell cycle checkpoint and chromosomal repair, the relationship between the regulation of gene expression by IR and its impact on cytogenetic responses to ionizing radiation has not been systematically studied. Here, the expression of 25 genes selected based on their transcriptional changes in response to IR or from their known DNA repair roles were individually knocked down by siRNA transfection in human fibroblast cells. Chromosome aberrations (CA) and micronuclei (MN) formation were measured as the cytogenetic endpoints. Our results showed that the yields of MN and/or CA formation were significantly increased by suppressed expression of some of the selected genes in DSB and other DNA repair pathways. Knocked-down expression of other genes showed significant impact on cell cycle progression, possibly because of severe impairment of DNA damage repair. Of these 11 genes that affected the cytogenetic response, 9 were up-regulated in the cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulating the biological consequences after IR. Failure to express these IR-responsive genes, such as by gene mutation, could seriously change the outcome of the post IR scenario and lead to carcinogenesis.

Zhang, Ye; Rohde, Larry; Wu, Honglu

316

Conditional Gene Expression in Mycobacterium abscessus  

PubMed Central

Mycobacterium abscessus is an emerging human pathogen responsible for lung infections, skin and soft-tissue infections and disseminated infections in immunocompromised patients. It may exist either as a smooth (S) or rough (R) morphotype, the latter being associated with increased pathogenicity in various models. Genetic tools for homologous recombination and conditional gene expression are desperately needed to allow the study of M. abscessus virulence. However, descriptions of knock-out (KO) mutants in M. abscessus are rare, with only one KO mutant from an S strain described so far. Moreover, of the three major tools developed for homologous recombination in mycobacteria, only the one based on expression of phage recombinases is working. Several conditional gene expression tools have recently been engineered for Mycobacterium tuberculosis and Mycobacterium smegmatis, but none have been tested yet in M. abscessus. Based on previous experience with genetic tools allowing homologous recombination and their failure in M. abscessus, we evaluated the potential interest of a conditional gene expression approach using a system derived from the two repressors system, TetR/PipOFF. After several steps necessary to adapt TetR/PipOFF for M. abscessus, we have shown the efficiency of this system for conditional expression of an essential mycobacterial gene, fadD32. Inhibition of fadD32 was demonstrated for both the S and R isotypes, with marginally better efficiency for the R isotype. Conditional gene expression using the dedicated TetR/PipOFF system vectors developed here is effective in S and R M. abscessus, and may constitute an interesting approach for future genetic studies in this pathogen.

Cortes, Melanie; Singh, Anil Kumar; Gaillard, Jean-Louis; Nassif, Xavier; Herrmann, Jean-Louis

2011-01-01

317

Promoter methylation confers kidney-specific expression of the Klotho gene  

PubMed Central

The aging suppressor geneKlotho is predominantly expressed in the kidney irrespective of species. Because Klotho protein is an essential component of an endocrine axis that regulates renal phosphate handling, the kidney-specific expression is biologically relevant; however, little is known about its underlying mechanisms. Here we provide in vitro and in vivo evidence indicating that promoter methylation restricts the expression of the Klotho gene in the kidney. Based on evolutionary conservation and histone methylation patterns, the region up to ?1200 bp was defined as a major promoter element of the human Klotho gene. This region displayed promoter activity equally in Klotho-expressing and -nonexpressing cells in transient reporter assays, but the activity was reduced to ?20% when the constructs were integrated into the chromatin in the latter. Both endogenous and transfected Klotho promoters were 30–40% methylated in Klotho-nonexpressing cells, but unmethylated in Klotho-expressing renal tubular cells. DNA demethylating agents increased Klotho expression 1.5- to 3.0-fold in nonexpressing cells and restored the activity of silenced reporter constructs. Finally, we demonstrated that a severe hypomorphic allele of Klotho had aberrant CpG methylation in kl/kl mice. These findings might be useful in therapeutic intervention for accelerated aging and several complications caused by Klotho down-regulation.—Azuma, M., Koyama, D., Kikuchi, J., Yoshizawa, H., Thasinas, D., Shiizaki, K., Kuro-o, M., Furukawa, Y., Kusano, E. Promoter methylation confers kidney-specific expression of the Klotho gene.

Azuma, Masahiro; Koyama, Daisuke; Kikuchi, Jiro; Yoshizawa, Hiromichi; Thasinas, Dissayabutra; Shiizaki, Kazuhiro; Kuro-o, Makoto; Furukawa, Yusuke; Kusano, Eiji

2012-01-01

318

Gene expression profiling in human neurodegenerative disease.  

PubMed

Transcriptome study in neurodegenerative disease has advanced considerably in the past 5 years. Increasing scientific rigour and improved analytical tools have led to more-reproducible data. Many transcriptome analysis platforms assay the expression of the entire genome, enabling a complete biological context to be captured. Gene expression profiling (GEP) is, therefore, uniquely placed to discover pathways of disease pathogenesis, potential therapeutic targets, and biomarkers. This Review summarizes microarray human GEP studies in the common neurodegenerative diseases amyotrophic lateral sclerosis (ALS), Parkinson disease (PD) and Alzheimer disease (AD). Several interesting reports have compared pathological gene expression in different patient groups, disease stages and anatomical areas. In all three diseases, GEP has revealed dysregulation of genes related to neuroinflammation. In ALS and PD, gene expression related to RNA splicing and protein turnover is disrupted, and several studies in ALS support involvement of the cytoskeleton. GEP studies have implicated the ubiquitin-proteasome system in PD pathogenesis, and have provided evidence of mitochondrial dysfunction in PD and AD. Lastly, in AD, a possible role for dysregulation of intracellular signalling pathways, including calcium signalling, has been highlighted. This Review also provides a discussion of methodological considerations in microarray sample preparation and data analysis. PMID:22890216

Cooper-Knock, Johnathan; Kirby, Janine; Ferraiuolo, Laura; Heath, Paul R; Rattray, Magnus; Shaw, Pamela J

2012-08-14

319

Regulation of Pituitary Gene Expression by Adrenalectomy  

Microsoft Academic Search

Excessive secretion of adrenal hormones, such as glucocorticoid and mineralocorticoid, leads to metabolic syndrome, including insulin resistance, obesity, and hypertension. These metabolic abnormalities are ameliorated by adrenalectomy (ADX). To identify pituitary mediators for ADX-induced physiological alterations, such as weight loss and hypotension, we investigated the effect of ADX on the pituitary transcriptome using serial analysis of gene expression (SAGE). SAGE

Yuichiro Nishida; Mayumi Yoshioka; Chester A. Ray; Carl Bolduc; Hiroaki Tanaka; Jonny St-Amand

2009-01-01

320

The cellular organization of gene expression  

Microsoft Academic Search

Recent cell biological observations have provided new insights into how transcription, pre-mRNA splicing and 3? processing are organized and coordinated with each other in the mammalian cell nucleus. Morphological observations are supported by biochemical evidence that suggests physical interactions between components of the transcription and RNA processing machineries. A working model of the cellular organization of gene expression is now

Tom Misteli; David L Spector

1998-01-01

321

Nutrient Regulation of Gene Expression 1  

Microsoft Academic Search

This paper reviews recent evidence for the roles and mechanisms of action of energy substrates in the mediation of abrupt changes in gene expression of key enzymes involved in regulation of hepatic fatty acid oxidation and ketogenesis during the perinatal transition, and of lipogenesis in adipose and liver during the weaning transition in young rats. Rapid and marked postnatal increases

Jean Girard; Florence Chatelain; Carina Prip-Buus; Fabienne Foufelle; Pascal Ferr

322

Repeatability of published microarray gene expression analyses  

Microsoft Academic Search

Given the complexity of microarray-based gene expression studies, guidelines encourage transparent design and public data availability. Several journals require public data deposition and several public databases exist. However, not all data are publicly available, and even when available, it is unknown whether the published results are reproducible by independent scientists. Here we evaluated the replication of data analyses in 18

David B Allison; Catherine A Ball; Issa Coulibaly; Xiangqin Cui; Aedín C Culhane; Mario Falchi; Cesare Furlanello; Giuseppe Jurman; Jon Mangion; Tapan Mehta; Michael Nitzberg; Grier P Page; Enrico Petretto; Vera van Noort

2008-01-01

323

Current Gene Expression Studies in Esophageal Carcinoma  

PubMed Central

Esophageal carcinoma is one of the deadliest cancers with highly aggressive potency, ranking as the sixth most common cancer among males and ninth most common cancer among females globally. Due to metastasis and invasion of surrounding tissues in early stage, the 5-year overall survival rate (14%) of esophageal cancer remains poor, even in comparison with the dismal survival rates (4%) from the 1970s. Numerous genes and proteins with abnormal expression and function involve in the pathogenesis of esophageal cancer, but the concrete process remains unclear. Microarray technique has been applied to investigating esophageal cancer. Many gene expression studies have been undertaken to look at the specific patterns of gene transcript levels in esophageal cancer. Human tissues and cell lines were used in these geneprofiling studies and a very valuable and interesting set of data has resulted from various microarray experiments. These expression studies have provided increased understanding of the complex pathological mechanisms involved in esophageal cancer. The eventual goal of microarray is to discover new markers for therapy and to customize therapy based on an individual tumor genetic composition. This review summarized the current state of gene expression profile studies in esophageal cancer.

Guo, Wei; Jiang, Yao-Guang

2009-01-01

324

Gene Expression Patterns in Human Placenta  

Microsoft Academic Search

The placenta is the principal metabolic, respiratory, excretory, and endocrine organ for the first 9 months of fetal life. Its role in fetal and maternal physiology is remarkably diverse. Because of the central role that the placenta has in fetal and maternal physiology and development, the possibility that variation in placental gene expression patterns might be linked to important abnormalities

Ruchira Sood; James L. Zehnder; Maurice L. Druzin; Patrick O. Brown

2006-01-01

325

Gene expression patterns in human placenta  

Microsoft Academic Search

The placenta is the principal metabolic, respiratory, excretory, and endocrine organ for the first 9 months of fetal life. Its role in fetal and maternal physiology is remarkably diverse. Because of the central role that the placenta has in fetal and maternal physiology and development, the possibility that variation in placental gene expression patterns might be linked to important abnormalities

Ruchira Sood; James L. Zehnder; Maurice L. Druzin; Patrick O. Brown

2006-01-01

326

Aberrant antigenic expression in extranodal NK/T-cell lymphoma: a multi-parameter study from Thailand  

PubMed Central

Background Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is not common worldwide, but it is the most common T- and NK-cell lymphomas in many Asian countries. Immunophenotypic profiles were studied based on limited series. The authors, therefore, studied on ENKTL according to characterize immunophenotypic profiles as well as the distribution of EBV subtype and LMP-1 gene deletion. Methods By using tissue microarray (TMA), immunohistochemical study and EBV encoded RNA (EBER) in situ hybridization were performed. T-cell receptor (TCR) gene rearrangement, EBV subtyping, and LMP-1 gene deletion were studied on the available cases. Results There were 22 cases eligible for TMA. ENKTL were positive for CD3 (91%), CD5 (9%), CD7 (32%), CD4 (14%), CD56 (82%), TIA-1 (100%), granzyme B (95%), perforin (86%), CD45 (83%), CD30 (75%), Oct2 (25%), and IRF4/MUM1 (33%). None of them was positive for ?F1, CD8, or CD57. TCR gene rearrangement was negative in all 18 tested cases. EBV was subtype A in all 15 tested cases, with 87% deleted LMP-1 gene. Cases lacking perforin expression demonstrated a significantly poorer survival outcome (p = 0.008). Conclusions The present study demonstrated TIA-1 and EBER as the two most sensitive markers. There were a few CD3 and/or CD56 negative cases noted. Interestingly, losses of CD45 and/or CD7 were not uncommon while Oct2 and IRF4/MUM1 could be positive in a subset of cases. Based on the present study in conjunction with the literature review, determination of PCR-based TCR gene rearrangement analysis might not be a useful technique for making diagnosis of ENKTL.

2011-01-01

327

Expression of mouse metallothionein genes in tobacco  

SciTech Connect

We have expressed a mouse metallothionein (NT) gene in tobacco under control of the cauliflower mosaic virus (CaMV) 35S promoter and a pea ribulose-1,5-bisphosphate carboxylase small subunit (rbcS) gene promoter. Seedlings in which MT gene expression is driven by the 35S promoter are resistant to toxic levels of cadmium. Mature plants carrying the 35S-MT gene accumulate less Cd in their leaves when exposed to low levels of Cd in laboratory growth conditions. Plants with the rbcS-MT construction express this gene in a light-regulated and tissue-specific manner, as expected. Moreover, the MT levels in leaves in these plants are about 20% of those seen in 35S-MT plants. These plants are currently being tested for Cd resistance. In addition, a small field evaluation of 35S-MT lines for Cd levels is being evaluated. These experiments will address the possibility of using MTs to alter Cd levels in crop species.

Maiti, I.B.; Yeargan, R.; Wagner, G.J.; Hunt, A.G. (Univ. of Kentucky, Lexington (USA))

1990-05-01

328

Nanosecond electric pulse effects on gene expression.  

PubMed

Gene electrotransfection using micro- or millisecond electric pulses is a well-established method for safe gene transfer. For efficient transfection, plasmid DNA has to reach the nucleus. Shorter, high-intensity nanosecond electric pulses (nsEPs) affect internal cell membranes and may contribute to an increased uptake of plasmid by the nucleus. In our study, nsEPs were applied to Chinese hamster ovary (CHO) cells after classical gene electrotransfer, using micro- or millisecond pulses with a plasmid coding the green fluorescent protein (GFP). Time gaps between classical gene electrotransfer and nsEPs were varied (0.5, 2, 6 and 24 h) and three different nsEP parameters were used: 18 ns-10 kV/cm, 10 ns-40 kV/cm and 15 ns-60 kV/cm. Results analyzed by either fluorescence microscopy or flow cytometry showed that neither the percentage of electrotransfected cells nor the amount of GFP expressed was increased by nsEP. All nsEP parameters also had no effects on GFP fluorescence intensity of human colorectal tumor cells (HCT-116) with constitutive expression of GFP. We thus conclude that nsEPs have no major contribution to gene electrotransfer in CHO cells and no effect on constitutive GFP expression in HCT-116 cells. PMID:23831956

Chopinet, Louise; Batista-Napotnik, Tina; Montigny, Audrey; Rebersek, Matej; Teissié, Justin; Rols, Marie-Pierre; Miklav?i?, Damijan

2013-07-06

329

Epigenetic Regulation of Gene Expression in Keratinocytes  

PubMed Central

Nucleus is a complex and highly compartmentalized organelle, which organization undergoes major changes during cell differentiation allowing cells to become specialized and fulfill their functions.During terminal differentiation of the epidermal keratinocytes, nucleus undergoes programmed transformation from active status, associated with execution of the genetic programs of cornification and epidermal barrier formation, to fully inactive condition and becomes a part of the keratinized cells of the cornified layer. Tremendous progress achieved within the last two decades in understanding the biology of the nucleus and epigenetic mechanisms controlling gene expression allowed defining several levels in the regulation of cell differentiation-associated gene expression programs, including an accessibility of the gene regulatory regions to DNA-protein interactions, covalent DNA and histone modifications and ATP-dependent chromatin remodeling, as well as higher-order chromatin remodeling and nuclear compartmentalization of the genes and transcription machinery. Here, we integrate our current knowledge of the mechanisms controlling gene expression during terminal keratinocyte differentiation with distinct levels of chromatin organization and remodeling. We also propose the directions to further explore the role of epigenetic mechanisms and their interactions with other regulatory systems in the control of keratinocyte differentiation in normal and diseased skin.

Botchkarev, Vladimir A.; Gdula, Michal R.; Mardaryev, Andrei N.; Sharov, Andrei A.; Fessing, Michael Y.

2012-01-01

330

Cyclin G1 and cyclin G2 are expressed in the periimplantation mouse uterus in a cell-specific and progesterone-dependent manner: evidence for aberrant regulation with Hoxa-10 deficiency.  

PubMed

Because uterine cell-specific proliferation, differentiation, and apoptosis are differentially regulated during the periimplantation period, we speculated that negative cell cycle regulators are also operative in the uterus during this period. This prompted us to examine the roles of two negative growth-regulatory genes, cyclin G1 and cyclin G2, in the periimplantation mouse uterus. We show that cyclin G1 and cyclin G2 genes are differentially regulated in the uterus during this period (d 1-8 of pregnancy) in a spatiotemporal manner. The results suggest that cyclin G1 is primarily associated with epithelial cell differentiation before implantation and stromal cell proliferation and differentiation during decidualization, whereas cyclin G2 is associated with terminal differentiation and apoptosis of the luminal epithelial and stromal cells at the site of blastocyst after implantation. Pharmacological and genetic studies provide evidence that the expression of cyclin G1, not cyclin G2, is regulated by progesterone via its nuclear receptor. Furthermore, the expression of these genes is aberrantly up-regulated in homeo box A-10 mutant uteri, suggesting that cyclin G1 and cyclin G2 genes act as downstream targets of homeobox A-10 and negatively impact uterine cell proliferation. Collectively, our present and previous studies suggest that negative cell cycle regulators collaborate with growth-promoting regulators in regulating uterine cell-specific proliferation, differentiation, and apoptosis relevant to implantation and decidualization. PMID:15661853

Yue, Limin; Daikoku, Takiko; Hou, Xiaonan; Li, Meiling; Wang, Haibin; Nojima, Hiroshi; Dey, Sudhansu K; Das, Sanjoy K

2005-01-20

331

Control mechanisms of plastid gene expression  

SciTech Connect

Plastid DNAs of higher plants contain approximately 150 genes that encode RNAs and proteins for genetic and photosynthetic functions of the organelle. Results published in the last few years illustrate that the spatial and temporal expression of these plastid genes is regulated, in part, at the transcriptional level, but that developmentally controlled changes in mRNA stability, translational activity, and protein phosphorylation also have an important role in the control of plastid functions. This comprehensive review summarizes and discusses the mechanisms by which regulation of gene expression is exerted at the transcriptional and post-transcriptional levels. It provides an overview of our current knowledge, but also emphasizes areas that are controversial and in which information on regulatory mechanisms is still incomplete. 455 refs., 3 figs., 3 tabs.

Gruissem, W.; Tonkyn, J.C. [Univ. of California, Berkeley, CA (United States)

1993-12-31

332

Identifying in-trans process associated genes in breast cancer by integrated analysis of copy number and expression data.  

PubMed

Genomic copy number alterations are common in cancer. Finding the genes causally implicated in oncogenesis is challenging because the gain or loss of a chromosomal region may affect a few key driver genes and many passengers. Integrative analyses have opened new vistas for addressing this issue. One approach is to identify genes with frequent copy number alterations and corresponding changes in expression. Several methods also analyse effects of transcriptional changes on known pathways. Here, we propose a method that analyses in-cis correlated genes for evidence of in-trans association to biological processes, with no bias towards processes of a particular type or function. The method aims to identify cis-regulated genes for which the expression correlation to other genes provides further evidence of a network-perturbing role in cancer. The proposed unsupervised approach involves a sequence of statistical tests to systematically narrow down the list of relevant genes, based on integrative analysis of copy number and gene expression data. A novel adjustment method handles confounding effects of co-occurring copy number aberrations, potentially a large source of false positives in such studies. Applying the method to whole-genome copy number and expression data from 100 primary breast carcinomas, 6373 genes were identified as commonly aberrant, 578 were highly in-cis correlated, and 56 were in addition associated in-trans to biological processes. Among these in-trans process associated and cis-correlated (iPAC) genes, 28% have previously been reported as breast cancer associated, and 64% as cancer associated. By combining statistical evidence from three separate subanalyses that focus respectively on copy number, gene expression and the combination of the two, the proposed method identifies several known and novel cancer driver candidates. Validation in an independent data set supports the conclusion that the method identifies genes implicated in cancer. PMID:23382830

Aure, Miriam Ragle; Steinfeld, Israel; Baumbusch, Lars Oliver; Liestøl, Knut; Lipson, Doron; Nyberg, Sandra; Naume, Bjørn; Sahlberg, Kristine Kleivi; Kristensen, Vessela N; Børresen-Dale, Anne-Lise; Lingjærde, Ole Christian; Yakhini, Zohar

2013-01-30

333

Mining Fuzzy Association Patterns in Gene Expression Databases  

Microsoft Academic Search

With the development of microarray technologies, large amount of gene expressions can be obtained at the same time in high-throughput manner. How to analyze the associations among genes from the gene expression database has become an important issue in recent years. However, it has not been explored concerning the fuzzy concepts of gene expression category in terms like \\

Vincent S. Tseng; Yen-Hsu Chen; Chun-Hao Chen; J. W. Shin

2006-01-01

334

Two FCA-Based Methods for Mining Gene Expression Data  

Microsoft Academic Search

Gene expression data are numerical and describe the level of expression of genes in different situations, thus featuring behaviour of the genes. Two methods based on FCA (Formal Concept Analysis) are considered for clustering gene expression data. The first one is based on interordinal scaling and can be realized using standard FCA algorithms. The second method is based on pattern

Mehdi Kaytoue-uberall; Sébastien Duplessis; Sergei O. Kuznetsov; Amedeo Napoli

2009-01-01

335

Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease  

Microsoft Academic Search

Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes.

Weiliang Qiu; Michael H. Cho; John H. Riley; Wayne H. Anderson; Dave Singh; Per Bakke; Amund Gulsvik; Augusto A. Litonjua; David A. Lomas; James D. Crapo; Terri H. Beaty; Bartolome R. Celli; Stephen Rennard; Ruth Tal-Singer; Steven M. Fox; Edwin K. Silverman; Craig P. Hersh; Mark M. Wurfel

2011-01-01

336

The Role of Fatty Acids in Gene Expression: Health Implications  

Microsoft Academic Search

The effect of nutrients on gene expression is an area of considerable interest as the number of genes coding for key regulatory proteins in metabolic pathways is investigated. This paper presents an overview of the role of omega-6 and omega-3 fatty acids on the expression of genes involved in lipogenesis, glycolysis, glucose transporters, inflammation, early gene expression, and vascular cell

Artemis P. Simopoulos

1996-01-01

337

Expression of Bovine Prochymosin Gene in Lactococcus Lactis  

Microsoft Academic Search

Bovine prochymosin (bPC) could act to initiate milk clotting. NICE (Nisin Controlled gene Expression system) in lactococcus lactis was one of the most successful and widely using Grampositive gene expression systems. It was composed by six experiments in this study. They are cloning of bovine preprochymosin gene, electrotransformation in lactococcus lactis, construction of expression vector of bPC gene, detection of

Daqing Sun; Xingguang Qu; Xiyan Han; Yuhan Bi; Guanghui Zhang; Bin Li; Lanxia Qin; Yujun Jiang

2009-01-01

338

From cryptic chromosomal lesions to pathologically relevant genes: integration of SNP-array with gene expression profiling in myelodysplastic syndrome with normal karyotype.  

PubMed

Myelodysplastic syndrome (MDS), a clonal disorder originating from hematopoietic stem cell, is characterized by a progressive character often leading to transformation to acute myeloid leukemia. We used single nucleotide polymorphism arrays (SNP-A) to identify previously cryptic chromosomal abnormalities such as copy number alterations and uniparental disomies (UPD) in cytogenetically normal MDS. In the aberrant regions, we attempted to localize candidate genes with potential relevance to the disease. Using SNP-A, we analyzed peripheral blood granulocytes from 37 MDS patients. The analysis identified 13 cryptic chromosomal defects in 10 patients (27%). Four UPD (affecting chromosomes 3q, 7q, 17q, and 20p), 5 deletions and 4 duplications were detected. Gene expression data measured on CD34+ cells were available for 4 patients with and 6 patients without SNP-A lesions. We performed an integrative analysis of genotyping and gene expression microarrays and found several genes with an altered expression located in the aberrant regions. The expression microarrays suggested BMP2 and TRIB3 located in 20p UPD as potential candidate genes contributing to MDS. We showed that the genome-wide integrative approach is beneficial to the comprehension of molecular backgrounds of diseases with incompletely understood etiopathology. PMID:22250017

Merkerova, Michaela Dostalova; Bystricka, Dagmar; Belickova, Monika; Krejcik, Zdenek; Zemanova, Zuzana; Polak, Jaroslav; Hajkova, Hana; Brezinova, Jana; Michalova, Kyra; Cermak, Jaroslav

2012-01-17

339

Cancer Outlier Analysis Based on Mixture Modeling of Gene Expression Data  

PubMed Central

Molecular heterogeneity of cancer, partially caused by various chromosomal aberrations or gene mutations, can yield substantial heterogeneity in gene expression profile in cancer samples. To detect cancer-related genes which are active only in a subset of cancer samples or cancer outliers, several methods have been proposed in the context of multiple testing. Such cancer outlier analyses will generally suffer from a serious lack of power, compared with the standard multiple testing setting where common activation of genes across all cancer samples is supposed. In this paper, we consider information sharing across genes and cancer samples, via a parametric normal mixture modeling of gene expression levels of cancer samples across genes after a standardization using the reference, normal sample data. A gene-based statistic for gene selection is developed on the basis of a posterior probability of cancer outlier for each cancer sample. Some efficiency improvement by using our method was demonstrated, even under settings with misspecified, heavy-tailed t-distributions. An application to a real dataset from hematologic malignancies is provided.

Matsui, Shigeyuki

2013-01-01

340

Cancer outlier analysis based on mixture modeling of gene expression data.  

PubMed

Molecular heterogeneity of cancer, partially caused by various chromosomal aberrations or gene mutations, can yield substantial heterogeneity in gene expression profile in cancer samples. To detect cancer-related genes which are active only in a subset of cancer samples or cancer outliers, several methods have been proposed in the context of multiple testing. Such cancer outlier analyses will generally suffer from a serious lack of power, compared with the standard multiple testing setting where common activation of genes across all cancer samples is supposed. In this paper, we consider information sharing across genes and cancer samples, via a parametric normal mixture modeling of gene expression levels of cancer samples across genes after a standardization using the reference, normal sample data. A gene-based statistic for gene selection is developed on the basis of a posterior probability of cancer outlier for each cancer sample. Some efficiency improvement by using our method was demonstrated, even under settings with misspecified, heavy-tailed t-distributions. An application to a real dataset from hematologic malignancies is provided. PMID:23690879

Mori, Keita; Oura, Tomonori; Noma, Hisashi; Matsui, Shigeyuki

2013-04-10

341

Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations.  

PubMed

Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene-gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results. PMID:23921631

Yaari, Gur; Bolen, Christopher R; Thakar, Juilee; Kleinstein, Steven H

2013-08-05

342

Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations  

PubMed Central

Enrichment analysis of gene sets is a popular approach that provides a functional interpretation of genome-wide expression data. Existing tests are affected by inter-gene correlations, resulting in a high Type I error. The most widely used test, Gene Set Enrichment Analysis, relies on computationally intensive permutations of sample labels to generate a null distribution that preserves gene–gene correlations. A more recent approach, CAMERA, attempts to correct for these correlations by estimating a variance inflation factor directly from the data. Although these methods generate P-values for detecting gene set activity, they are unable to produce confidence intervals or allow for post hoc comparisons. We have developed a new computational framework for Quantitative Set Analysis of Gene Expression (QuSAGE). QuSAGE accounts for inter-gene correlations, improves the estimation of the variance inflation factor and, rather than evaluating the deviation from a null hypothesis with a P-value, it quantifies gene-set activity with a complete probability density function. From this probability density function, P-values and confidence intervals can be extracted and post hoc analysis can be carried out while maintaining statistical traceability. Compared with Gene Set Enrichment Analysis and CAMERA, QuSAGE exhibits better sensitivity and specificity on real data profiling the response to interferon therapy (in chronic Hepatitis C virus patients) and Influenza A virus infection. QuSAGE is available as an R package, which includes the core functions for the method as well as functions to plot and visualize the results.

Yaari, Gur; Bolen, Christopher R.; Thakar, Juilee; Kleinstein, Steven H.

2013-01-01

343

From gene expressions to genetic networks  

NASA Astrophysics Data System (ADS)

A method based on the principle of entropy maximization is used to identify the gene interaction network with the highest probability of giving rise to experimentally observed transcript profiles [1]. In its simplest form, the method yields the pairwise gene interaction network, but it can also be extended to deduce higher order correlations. Analysis of microarray data from genes in Saccharomyces cerevisiae chemostat cultures exhibiting energy metabollic oscillations identifies a gene interaction network that reflects the intracellular communication pathways. These pathways adjust cellular metabolic activity and cell division to the limiting nutrient conditions that trigger metabolic oscillations. The success of the present approach in extracting meaningful genetic connections suggests that the maximum entropy principle is a useful concept for understanding living systems, as it is for other complex, nonequilibrium systems. The time-dependent behavior of the genetic network is found to involve only a few fundamental modes [2,3]. [4pt] REFERENCES:[0pt] [1] T. R. Lezon, J. R. Banavar, M. Cieplak, A. Maritan, and N. Fedoroff, Using the principle of entropy maximization to infer genetic interaction networks from gene expression patterns, Proc. Natl. Acad. Sci. (USA) 103, 19033-19038 (2006) [0pt] [2] N. S. Holter, M. Mitra, A. Maritan, M. Cieplak, J. R. Banavar, and N. V. Fedoroff, Fundamental patterns underlying gene expression profiles: simplicity from complexity, Proc. Natl. Acad. Sci. USA 97, 8409-8414 (2000) [0pt] [3] N. S. Holter, A. Maritan, M. Cieplak, N. V. Fedoroff, and J. R. Banavar, Dynamic modeling of gene expression data, Proc. Natl. Acad. Sci. USA 98, 1693-1698 (2001)

Cieplak, Marek

2009-03-01

344

Aberrant methylation and loss of CADM2 tumor suppressor expression is associated with human renal cell carcinoma tumor progression.  

PubMed

Cell adhesion molecules (CADMs) comprise a protein family whose functions include maintenance of cell polarity and tumor suppression. In this report, we show that the CADM2 gene is repressed in human clear renal cell carcinoma by DNA promoter hypermethylation and/or loss of heterozygosity. Moreover, the loss of CADM2 expression is associated with a higher tumor pathology stage (p<0.05). The re-expression of CADM2 in the renal cancer cell line 786-O significantly suppressed tumor cell growth in vitro and in mouse xenografts by a G1 phase cell cycle arrest and the induction of apoptosis. Lentivirus-mediated CADM2 expression also significantly suppressed cancer cell anchorage-independent growth and invasion. Furthermore, the inhibition of endogenous CADM2 expression using siRNAs induced a tumorigenic phenotype in polarized non-tumorigenic MDCK cells. Thus, we conclude that CADM2 functions as a novel tumor suppressor and may serve as a potential therapeutic target for human renal cell carcinoma. PMID:23643812

He, Wei; Li, Xuesong; Xu, Shuping; Ai, Junkui; Gong, Yanqing; Gregg, Jennifer L; Guan, Ruili; Qiu, Wei; Xin, Dianqi; Gingrich, Jeffrey R; Guo, Yinglu; Chang, Guimin

2013-05-03

345

Regulation of methane genes and genome expression  

SciTech Connect

At the start of this project, it was known that methanogens were Archaeabacteria (now Archaea) and were therefore predicted to have gene expression and regulatory systems different from Bacteria, but few of the molecular biology details were established. The goals were then to establish the structures and organizations of genes in methanogens, and to develop the genetic technologies needed to investigate and dissect methanogen gene expression and regulation in vivo. By cloning and sequencing, we established the gene and operon structures of all of the “methane” genes that encode the enzymes that catalyze methane biosynthesis from carbon dioxide and hydrogen. This work identified unique sequences in the methane gene that we designated mcrA, that encodes the largest subunit of methyl-coenzyme M reductase, that could be used to identify methanogen DNA and establish methanogen phylogenetic relationships. McrA sequences are now the accepted standard and used extensively as hybridization probes to identify and quantify methanogens in environmental research. With the methane genes in hand, we used northern blot and then later whole-genome microarray hybridization analyses to establish how growth phase and substrate availability regulated methane gene expression in Methanobacterium thermautotrophicus ?H (now Methanothermobacter thermautotrophicus). Isoenzymes or pairs of functionally equivalent enzymes catalyze several steps in the hydrogen-dependent reduction of carbon dioxide to methane. We established that hydrogen availability determine which of these pairs of methane genes is expressed and therefore which of the alternative enzymes is employed to catalyze methane biosynthesis under different environmental conditions. As were unable to establish a reliable genetic system for M. thermautotrophicus, we developed in vitro transcription as an alternative system to investigate methanogen gene expression and regulation. This led to the discovery that an archaeal protein, designated TFE, that had sequences in common with the eukaryotic general transcription factor TFIIE, stimulated archaeal transcription initiation and that the archaeal TATA-box binding protein (TBP) remained attached to the promoter region whereas the transcription factor TFB dissociated from the template DNA following initiation. DNA sequences that directed the localized assembly of archaeal histones into archaeal nucleosomes were identified, and we established that transcription by an archaeal RNA polymerase was slowed but not blocked by archaeal nucleosomes. We developed a new protocol to purify archaeal RNA polymerases and with this enzyme and additional improvements to the in vitro transcription system, we established the template requirements for archaeal transcription termination, investigated the activities of proteins predicted to be methane gene regulators, and established how TrpY, a novel archaeal regulator of expression of the tryptophan biosynthetic operon functions in M. thermautotrophicus. This also resulted in the discovery that almost all M. thermautotrophicus mutants isolated as spontaneously resistant to 5-methyl tryptophan (5MTR) had mutations in trpY and were therefore 5MTR through de-repressed trp operon expression. This established a very simple, practical procedure to determine and quantify the DNA sequence changes that result from exposure of this Archaeon to any experimental mutagenesis protocol. Following the discovery that the Thermococcus kodakaraensis was amenable to genetic manipulation, we established this technology at OSU and subsequently added plasmid expression, a reporter system and additional genetic selections to the T. kodakaraensis genetic toolbox. We established that transcription and translation are coupled in this Archaeon, and by combining in vitro transcription and in vivo genetics, we documented that both TFB1 and TFB2 support transcription initiation in T. kodakaraensis. We quantified the roles of ribosome binding sequences and alternative initiation codons in translation initiation, established that polarity e

John N. Reeve

2009-09-09

346

Cell line OCI\\/AML3 bears exon-12 NPM gene mutation-A and cytoplasmic expression of nucleophosmin  

Microsoft Academic Search

We recently identified a new acute myeloid leukemia (AML) subtype characterized by mutations at exon-12 of the nucleophosmin (NPM) gene and aberrant cytoplasmic expression of NPM protein (NPMc+). NPMc+ AML accounts for about 35% of adult AML and it is associated with normal karyotype, wide morphological spectrum, CD34-negativity, high frequency of FLT3-ITD mutations and good response to induction therapy. In

H Quentmeier; M P Martelli; W G Dirks; N Bolli; A Liso; R A F MacLeod; I Nicoletti; R Mannucci; A Pucciarini; B Bigerna; M F Martelli; C Mecucci; H G Drexler; B Falini

2005-01-01

347

Disordered expression of HOX genes in human non-small cell lung cancer.  

PubMed

We hypothesized that the disordered tissue architecture in cancer results from the cells executing the program designed during ontogeny in a spatio-temporally inappropriate manner. HOX genes are known as master regulators of embryonic morphogenesis, and encode transcription factors which regulate the transcription of the downstream genes to realize the program of body plan. In this study, we quantified the expression levels of 39 HOX genes in 41 human non-small cell lung cancer (non-SCLC) and non-cancerous lung tissues by a comprehensive analysis system based on the real-time RT-PCR method. We found that the expression levels of HOXA1, A5, A10 and C6 in squamous cell carcinoma tissues (and HOXA5 and A10 in adenocarcinoma tissues) were significantly higher than those in the non-cancerous tissues. Comparison of HOX gene expressions between adenocarcinoma and squamous cell carcinoma tissues showed higher expressions of HOXA1, D9, D10 and D11 in squamous cell carcinoma tissues than in adenocarcinoma tissues. Immunohistochemical analysis revealed that HOXA5 and A10 proteins were localized in the cytoplasm of tumor cells in both adenocarcinoma and squamous cell carcinoma tissues. These results suggest that the disordered patterns of HOX gene expressions were involved not only in the development of non-SCLC but also in the histologically aberrant diversity such as adenocarcinoma and squamous cell carcinoma. PMID:16525661

Abe, Motoki; Hamada, Jun-Ichi; Takahashi, Osamu; Takahashi, Yoko; Tada, Mitsuhiro; Miyamoto, Masaki; Morikawa, Toshiaki; Kondo, Satoshi; Moriuchi, Tetsuya

2006-04-01

348

Undifferentiated embryonic cell transcription factor 1 regulates ESC chromatin organization and gene expression.  

PubMed

Previous reports showed that embryonic stem (ES) cells contain hyperdynamic and globally transcribed chromatin-properties that are important for ES cell pluripotency and differentiation. Here, we demonstrate a role for undifferentiated embryonic cell transcription factor 1 (UTF1) in regulating ES cell chromatin structure. Using chromatin immunoprecipitation-on-chip analysis, we identified >1,700 UTF1 target genes that significantly overlap with previously identified Nanog, Oct4, Klf-4, c-Myc, and Rex1 targets. Gene expression profiling showed that UTF1 knock down results in increased expression of a large set of genes, including a significant number of UTF1 targets. UTF1 knock down (KD) ES cells are, irrespective of the increased expression of several self-renewal genes, Leukemia inhibitory factor (LIF) dependent. However, UTF1 KD ES cells are perturbed in their differentiation in response to dimethyl sulfoxide (DMSO) or after LIF withdrawal and display increased colony formation. UTF1 KD ES cells display extensive chromatin decondensation, reflected by a dramatic increase in nucleosome release on micrococcal nuclease (MNase) treatment and enhanced MNase sensitivity of UTF1 target genes in UTF1 KD ES cells. Summarizing, our data show that UTF1 is a key chromatin component in ES cells, preventing ES cell chromatin decondensation, and aberrant gene expression; both essential for proper initiation of lineage-specific differentiation of ES cells. PMID:20715181

Kooistra, Susanne M; van den Boom, Vincent; Thummer, Rajkumar P; Johannes, Frank; Wardenaar, René; Tesson, Bruno M; Veenhoff, Liesbeth M; Fusetti, Fabrizia; O'Neill, Laura P; Turner, Bryan M; de Haan, Gerald; Eggen, Bart J L

2010-10-01

349

Analysis of differential gene expression by bead-based fiber-optic array in growth-hormone-secreting pituitary adenomas  

PubMed Central

Growth-hormone-secreting pituitary adenomas (GHomas) account for approximately 20% of all pituitary neoplasms. However, the pathogenesis of GHomas remains to be elucidated. To explore the possible pathogenesis of GHomas, we used bead-based fiber-optic arrays to examine the gene expression in five GHomas and compared them to three healthy pituitaries. Four differentially expressed genes were chosen randomly for validation by quantitative real-time reverse transcription-polymerase chain reaction. We then performed pathway analysis on the identified differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Array analysis showed significant increases in the expression of 353 genes and 206 expressed sequence tags (ESTs) and decreases in 565 genes and 29 ESTs. Bioinformatic analysis showed that the genes HIGD1B, HOXB2, ANGPT2, HPGD and BTG2 may play an important role in the tumorigenesis and progression of GHomas. Pathway analysis showed that the wingless-type signaling pathway and extracellular-matrix receptor interactions may play a key role in the tumorigenesis and progression of GHomas. Our data suggested that there are numerous aberrantly expressed genes and pathways involved in the pathogenesis of GHomas. Bead-based fiber-optic arrays combined with pathway analysis of differentially expressed genes appear to be a valid method for investigating the pathogenesis of tumors.

JIANG, ZHIQUAN; GUI, SONGBO; ZHANG, YAZHUO

2010-01-01

350

Evolutionary rate and gene expression across different brain regions  

Microsoft Academic Search

ABSTRACT: BACKGROUND: The evolutionary rate of a protein is a basic measure of evolution at the molecular level. Previous studies have shown that genes expressed in the brain have significantly lower evolutionary rates than those expressed in somatic tissues. RESULTS: We study the evolutionary rates of genes expressed in 21 different human brain regions. We find that genes highly expressed

Tamir Tuller; Martin Kupiec; Eytan Ruppin

2008-01-01

351

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma.  

PubMed

Five osteosarcoma (OS) cell lines, 37 OS tumors and 9 corresponding non-neoplastic samples were genotyped by Affymetrix 10 K 2.0 SNP array. Regions of high level amplification and homozygous deletion were identified and validated by quantitative PCR and FISH. Certain recurrent cytogenetic alterations were more frequent in recurrent/metastatic than in primary OS. These included deletion of 6q14.1, 6q16.2-q22.31, and 8p23.2-p12, amplification of 8q21.12, 8q22.3-q24.3 and 17p12, and loss of heterozygosity (LOH) at 2q24.3-q31.2, 5q11.2, 6p21.31-p21.1, 6q14.1-q16.2, 8p22-p12, 9q22.1, 10q21.1-q22.1, 10q23.31-q24.1, 12q15-q21.1 and 21q21.2-q21.3. Most of the LOH calls were associated with deletion, but a subset of them was associated with normal or increased copy number (CN). A consensus 3q13.31 deletion localized to a region within the limbic system-associated membrane protein (LSAMP) gene was also identified. The FISH evaluations demonstrated highly-localized homozygous or heterozygous LSAMP deletions in 6 of 11 primary OS. qRT-PCR evaluations of the two major alternative LSAMP transcripts demonstrated reduced expression of 1b isoform transcript in each of three OS with LSAMP exon 1b deletion. Further, the 1a isoform transcripts in these same OS had either reduced expression or a premature termination codon in LSAMP exon 2. This SNP genotyping study identified chromosomal aberrations associated with disease progression in OS and disclosed LSAMP as a novel tumor suppressor gene in OS. The study also demonstrated that CN and LOH analyses were able to detect distinct subsets of genetic abnormalities in OS. PMID:19724913

Yen, Chueh-Chuan; Chen, Wei-Ming; Chen, Tain-Hsiung; Chen, Winby York-Kwan; Chen, Paul Chih-Hsueh; Chiou, Hong-Jen; Hung, Giun-Yi; Wu, Hung-Ta Hondar; Wei, Chao-Jung; Shiau, Cheng-Ying; Wu, Yu-Chung; Chao, Ta-Chung; Tzeng, Cheng-Hwai; Chen, Po-Min; Lin, Chi-Hung; Chen, Yann-Jang; Fletcher, Jonathan A

2009-10-01

352

Comprehensive gene expression analysis by transcript profiling.  

PubMed

After the completion of the genomic sequence of Arabidopsis thaliana, it is now a priority to identify all the genes, their patterns of expression and functions. Transcript profiling is playing a substantial role in annotating and determining gene functions, having advanced from one-gene-at-a-time methods to technologies that provide a holistic view of the genome. In this review, comprehensive transcript profiling methodologies are described, including two that are used extensively by the authors, cDNA-AFLP and cDNA microarraying. Both these technologies illustrate the requirement to integrate molecular biology, automation, LIMS and data analysis. With so much uncharted territory in the Arabidopsis genome, and the desire to tackle complex biological traits, such integrated systems will provide a rich source of data for the correlative, functional annotation of genes. PMID:11860215

Donson, Jonathan; Fang, Yiwen; Espiritu-Santo, Gregg; Xing, Weimei; Salazar, Andres; Miyamoto, Susie; Armendarez, Veronica; Volkmuth, Wayne

2002-01-01

353

Coevolution of gene expression among interacting proteins  

SciTech Connect

Physically interacting proteins or parts of proteins are expected to evolve in a coordinated manner that preserves proper interactions. Such coevolution at the amino acid-sequence level is well documented and has been used to predict interacting proteins, domains, and amino acids. Interacting proteins are also often precisely coexpressed with one another, presumably to maintain proper stoichiometry among interacting components. Here, we show that the expression levels of physically interacting proteins coevolve. We estimate average expression levels of genes from four closely related fungi of the genus Saccharomyces using the codon adaptation index and show that expression levels of interacting proteins exhibit coordinated changes in these different species. We find that this coevolution of expression is a more powerful predictor of physical interaction than is coevolution of amino acid sequence. These results demonstrate previously uncharacterized coevolution of gene expression, adding a different dimension to the study of the coevolution of interacting proteins and underscoring the importance of maintaining coexpression of interacting proteins over evolutionary time. Our results also suggest that expression coevolution can be used for computational prediction of protein protein interactions.

Fraser, Hunter B.; Hirsh, Aaron E.; Wall, Dennis P.; Eisen,Michael B.

2004-03-01

354

Correlation between Gene Expression and GO Semantic Similarity  

Microsoft Academic Search

This research analyzes some aspects of the relationship between gene expression, gene function, and gene annotation. Many recent studies are implicitly based on the assumption that gene products that are biologically and functionally related would maintain this similarity both in their expression profiles as well as in their Gene Ontology (GO) annotation. We analyze how accurate this assumption proves to

Jose L. Sevilla; Victor Segura; Adam Podhorski; Elizabeth Guruceaga; Jose M. Mato; Luis A. Martinez-Cruz; Fernando J. Corrales; Angel Rubio

2005-01-01

355

Gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines  

PubMed Central

Background Asbestos has been shown to cause chromosomal damage and DNA aberrations. Exposure to asbestos causes many lung diseases e.g. asbestosis, malignant mesothelioma, and lung cancer, but the disease-related processes are still largely unknown. We exposed the human cell lines A549, Beas-2B and Met5A to crocidolite asbestos and determined time-dependent gene expression profiles by using Affymetrix arrays. The hybridization data was analyzed by using an algorithm specifically designed for clustering of short time series expression data. A canonical correlation analysis was applied to identify correlations between the cell lines, and a Gene Ontology analysis method for the identification of enriched, differentially expressed biological processes. Results We recognized a large number of previously known as well as new potential asbestos-associated genes and biological processes, and identified chromosomal regions enriched with genes potentially contributing to common responses to asbestos in these cell lines. These include genes such as the thioredoxin domain containing gene (TXNDC) and the potential tumor suppressor, BCL2/adenovirus E1B 19kD-interacting protein gene (BNIP3L), GO-terms such as "positive regulation of I-kappaB kinase/NF-kappaB cascade" and "positive regulation of transcription, DNA-dependent", and chromosomal regions such as 2p22, 9p13, and 14q21. We present the complete data sets as Additional files. Conclusion This study identifies several interesting targets for further investigation in relation to asbestos-associated diseases.

Nymark, Penny; Lindholm, Pamela M; Korpela, Mikko V; Lahti, Leo; Ruosaari, Salla; Kaski, Samuel; Hollmen, Jaakko; Anttila, Sisko; Kinnula, Vuokko L; Knuutila, Sakari

2007-01-01

356

Cyclin E2, a Novel G1 Cyclin That Binds Cdk2 and Is Aberrantly Expressed in Human Cancers  

PubMed Central

A novel cyclin gene was discovered by searching an expressed sequence tag database with a cyclin box profile. The human cyclin E2 gene encodes a 404-amino-acid protein that is most closely related to cyclin E. Cyclin E2 associates with Cdk2 in a functional kinase complex that is inhibited by both p27Kip1 and p21Cip1. The catalytic activity associated with cyclin E2 complexes is cell cycle regulated and peaks at the G1/S transition. Overexpression of cyclin E2 in mammalian cells accelerates G1, demonstrating that cyclin E2 may be rate limiting for G1 progression. Unlike cyclin E1, which is expressed in most proliferating normal and tumor cells, cyclin E2 levels were low to undetectable in nontransformed cells and increased significantly in tumor-derived cells. The discovery of a novel second cyclin E family member suggests that multiple unique cyclin E-CDK complexes regulate cell cycle progression.

M. Gudas, Jean; Payton, Marc; Thukral, Sushil; Chen, Eddy; Bass, Michael; Robinson, Murray O.; Coats, Steve

1999-01-01

357

Globin gene expression in somatic cell hybrids.  

PubMed

Fusions between somatic cell lines have previously yielded evidence for the existence of trans-acting gene regulatory factors. For this reason, we developed a cell line containing a "locked in" human 11-X translocation chromosome (containing the beta-globin-like gene cluster) in MEL cells. The human 11-X chromosome is stably integrated in the "M11-X" cell line, and single-copy human gamma and beta genes are present. After induction with HMBA, M11-X cells produced 500 copies per cell of correctly initiated, processed, and terminated human beta-globin mRNA; authentic human beta-globin chains were also produced at a low level. Despite the presence of normally arranged human gamma-globin genes, no gamma-globin mRNA could be detected after HMBA induction. However, cytosine residues near the gamma-globin gene promoters are completely methylated in these cells, suggesting that the gamma-globin genes may be repressed in part by DNA methylation. The pattern of human globin gene expression in M11-X cells may be affected by methylation and/or by trans-acting factors produced by these tetraploid cells. PMID:6320217

Anderson, W F; Chiang, Y L; Sanders-Haigh, L; Ley, T J

1983-01-01

358

Transient gene expression and influence of promoters on foreign gene expression in Arabidopsis thaliana  

Microsoft Academic Search

Summary  The influence of a variety of parameters was investigated on polyethylene glycol (PEG)-mediated transient nptII and gus gene expression in mesophyll protoplasts of Arabidopsis thaliana ecotype, Estland, in order to develop a suitable transient gene expression system. The investigation revealed that a combination\\u000a of 20% PEG, incubation time of 15 min, 20–30 g plasmid concentration per ml along with 50

Rita Gandhi; Satish C. Maheshwari; Paramjit Khurana

1999-01-01

359

Gene expression profiles in skeletal muscle after gene electrotransfer  

PubMed Central

Background Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have therefore investigated transcriptional changes through gene expression profile analyses, morphological changes by histological analysis, and physiological changes by force generation measurements. DNA electrotransfer was obtained using a combination of a short high voltage pulse (HV, 1000 V/cm, 100 ?s) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. Results Differentially expressed genes were investigated by microarray analysis, and descriptive statistics were performed to evaluate the effects of 1) electroporation, 2) DNA injection, and 3) time after treatment. The biological significance of the results was assessed by gene annotation and supervised cluster analysis. Generally, electroporation caused down-regulation of structural proteins e.g. sarcospan and catalytic enzymes. Injection of DNA induced down-regulation of intracellular transport proteins e.g. sentrin. The effects on muscle fibres were transient as the expression profiles 3 weeks after treatment were closely related with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern in some fibres after DNA+HV+LV treatment, while HV+LV pulses alone showed preservation of cell integrity. No difference in the force generation capacity was observed in the muscles 2 weeks after DNA electrotransfer. Conclusion The small and transient changes found in the gene expression profiles are of great importance, as this demonstrates that DNA electrotransfer is safe with minor effects on the muscle host cells. These findings are essential for introducing the DNA electrotransfer to muscle for clinical use. Indeed the HV+LV pulse combination used has been optimised to ensure highly efficient and safe DNA electrotransfer.

Hojman, Pernille; Zibert, John R; Gissel, Hanne; Eriksen, Jens; Gehl, Julie

2007-01-01

360

Gene expression: Biomarker of antidepressant therapy?  

PubMed

Abstract While antidepressant therapy is an essential treatment of major depression, a substantial group of treated patients do not respond to therapy, or suffer from severe side effects. Moreover, the time of onset of the clinical improvement is often delayed. Antidepressants as currently available usually enhance serotonergic, noradrenergic and dopaminergic neurotransmission and may contribute to the inadequate remission rates for major depression. Therefore biomarkers enabling the identification of subgroups of patients and also finding unprecedented targets would provide the basis for personalized medication and thus improve treatment efficacy and reduce side effects. Several pharmacogenetic studies on antidepressant treatment response using single nucleotide polymorphism (SNPs) mapping have been performed but provided only modest findings. Therefore the analysis of gene expression to integrate genomic activity and environmental effects promises a new approach to cope with the complexity of factors influencing antidepressant treatment. Here gene expression studies focusing on candidate genes and genome-wide approaches using RNA derived from peripheral blood cells are reviewed. The most promising findings exist for hypothalamic-pituitary-adrenal (HPA) axis, inflammation and neuroplasticity related genes. However, straightforward translation into tailored treatment is still unlikely. Contradictory results limit the clinical use of the findings. Future studies are necessary, which could include functional analysis and consider gene-environment interactions. PMID:24151803

Menke, Andreas

2013-10-01

361

Gene expression microarrays and respiratory muscles.  

PubMed

The routine measurement of the expression of tens of thousands of gene transcripts, simultaneously, is a defining advance of the last decade which has been made possible by microarray technology. Using this very powerful approach, a pattern has emerged from a number of studies that suggest a molecular niche for the diaphragm which is quite different from that occupied by limb muscle. All indications are that this is true not only in regard to differential gene transcription patterns in healthy muscles but also in the changes in transcription occurring in association with different diseases. Furthermore, respiratory muscle mounts a rich gene expression response to a number of disturbances, be they primary genetic defects (e.g. various types of muscular dystrophies) or non-genetic perturbations (e.g. controlled mechanical ventilation). Large numbers of genes undergo altered levels of transcription, ranging from tens to hundreds (typical) to thousands. These genes are involved in diverse cellular processes, such as contraction, intermediate metabolism, oxidative stress, apoptosis and cellular adhesion. Functional groups of genes identified as having changed expression differ in many respects from one disease to another. Previously identified pathways of muscle injury and repair are often perturbed to greater extents than previously anticipated, and processes not previously suspected of having important roles in the pathophysiology of specific disorders have been identified. Elucidation of these under-appreciated molecular events may lead to novel therapeutic interventions based on disrupting the downstream adverse consequences of the primary event or facilitating events which ameliorate the injury and/or promote muscle healing. PMID:17185048

van Lunteren, Erik; Leahy, Patrick

2006-11-23

362

GeneAnnot: Interfacing GeneCards with high-throughput gene expression compendia  

Microsoft Academic Search

The interpretation of microarray expression results often includes extensive efforts to identify and annotate the gene representatives immobilised on the arrays. In this paper we describe the usage of our automatic GeneAnnot system, which links between Affymetrix arrays and the rich human gene annotations available in GeneCards. We explain GeneCards search options and results display; elaborate on the presentation of

Vered Chalifa-caspi; Orit Shmueli; Hila Benjamin-rodrig; Naomi Rosen; Michael Shmoish; Itai Yanai; Ron Ophir; Pavel Kats; Marilyn Safran; Doron Lancet

2003-01-01

363

Cyclooxygenase gene expression in human endometrium and decidua.  

PubMed

The objective of this study was to determine if genes for cyclooxygenase (COX) and 5-lipoxygenase, key enzymes in the synthesis of eicosanoids, are expressed in human endometrium and to determine if the level of expression is affected by decidualization or preeclampsia, a form of pregnancy-induced hypertension. RT-PCR was used to detect mRNA in tissues obtained from various patients. Results demonstrated that COX and 5-lipoxygenase genes are expressed in endometrium and decidua. COX gene expression in endometrium is 2-3-fold greater than in decidua while 5-lipoxygenase gene expression is similar. Neither COX nor 5-lipoxygenase gene expression in decidua is altered by changes resulting from preeclampsia. Thus, genes for key enzymes in the synthesis of eicosanoids are expressed in human endometrium and decidua. Selective down-regulation is evident as decidualization results in a significant reduction in the gene expression of COX, while 5-lipoxygenase gene expression remains unchanged. PMID:8066098

Shaw, K J; Ng, C; Kovacs, B W

1994-05-01

364

Integrating gene expression and GO classification for PCA by preclustering  

Microsoft Academic Search

Background: Gene expression data can be analyzed by summarizing groups of individual gene expression profiles based on GO annotation information. The mean expression profile per group can then be used to identify interesting GO categories in relation to the experimental settings. However, the expression profiles present in GO classes are often heterogeneous, i.e., there are several different expression profiles within

Jorn R. de Haan; Ester Piek; René C. van Schaik; Jacob de Vlieg; Susanne Bauerschmidt; Lutgarde M. C. Buydens; Ron Wehrens

2010-01-01

365

Noninvasive Monitoring of Target Gene Expression by Imaging Reporter Gene Expression in Living Animals Using Improved Bicistronic Vectors  

Microsoft Academic Search

Indirect, noninvasive imaging of therapeutic gene expression based on levels of reporter gene expression is a powerful tool to devise improved therapeutic strategies in cancer gene therapy. The use of bicistronic vectors carrying internal ribosome entry sites (IRESs) allows the coexpression of multiple gene products from the same promoter but leads to considerable attenuation of the downstream gene. In this

Yanling Wang; Meera Iyer; Alexander J. Annala; Steve Chappell; Vincent Mauro; Sanjiv S. Gambhir

366

Gene expression in Pseudomonas aeruginosa swarming motility  

PubMed Central

Background The bacterium Pseudomonas aeruginosa is capable of three types of motilities: swimming, twitching and swarming. The latter is characterized by a fast and coordinated group movement over a semi-solid surface resulting from intercellular interactions and morphological differentiation. A striking feature of swarming motility is the complex fractal-like patterns displayed by migrating bacteria while they move away from their inoculation point. This type of group behaviour is still poorly understood and its characterization provides important information on bacterial structured communities such as biofilms. Using GeneChip® Affymetrix microarrays, we obtained the transcriptomic profiles of both bacterial populations located at the tip of migrating tendrils and swarm center of swarming colonies and compared these profiles to that of a bacterial control population grown on the same media but solidified to not allow swarming motility. Results Microarray raw data were corrected for background noise with the RMA algorithm and quantile normalized. Differentially expressed genes between the three conditions were selected using a threshold of 1.5 log2-fold, which gave a total of 378 selected genes (6.3% of the predicted open reading frames of strain PA14). Major shifts in gene expression patterns are observed in each growth conditions, highlighting the presence of distinct bacterial subpopulations within a swarming colony (tendril tips vs. swarm center). Unexpectedly, microarrays expression data reveal that a minority of genes are up-regulated in tendril tip populations. Among them, we found energy metabolism, ribosomal protein and transport of small molecules related genes. On the other hand, many well-known virulence factors genes were globally repressed in tendril tip cells. Swarm center cells are distinct and appear to be under oxidative and copper stress responses. Conclusions Results reported in this study show that, as opposed to swarm center cells, tendril tip populations of a swarming colony displays general down-regulation of genes associated with virulence and up-regulation of genes involved in energy metabolism. These results allow us to propose a model where tendril tip cells function as «scouts» whose main purpose is to rapidly spread on uncolonized surfaces while swarm center population are in a state allowing a permanent settlement of the colonized area (biofilm-like).

2010-01-01

367

Engineering Genes for Predictable Protein Expression  

PubMed Central

The DNA sequence used to encode a polypeptide can have dramatic effects on its expression. Lack of readily available tools has until recently inhibited meaningful experimental investigation of this phenomenon. Advances in synthetic biology and the application of modern engineering approaches now provide the tools for systematic analysis of the sequence variables affecting heterologous expression of recombinant proteins. We here discuss how these new tools are being applied and how they circumvent the constraints of previous approaches, highlighting some of the surprising and promising results emerging from the developing field of gene engineering.

Gustafsson, Claes; Minshull, Jeremy; Govindarajan, Sridhar; Ness, Jon; Villalobos, Alan; Welch, Mark

2013-01-01

368

Aberrant splicing in neurological diseases.  

PubMed

Splicing of precursor messenger RNA (pre-mRNA) removes the intervening sequences (introns) and joins the expressed regions (exons) in the nucleus, before an intron-containing eukaryotic mRNA transcript can be exported and translated into proteins in the cytoplasm. While some sequences are always included or excluded (constitutive splicing), others can be selectively used (alternative splicing) in this process. Particularly by alternative splicing, up to tens of thousands of variant transcripts can be produced from a single gene, which contributes greatly to the proteomic diversity for such complex cellular functions as 'wiring' neurons in the nervous system. Disruption of this process leads to aberrant splicing, which accounts for the defects of up to 50% of mutations that cause certain human genetic diseases. In this review, we describe the different mechanisms of aberrant splicing that cause or have been associated with neurological diseases. WIREs RNA 2013, 4:631-649. doi: 10.1002/wrna.1184 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article. PMID:23821330

Feng, Dairong; Xie, Jiuyong

2013-07-02

369

Generation of patterns from gene expression data by assigning confidence to differentially expressed genes  

Microsoft Academic Search

Motivation: A protocol is described to attach expression patterns to genes represented in a collection of hybridiza- tion array experiments. Discrete values are used to pro- vide an easily interpretable description of differential ex- pression. Binning cutoffs for each sample type are cho- sen automatically, depending on the desired false-positive rate for the predictions of differential expression. Confi- dence levels

Elisabetta Manduchi; Gregory R. Grant; Steven E. Mckenzie; G. Christian Overton; Saul Surrey; Christian J. Stoeckert Jr.

2000-01-01

370

Gene expression profiling in pulmonary hypertension.  

PubMed

The application of functional genomics toward the investigation of complex medical conditions has moved from a futuristic dream to a medical reality in less then a decade. The ability to examine the expression level of thousands of genes simultaneously has opened the door for entirely new approaches toward experimental observation and discovery. The resulting data from these genomic studies is being collected at an unprecedented scale. This wealth of data can present its own obstacles in terms of analysis. However, as new and more powerful means of examining these experiments are developed, medical science is reaping significant benefit. The power of microarray gene expression analysis has been directed at a diverse and complex array of diseases. As will be discussed in this article, the investigation of pulmonary hypertension has already benefited greatly from the application of this technology. PMID:17202300

Bull, Todd M; Coldren, Christopher D; Geraci, Mark W; Voelkel, Norbert F

2007-01-01

371

Gene expression and hypoxia in breast cancer  

PubMed Central

Hypoxia is a feature of most solid tumors and is associated with poor prognosis in several cancer types, including breast cancer. The master regulator of the hypoxic response is the Hypoxia-inducible factor 1? (HIF-1?). It is becoming clear that HIF-1? expression alone is not a reliable marker of tumor response to hypoxia, and recent studies have focused on determining gene and microRNA (miRNA) signatures for this complex process. The results of these studies are likely to pave the way towards the development of a robust hypoxia signature for breast and other cancers that will be useful for diagnosis and therapy. In this review, we outline the existing markers of hypoxia and recently identified gene and miRNA expression signatures, and discuss their potential as prognostic and predictive biomarkers. We also highlight how the hypoxia response is being targeted in the development of cancer therapies.

2011-01-01

372

Altered mitochondrial gene expression in the nonchromosomal stripe 2 mutant of maize  

PubMed Central

The genetic and molecular analyses of higher plant mitochondria can be facilitated by studying maternally-inherited mutations, such as the nonchromosomal stripe (NCS) mutants of maize, that have deleterious effects on plant growth. We have previously demonstrated a correlation between specific alterations in mitochondrial DNA and the expression of NCS phenotypes. In the present studies, the effects of the NCS2 mutation on mitochondrial gene expression are evaluated. Proteins synthesized by mitochondria isolated from NCS2 mutants and from related plants with normal growth have been compared. NCS2 mitochondria synthesize much reduced amounts of a single polypeptide. Probes corresponding to the mitochondrial DNA region altered in NCS2 hybridize to an aberrant set of transcripts in NCS2 mitochondria. Transcripts homologous to several previously characterized plant mitochondrial genes are similar in NCS2 and related non-mutant mitochondria. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.

Feiler, Heidi S.; Newton, Kathleen J.

1987-01-01

373

Gene expression and gene therapy in experimental duodenal ulceration  

Microsoft Academic Search

Gastroduodenal ulceration is still poorly understood and changes in gene expression may provide new mechanistic insights. Previously, we demonstrated that angiogenic growth factors are potent ulcer healing agents, and the synthesis of bFGF, PDGF and VEGF is enhanced early in duodenal ulcer healing. The initial molecular event in duodenal ulceration seems to be the organ-specific early release of ET-1 in

Sandor Szabo; Xiaoming Deng; Tetyana Khomenko; Masashi Yoshida; Martin R Jadus; Zsuzsa Sandor; Zoltan Gombos; Hiroko Matsumoto

2001-01-01

374

Identification of genes responsive to PFOS using gene expression profiling  

Microsoft Academic Search

Perfluorooctane sulfonic acid (PFOS) is widely distributed in the environment including in the tissues of wildlife and humans, however, its mechanism of action remains unclear. Here, the Affymetrix rat genome U34A genechip was used to identify alterations in gene expression due to PFOS exposure. Rat hepatoma cells were treated with PFOS at 2–50mg\\/L (4–100?M) for 96h. Sprague-Dawley rats were orally

Wenyue Hu; Paul D. Jones; Trine Celius; John P. Giesy

2005-01-01

375

Transcriptional regulation of GLUT4 gene expression  

Microsoft Academic Search

The in-vivo expression of the muscle\\/adipose-specific GLUT4 gene is down regulated under conditions of relative insulin-deficiency such as fasting and streptozotocin (STZ)-induced diabetes. These alterations in GLUT4 transcription occur in a tissue-specific manner with a significantly greater reduction in cardiac and adiopose tissue compared to skeletal muscle. To identify thecis-DNA elements responsible for this complex pattern of tissue-specific and nutritional\\/metabolic

Ann Louise Olson; Jeffrey E. Pessin

1996-01-01

376

Expression of the mitochondrial creatine kinase genes  

Microsoft Academic Search

Mitochondrial Creatine Kinase (MtCK) is responsible for the transfer of high energy phosphate from mitochondria to the cytosolic carrier, creatine, and exists in mammals as two isoenzymes encoded by separate genes. In rats and humans, sarcomere-specific MtCK (sMtCK) is expressed only in skeletal and heart muscle, and has 87% nucleotide identity across the 1257 bp coding region. The ubiquitous isoenzyme

R. Mark Payne; Arnold W. Strauss

1994-01-01

377

Regulation of HIV1 gene expression  

Microsoft Academic Search

The quantity and quality of HIV-1 gene expression is temporally controlled by a cascade of sequential regulatory interactions. basal HIV-1 transcription is determined by interaction of cellular regulatory proteins with specific DNA target sequences within the HIV-1 long-terminal repeat. The most notable of these protein: DNA interactions involves NF-âµB, a transcription factor that plays a pivotal role in the activation

Cullen

1991-01-01

378

Photosynthetic redox control of nuclear gene expression  

Microsoft Academic Search

Chloroplasts contain 3000-4000 different proteins but only a small subset of them is encoded in the plastid genome while the majority is encoded in the nucleus. Expression of these genes therefore requires a high degree of co-ordination between nucleus and chloro- plast. This is achieved by a bilateral information ex- change between both compartments including nucleus-to-plastid (anterograde) and plastid-to-nucleus (retrograde)

Vidal Fey; Raik Wagner; Katharina Brautigam; Thomas Pfannschmidt

2005-01-01

379

Gene Expression Profile Classification: A Review  

Microsoft Academic Search

In this review, we have discussed the class-prediction and discovery methods that are applied to gene expression data, along with the implications of the findings. We attempted to present a unified approach that considers both class-prediction and class-discovery. We devoted a substantial part of this review to an overview of pattern classification\\/recognition methods and discussed important issues such as preprocessing

Musa H. Asyali; Dilek Colak; Omer Demirkaya; Mehmet S. Inan

2006-01-01

380

Rosetta error model for gene expression analysis  

Microsoft Academic Search

Motivation: In microarray gene expression studies, the number of replicated microarrays is usually small because of cost and sample availability, resulting in unreliable variance estimation and thus unreliable statistical hypothesis tests. The unreliable variance estimation is further complicated by the fact that the technology-specific variance is intrinsically intensity-dependent. Results: The Rosetta error model captures the variance-intensity relationship for various types

Lee Weng; Hongyue Dai; Yihui Zhan; Yudong D. He; Sergey B. Stepaniants; Douglas E. Bassett

2006-01-01

381

Gene Expression Microarrays in Cancer Research  

Microsoft Academic Search

The advent of microarray technology has enabled scientists to simultaneously investigate the expression of thousands of genes.\\u000a This technology has been widely used in cancer research to better characterize cancer behaviors at mRNA level and to obtain\\u000a new insights into various stages of carcinogenesis. A microarray-based experiment generally involves three major components:\\u000a microarray manufacturing, sample processing, and data analysis, with

Jian Yan; Weikuan Gu

382

Gene Expression Profiles of Sporadic Canine Hemangiosarcoma Are Uniquely Associated with Breed  

PubMed Central

The role an individual's genetic background plays on phenotype and biological behavior of sporadic tumors remains incompletely understood. We showed previously that lymphomas from Golden Retrievers harbor defined, recurrent chromosomal aberrations that occur less frequently in lymphomas from other dog breeds, suggesting spontaneous canine tumors provide suitable models to define how heritable traits influence cancer genotypes. Here, we report a complementary approach using gene expression profiling in a naturally occurring endothelial sarcoma of dogs (hemangiosarcoma). Naturally occurring hemangiosarcomas of Golden Retrievers clustered separately from those of non-Golden Retrievers, with contributions from transcription factors, survival factors, and from pro-inflammatory and angiogenic genes, and which were exclusively present in hemangiosarcoma and not in other tumors or normal cells (i.e., they were not due simply to variation in these genes among breeds). Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) was among genes preferentially enriched within known pathways derived from gene set enrichment analysis when characterizing tumors from Golden Retrievers versus other breeds. Heightened VEGFR1 expression in these tumors also was apparent at the protein level and targeted inhibition of VEGFR1 increased proliferation of hemangiosarcoma cells derived from tumors of Golden Retrievers, but not from other breeds. Our results suggest heritable factors mold gene expression phenotypes, and consequently biological behavior in sporadic, naturally occurring tumors.

Tamburini, Beth A.; Trapp, Susan; Phang, Tzu Lip; Schappa, Jill T.; Hunter, Lawrence E.; Modiano, Jaime F.

2009-01-01

383

Gene Expression Profiling via Multigene Concatemers  

PubMed Central

We established a novel method, Gene Expression Profiling via Multigene Concatemers (MgC-GEP), to study multigene expression patterns simultaneously. This method consists of the following steps: (1) cDNA was obtained using specific reverse primers containing an adaptor. (2) During the initial 1–3 cycles of polymerase chain reaction (PCR), the products containing universal adaptors with digestion sites at both termini were amplified using specific forward and reverse primers containing the adaptors. (3) In the subsequent 4–28 cycles,