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1

HOX Gene Aberrant Expression in Skin Melanoma: A Review  

PubMed Central

The homeobox family and its subset of HOX gene products represent a family of transcription factors directing DNA-protein and protein-protein interactions. In the embryo, they are central regulators in cell differentiation during morphogenesis. A series of genes of the four HOX gene clusters A, B, C, and D were reported to show aberrant expressions in oncogenesis, particularly in cutaneous malignant melanoma (CMM). They are involved in cell proliferation and progression in the CMM metastatic path. We present relevant peer-reviewed literature findings about the aberrant expression of HOX genes in CMM. The number of CMM cell nuclei exhibiting aberrant HOX protein expression appears correlated with tumour progression.

Pierard, Gerald E.; Pierard-Franchimont, Claudine

2012-01-01

2

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

3

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

4

Aberrant Gene Expression in Dogs with Portosystemic Shunts  

PubMed Central

Congenital portosystemic shunts are developmental anomalies of the splanchnic vascular system that cause portal blood to bypass the liver. Large-breed dogs are predisposed for intrahepatic portosystemic shunts (IHPSS) and small-breed dogs for extrahepatic portosystemic shunts (EHPSS). While the phenotype resulting from portal bypass of the liver of the two types of shunt is identical, the genotype and molecular pathways involved are probably different. The aim of this study was to gain insight into the pathways involved in the different types of portosystemic shunting. Microarray analysis of mRNA expression in liver tissue from dogs with EHPSS and IHPSS revealed that the expression of 26 genes was altered in either IHPSS or EHPSS samples compared with that in liver samples from control dogs. Quantitative real-time PCR of these genes in 14 IHPSS, 17 EHPSS, and 8 control liver samples revealed a significant differential expression of ACBP, CCBL1, GPC3, HAMP, PALLD, VCAM1, and WEE1. Immunohistochemistry and Western blotting confirmed an increased expression of VCAM1 in IHPSS but its absence in EHPSS, an increased WEE1 expression in IHPSS but not in EHPSS, and a decreased expression of CCBL1 in both shunt types. Regarding their physiologic functions, these findings may indicate a causative role for VCAM1 in IHPSS and WEE1 for IHPSS. CCBL1 could be an interesting candidate to study not yet elucidated aspects in the pathophysiology of hepatic encephalopathy.

Grinwis, Guy C. M.; Kummeling, Anne; van Gils, Ingrid H. M.; Koerkamp, Marian J. A. Groot.; van Leenen, Dik; Holstege, Frank C. P.; Penning, Louis C.; Rothuizen, Jan; Leegwater, Peter A. J.; Spee, Bart

2013-01-01

5

From DNA Copy Number to Gene Expression: Local aberrations, Trisomies and Monosomies  

NASA Astrophysics Data System (ADS)

The goal of my PhD research was to study the effect of DNA copy number changes on gene expression. DNA copy number aberrations may be local, encompassing several genes, or on the level of an entire chromosome, such as trisomy and monosomy. The main dataset I studied was of Glioblastoma, obtained in the framework of a collaboration, but I worked also with public datasets of cancer and Down's Syndrome. The molecular basis of expression changes in Glioblastoma. Glioblastoma is the most common and aggressive type of primary brain tumors in adults. In collaboration with Prof. Hegi (CHUV, Switzerland), we analyzed a rich Glioblastoma dataset including clinical information, DNA copy number (array CGH) and expression profiles. We explored the correlation between DNA copy number and gene expression at the level of chromosomal arms and local genomic aberrations. We detected known amplification and over expression of oncogenes, as well as deletion and down-regulation of tumor suppressor genes. We exploited that information to map alterations of pathways that are known to be disrupted in Glioblastoma, and tried to characterize samples that have no known alteration in any of the studied pathways. Identifying local DNA aberrations of biological significance. Many types of tumors exhibit chromosomal losses or gains and local amplifications and deletions. A region that is aberrant in many tumors, or whose copy number change is stronger, is more likely to be clinically relevant, and not just a by-product of genetic instability. We developed a novel method that defines and prioritizes aberrations by formalizing these intuitions. The method scores each aberration by the fraction of patients harboring it, its length and its amplitude, and assesses the significance of the score by comparing it to a null distribution obtained by permutations. This approach detects genetic locations that are significantly aberrant, generating a 'genomic aberration profile' for each sample. The 'genomic aberration profile' is then combined with chromosomal arm status (gain/loss) to define a succinct genomic signature for each tumor. Unsupervised clustering of the samples based on these genomic signatures can reveal novel tumor subtypes. This approach was applied to datasets from three types of brain tumors: Glioblastoma, Medulloblastoma and Neuroblastoma, and identified a new subtype in Medulloblastoma, characterized by many chromosomal aberrations. Elucidating the transcriptional effect of monosomy and trisomy. Trisomy and monosomy are expected to impact the expression of genes that are located on the affected chromosome. Analysis of several cancer datasets revealed that not all the genes on the aberrant chromosome are affected by the change of copy number. Affected genes exhibit a wide range of expression changes with varying penetrance. Specifically, (1) The effect of trisomy is much more conserved among individuals than the effect of monosomy and (2) the expression level of a gene in the diploid is significantly correlated with the level of change between the diploid and the trisomy or monosomy.

Shay, Tal

6

Integrative analysis reveals the direct and indirect interactions between DNA copy number aberrations and gene expression changes  

Microsoft Academic Search

Motivation: DNA copy number aberrations (CNAs) and gene expression (GE) changes provide valuable information for studying chromosomal instability and its consequences in cancer. While it is clear that the structural aberrations and the transcript levels are intertwined, their relationship is more complex and subtle than initially suspected. Most studies so far have focused on how a CNA affects the expression

Hyunju Lee; Sek Won Kong; Peter J. Park

2008-01-01

7

Aberrant expression of posterior HOX genes in well differentiated histotypes of thyroid cancers.  

PubMed

Molecular etiology of thyroid cancers has been widely studied, and several molecular alterations have been identified mainly associated with follicular and papillary histotypes. However, the molecular bases of the complex pathogenesis of thyroid carcinomas remain poorly understood. HOX genes regulate normal embryonic development, cell differentiation and other critical processes in eukaryotic cell life. Several studies have shown that HOX genes play a role in neoplastic transformation of several human tissues. In particular, the genes belonging to HOX paralogous group 13 seem to hold a relevant role in both tumor development and progression. We have identified a significant prognostic role of HOX D13 in pancreatic cancer and we have recently showed the strong and progressive over-expression of HOX C13 in melanoma metastases and deregulation of HOX B13 expression in bladder cancers. In this study we have investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX paralogous group 13 genes/proteins expression in thyroid cancer evolution and progression, also evaluating its ability to discriminate between main histotypes. Our results showed an aberrant expression, both at gene and protein level, of all members belonging to paralogous group 13 (HOX A13, HOX B13, HOX C13 and HOX D13) in adenoma, papillary and follicular thyroid cancers samples. The data suggest a potential role of HOX paralogous group 13 genes in pathogenesis and differential diagnosis of thyroid cancers. PMID:24189220

Cantile, Monica; Scognamiglio, Giosuè; La Sala, Lucia; La Mantia, Elvira; Scaramuzza, Veronica; Valentino, Elena; Tatangelo, Fabiana; Losito, Simona; Pezzullo, Luciano; Chiofalo, Maria Grazia; Fulciniti, Franco; Franco, Renato; Botti, Gerardo

2013-01-01

8

Aberrant Gene Expression Profiles in Pluripotent Stem Cells Induced from Fibroblasts of a Klinefelter Syndrome Patient*  

PubMed Central

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.

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

2012-01-01

9

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

10

Involvement of aberrant DNA methylation on reduced expression of lysophosphatidic acid receptor-1 gene in rat tumor cell lines  

SciTech Connect

Lysophosphatidic acid (LPA) is a bioactive phospholipid that stimulates cell proliferation, migration, and protects cells from apoptosis. It interacts with specific G protein-coupled transmembrane receptors. Recently, it has been reported that alterations of LPA receptor expression might be important in the malignant transformation of tumor cells. Therefore, to assess an involvement of DNA methylation in reduced expression of the LPA receptor-1 (lpa1) gene, we investigated the expression of the lpa1 gene and its DNA methylation patterns in rat tumor cell lines. Both rat brain-derived neuroblastoma B103 and liver-derived hepatoma RH7777 cells used in this study indicated no expression of lpa1. For the analysis of methylation status, bisulfite sequencing was performed with B103 and RH7777 cells, comparing with other lpa1 expressed cells and normal tissues of brain and liver. The lpa1 expressed cells and tissues were all unmethylated in this region of lpa1. In contrast, both B103 and RH7777 cells were highly methylated, correlating with reduced expression of the lpa1. Treatment with 5-aza 2'-deoxycytidine induced expression of lpa1 gene in B103 and RH7777 cells after 24 h. In RH7777 cells treated with 5-aza 2'-deoxycytidine, stress fiber formation was also observed in response to LPA in RH7777 cells, but not in untreated RH7777 cells. These results suggest that aberrant DNA methylation of the lpa1 gene may be involved in its reduced expression in rat tumor cells.

Tsujiuchi, Toshifumi [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)]. E-mail: ttujiuch@life.kindai.ac.jp; Shimizu, Kyoko [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Onishi, Mariko [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Sugata, Eriko [Laboratory of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Fujii, Hiromasa [Department of Orthopedic Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Mori, Toshio [RI Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Honoki, Kanya [Department of Orthopedic Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521 (Japan); Fukushima, Nobuyuki [Laboratory of Molecular Neurobiology, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)

2006-10-27

11

Aberrant gene expression profile in a mouse model of endometriosis mirrors that observed in women  

PubMed Central

Objective To define the altered gene expression profile of endometriotic lesions in a mouse model of surgically-induced endometriosis Design Autologous experimental mouse model. Setting Medical school department. Animals Adult C57Bl6 mice. Intervention(s) Endometriosis was surgically-induced by auto-transplantation of uterine tissue to the intestinal mesentery. Endometriotic lesions and eutopic uteri were recovered at 3 or 29 days post-induction. Main Outcome Measure(s) Altered gene expression was measured in the endometriotic lesion relative to the eutopic uterus by genome wide cDNA microarray analysis and was confirmed by real time RT-PCR for six genes. Relevant categories of altered genes were identified using gene ontology analysis to determine groups of genes enriched for altered expression. Result(s) The expression of 479 and 114 genes was altered in the endometriotic lesion compared to the eutopic uterus at 3 or 29 days post-induction, respectively. Gene ontology enrichment analysis revealed that genes associated with the extracellular matrix, cell adhesions, immune function, cell growth, and angiogenesis were altered in the endometriotic lesion compared to the eutopic uterus. Conclusion(s) Based on gene expression analysis, the mouse model of surgically-induced endometriosis appears to be a good model for studying the pathophysiology and treatment of endometriosis.

Pelch, Katherine E.; Schroder, Amy L.; Kimball, Paul A.; Sharpe-Timms, Kathy L.; Davis, J. W.; Nagel, Susan C.

2010-01-01

12

Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes  

PubMed Central

Epigenetic gene silencing is an important mechanism in the initiation and progression of cancer. Abnormal DNA CpG island hypermethylation and histone modifications are involved in aberrant silencing of tumour-suppressor genes. LSD1 (lysine-specific demethylase 1) was the first enzyme identified to specifically demethylate H3K4 (Lys4 of histone H3). Methylated H3K4 is an important mark associated with transcriptional activation. The flavin adenine dinucleotide-binding amine oxidase domain of LSD1 is homologous with two polyamine oxidases, SMO (spermine oxidase) and APAO (N1-acetylpolyamine oxidase). We have demonstrated previously that long-chain polyamine analogues, the oligoamines, are inhibitors of LSD1. In the present paper we report the synergistic effects of specific oligoamines in combination with DFMO (2-difluoromethylornithine), an inhibitor of ornithine decarboxylase, in human colorectal cancer cells. DFMO treatment depletes natural polyamines and increases the uptake of exogenous polyamines. The combination of oligoamines and DFMO results in a synergistic re-expression of aberrantly silenced tumour-suppressor genes, including SFRP2 (secreted frizzled-related protein 2), which encodes a Wnt signalling pathway antagonist and plays an anti-tumorigenic role in colorectal cancer. The treatment-induced re-expression of SFRP2 is associated with increased H3K4me2 (di-methyl H3K4) in the gene promoter. The combination of LSD1-inhibiting oligoamines and DFMO represents a novel approach to epigenetic therapy of cancer.

Wu, Yu; Steinbergs, Nora; Murray-Stewart, Tracy; Marton, Laurence J.; Casero, Robert A.

2011-01-01

13

Toxicogenomic Analysis of Aberrant Gene Expression in Liver Tumors and Nontumorous Livers of Adult Mice Exposed in utero to Inorganic Arsenic  

Microsoft Academic Search

Arsenic is a known human carcinogen. We have reported that brief exposure of pregnant C3H mice to arsenite in their drinking water during gestation induced hepatocellular carcinoma (HCC) in male offspring after they became adults. Tumor formation is typically associated with multiple gene expression changes, and this study examined aberrant gene expression associated with transplacental arsenic hepatocarcinogenesis. Liver tumors and

Jie Liu; Yaxiong Xie; Jerrold M. Ward; Bhalchandra A. Diwan; Michael P. Waalkes

2004-01-01

14

Aberrant expression of imprinted genes and their regulatory network in cloned cattle.  

PubMed

Domesticated animals cloned by somatic cell nuclear transfer (SCNT) generally have poor developmental competency, with many developmental abnormalities attributed to incomplete reprogramming of the nuclear genome and abnormal expression of genes important for regulation of growth and development. To investigate the molecular mechanism leading to the abnormalities of cloned animals, pathologic and histologic analyses were conducted on seven cloned cattle that were oversized at birth and had cardiac and pulmonary abnormalities. Quantitative reverse transcription (RT)-polymerase chain reaction (PCR) analysis of four imprinted genes IGF2, IGF2R, H19, and GRB10, as well as genes from related regulatory networks, were performed in liver, lung, kidney, and muscle to investigate disruption of expression. Expression of IGFBP2 was not detected in morphologically normal cloned cattle, but was detected in the liver, lung, kidney, and thymus of abnormal calves. Expression levels of IGF1 and imprinted genes IGF2 and H19 were substantially higher in these organs of abnormal cattle. In contrast, expression levels of GRB10, CTSD, and TRPV2 were substantially lower in abnormal cattle. Transcript abundance of IGFBP6 was higher in kidney, but lower in liver and lung. In conclusion, we inferred that altered expression of imprinted and related genes may be closely related to increased birth weight and pathologic changes in abnormal cloned cattle. PMID:22704394

Gong, Z-J; Zhou, Y-Y; Xu, M; Cai, Q; Li, H; Yan, J-B; Wang, J; Zhang, H-J; Fan, S-Y; Yuan, Q; Huang, S-Z; Zeng, F

2012-09-01

15

Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.  

PubMed

Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation have not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumors and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through 2 different forms of aberrant gene expression. PMID:19957330

Cheng, Yu-Wei; Idrees, Kamran; Shattock, Richard; Khan, Sajid A; Zeng, Zhaoshi; Brennan, Cameron W; Paty, Philip; Barany, Francis

2010-08-01

16

Loss of imprinting and marked gene elevation are two forms of aberrant IGF2 expression in colorectal cancer  

PubMed Central

Loss of imprinting (LOI) of IGF2 is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation has not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumor and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through two different forms of aberrant gene expression.

Cheng, Yu-Wei; Idrees, Kamran; Shattock, Richard; Khan, Sajid A.; Zeng, Zhaoshi; Brennan, Cameron W.; Paty, Philip; Barany, Francis

2012-01-01

17

Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function.  

PubMed Central

Some human small cell lung carcinomas (SCLC) secrete proopiomelanocortin (POMC) derived peptides, but in contrast to the pituitary, glucocorticoids fail to inhibit this hormone production. We have previously described an in vitro model using human SCLC cell lines that express POMC and are resistant to glucocorticoids. We have now identified the glucocorticoid receptor (GR) in the SCLC cell line COR L24 using a whole cell ligand binding assay (Kd = 5.7 nM; Bmax = 11 fmol/million cells), while another cell line, DMS 79, lacked significant glucocorticoid binding. To analyze GR function both positive (GMCO) and negative (TRE)3-tkCAT), glucocorticoid-regulated reporter gene constructs were transfected into COR L24 cells. In the SCLC cell line, neither hydrocortisone nor dexamethasone (500-2,000 nM) significantly induced chloramphenicol acetyltransferase expression from GMCO; in addition, they did not suppress chloramphenicol acetyltransferase expression from (TRE)3-tkCAT. Similar results were obtained with two other POMC-expressing SCLC cell lines. Expression of wild type GR in COR L24 cells restored glucocorticoid signaling, with marked induction of GMCO reporter gene expression by dexamethasone (9,100 +/- 910%; n = 3), and an estimated EC50 of 10 nM. This failure of the GR explains the resistance of the POMC gene to glucocorticoid inhibition and may have implications for cell growth in SCLC. Images

Ray, D W; Littlewood, A C; Clark, A J; Davis, J R; White, A

1994-01-01

18

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

Microsoft Academic Search

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

Shuqi Xiao; Delin Mo; Qiwei Wang; Jianyu Jia; Limei Qin; Xiangchun Yu; Yuna Niu; Xiao Zhao; Xiaohong Liu; Yaosheng Chen

2010-01-01

19

Aberrant Gene Expression and Sexually Incompatible Genomic Imprinting in Oocytes Derived from XY Mouse Embryonic Stem Cells In Vitro  

PubMed Central

Mouse embryonic stem cells (ESCs) have the potential to differentiate into germ cells (GCs) in vivo and in vitro. Interestingly, XY ESCs can give rise to both male and female GCs in culture, irrespective of the genetic sex. Recent studies showed that ESC-derived primordial GCs contributed to functional gametogenesis in vivo; however, in vitro differentiation techniques have never succeeded in generating mature oocytes from ESCs due to cryptogenic growth arrest during the preantral follicle stages of development. To address this issue, a mouse ESC line, capable of producing follicle-like structures (FLSs) efficiently, was established to investigate their properties using conventional molecular biological methods. The results revealed that the ESC-derived FLSs were morphologically similar to ovarian primary-to-secondary follicles but never formed an antrum; instead, the FLSs eventually underwent abnormal development or cell death in culture, or formed teratomas when transplanted under the kidney capsule in mice. Gene expression analyses demonstrated that the FLSs lacked transcripts for genes essential to late folliculogenesis, including gonadotropin receptors and steroidogenic enzymes, whereas some other genes were overexpressed in FLSs compared to the adult ovary. The E-Cadherin protein, which is involved in cell-to-cell interactions, was also expressed ectopically. Remarkably, it was seen that oocyte-like cells in the FLSs exhibited androgenetic genomic imprinting, which is ordinarily indicative of male GCs. Although the FLSs did not express male GC marker genes, the DNA methyltransferase, Dnmt3L, was expressed at an abnormally high level. Furthermore, the expression of sex determination factors was ambiguous in FLSs as both male and female determinants were expressed weakly. These data suggest that the developmental dysfunction of the ESC-derived FLSs may be attributable to aberrant gene expression and genomic imprinting, possibly associated with uncertain sex determination in culture.

Nitta, Mai; Imamura, Masanori; Inoue, Yu; Kunitomo, Yasuo; Lin, Zachary Yu-Ching; Ogawa, Takuya; Yogo, Keiichiro; Ishida-Kitagawa, Norihiro; Fukunaga, Noritaka; Okano, Hideyuki; Sato, Eimei; Takeya, Tatsuo; Miyoshi, Jun

2013-01-01

20

Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations  

Microsoft Academic Search

Hematologic malignancies are characterized by fusion genes of biological\\/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23\\/MLL rearrangements, t(1;19)[TCF3\\/PBX1], t(12;21)[ETV6\\/RUNX1], t(8;21)[RUNX1\\/CBFA2T1], t(8;14)[IGH@\\/MYC], t(8;14)[TRA@\\/MYC], t(9;22)[BCR\\/ABL1], t(10;11)[PICALM\\/MLLT10], t(15;17)[PML\\/RARA], or inv(16)[CBFB\\/MYH11]. Unsupervised classification

A Andersson; P Edén; D Lindgren; J Nilsson; C Lassen; J Heldrup; M Fontes; Å Borg; F Mitelman; B Johansson; M Höglund; T Fioretos

2005-01-01

21

Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations.  

PubMed

Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14)[IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11)[PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design. PMID:15843827

Andersson, A; Edén, P; Lindgren, D; Nilsson, J; Lassen, C; Heldrup, J; Fontes, M; Borg, A; Mitelman, F; Johansson, B; Höglund, M; Fioretos, T

2005-06-01

22

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

23

Different polynomial expressions for wavefront aberrations  

NASA Astrophysics Data System (ADS)

The wavefront aberration is the difference between the real wavefront forming an image of an object point and a close reference sphere, described as an aberration function. This wavefront aberration function has been expressed by different authors as different polynomial families or polynomial series. This polynomial has their own characteristics and applications. The physical interpretation is customarily done in terms of Seidel, Zernike, Stephenson and many other aberrations. We will compare these different representations and will propose a new one.

Malacara-Hernández, Daniel; Gomez-Vieyra, Armando; Rodriguez-Vera, Ramón; Basurto-Uribe, Eduardo

2011-05-01

24

Genes with aberrant expression in murine preneoplastic intestine show epigenetic and expression changes in normal mucosa of colon cancer patients.  

PubMed

An understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr?/? BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to Mthfr?/? BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon. PMID:24169962

Leclerc, Daniel; Lévesque, Nancy; Cao, Yuanhang; Deng, Liyuan; Wu, Qing; Powell, Jasmine; Sapienza, Carmen; Rozen, Rima

2013-11-01

25

Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer  

PubMed Central

Background A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response. Methods A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software). Results Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue. Conclusions The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients.

2014-01-01

26

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

27

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

28

High-resolution detection of recurrent aberrations in lung adenocarcinomas by array comparative genomic hybridization and expression analysis of selective genes by quantitative PCR.  

PubMed

Genomic abnormalities are the hallmark of cancers and may harbor potential candidate genes important for cancer development and progression. We performed array comparative genomic hybridization (array CGH) on 36 cases of primary lung adenocarcinoma (AD) using an array containing 2621 BAC or PAC clones spanning the genome at an average interval of 1 Mb. Array CGH identified the commonest aberrations consisting of DNA gains within 1p, 1q, 5p, 5q, 7p, 7q, 8q, 11q, 12p, 13q, 16p, 17q, 20q, and losses with 6q, 9p, 10q and 18q. High-level copy gains involved mainly 7p21-p15 and 20q13.3. Dual color fluorescence in situ hybridization (FISH) was performed on a selective locus for validation of array CGH results. Genomic aberrations were compared with different clinicopathological features and a trend of higher number of aberrations in tumors with aggressive phenotypes and current tobacco exposure was identified. According to array CGH data, 23 candidate genes were selected for quantitative PCR (qPCR) analysis. The concordance observed between the genomic and expression changes in most of the genes suggested that they could be candidate cancer-related genes that contributed to the development of lung AD. PMID:24728343

Zhu, Hong; Wong, Maria Pik; Tin, Vicky

2014-06-01

29

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  

PubMed Central

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?-hydroxysteroid dehydrogenase-7 (HSD17?7; involved in estradiol production) and decreased expression of HSD17?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; Xie, Yaxiong; Cooper, Ryan; Ducharme, Danica M.K.; Tennant, Raymond; Diwan, Bhalchandra A.; Waalkes, Michael P.

2009-01-01

30

Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations.  

PubMed

Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia. PMID:24441149

Abbas, Saman; Sanders, Mathijs A; Zeilemaker, Annelieke; Geertsma-Kleinekoort, Wendy M C; Koenders, Jasper E; Kavelaars, Francois G; Abbas, Zabiollah G; Mahamoud, Souad; Chu, Isabel W T; Hoogenboezem, Remco; Peeters, Justine K; van Drunen, Ellen; van Galen, Janneke; Beverloo, H Berna; Löwenberg, Bob; Valk, Peter J M

2014-05-01

31

Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations  

PubMed Central

Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Fluorescence in situ hybridization on 40 cases of acute myeloid leukemia with high BCL11B mRNA expression [2.5-fold above median; 40 out of 530 cases (7.5%)] revealed 14q32 abnormalities in two additional cases. In the four BCL11B-rearranged cases the 14q32 locus was fused to different partner chromosomes. In fact, in two cases, we demonstrated that the focal 14q32 amplifications were integrated into transcriptionally active loci. The translocations involving BCL11B result in increased expression of full-length BCL11B protein. The BCL11B-rearranged acute myeloid leukemias expressed both myeloid and T-cell markers. These biphenotypic acute leukemias all carried FLT3 internal tandem duplications, a characteristic marker of acute myeloid leukemia. BCL11B mRNA expression in acute myeloid leukemia appeared to be strongly associated with expression of other T-cell-specific genes. Myeloid 32D(GCSF-R) cells ectopically expressing Bcl11b showed decreased proliferation rate and less maturation. In conclusion, by an integrated approach involving high-throughput genome-wide genotyping and gene expression profiling we identified BCL11B as a candidate oncogene in acute myeloid leukemia.

Abbas, Saman; Sanders, Mathijs A.; Zeilemaker, Annelieke; Geertsma-Kleinekoort, Wendy M.C.; Koenders, Jasper E.; Kavelaars, Francois G.; Abbas, Zabiollah G.; Mahamoud, Souad; Chu, Isabel W.T.; Hoogenboezem, Remco; Peeters, Justine K.; van Drunen, Ellen; van Galen, Janneke; Beverloo, H. Berna; Lowenberg, Bob; Valk, Peter J.M.

2014-01-01

32

Transplacental arsenic plus postnatal 12-O-teradecanoyl phorbol-13-acetate exposures associated with hepatocarcinogenesis induce similar aberrant gene expression patterns in male and female mouse liver  

SciTech Connect

Our prior work shows that in utero arsenic exposure alone is a complete transplacental carcinogen, producing hepatocellular carcinoma in adult male offspring but not in females. In a follow-up study to potentially promote arsenic-initiated tumors, mice were exposed to arsenic (85 ppm) from gestation day 8 to 18 and then exposed to 12-O-teradecanoyl phorbol-13-acetate (TPA), a well-known tumor promoter after weaning. The dermal application of TPA (2 {mu}g/0.1 ml acetone, twice/week for 21 weeks) after transplacental arsenic did not further increase arsenic-induced liver tumor formation in adult males but significantly increased liver tumor formation in adult females. Thus, for comparison, liver tumors and normal liver samples taken from adult male and female mice at necropsy were analyzed for aberrant gene/protein expression by microarray, real-time RT-PCR and Western blot analysis. Arsenic/TPA treatment resulted in increased expression of {alpha}-fetoprotein, k-ras, c-myc, estrogen receptor-{alpha}, cyclin D1, cdk2na, plasminogen activator inhibitor-1, cytokeratin-8, cytokeratin-18, glutathione S-transferases and insulin-like growth factor binding proteins in liver and liver tumors from both male and female mice. Arsenic/TPA also decreased the expression of BRCA1, betaine-homocysteine methyltransferase, CYP7B1, CYP2F2 and insulin-like growth factor-1 in normal and cancerous livers. Alterations in these gene products were associated with arsenic/TPA-induced liver tumors, regardless of sex. Thus, transplacental arsenic plus postnatal TPA exposure induced similar aberrant gene expression patterns in male and female mouse liver, which are persistent and potentially important to the mechanism of arsenic initiation of hepatocarcinogenesis.

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); Merrick, B. Alex [National Center for Toxicogenomics, NIEHS, Research Triangle Park, NC 27709 (United States); Shen Jun [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 27709 (United States); Collins, Jennifer [National Center for Toxicogenomics, NIEHS, Research Triangle Park, NC 27709 (United States); Diwan, Bhalchandra A. [Basic Research Program, SAIC, NCI-Frederick, Frederick, MD 21702 (United States); Logsdon, Daniel [Basic Research Program, SAIC, NCI-Frederick, Frederick, MD 21702 (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)

2006-06-15

33

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

34

Tacrolimus Increases Nox4 Expression in Human Renal Fibroblasts and Induces Fibrosis-Related Genes by Aberrant TGF-Beta Receptor Signalling  

PubMed Central

Chronic nephrotoxicity of immunosuppressives is one of the main limiting factors in the long-term outcome of kidney transplants, leading to tissue fibrosis and ultimate organ failure. The cytokine TGF-? is considered a key factor in this process. In the human renal fibroblast cell line TK-173, the macrolide calcineurin inhibitor tacrolimus (FK-506) induced TGF-?-like effects, manifested by increased expression of NAD(P)H-oxidase 4 (Nox4), transgelin, tropomyosin 1, and procollagen ?1(V) mRNA after three days. The macrolide mTOR inhibitor rapamycin had similar effects, while cyclosporine A did not induce fibrose-related genes. Concentration dependence curves were sigmoid, where mRNA expression was induced already at low nanomolar levels of tacrolimus, and reached saturation at 100–300 nM. The effects were independent of extracellular TGF-? as confirmed by the use of neutralizing antibodies, and thus most likely caused by aberrant TGF-? receptor signaling, where binding of tacrolimus to the regulatory FKBP12 protein results in a “leaky” TGF-? receptor. The myofibroblast marker ?-smooth muscle actin was neither induced by tacrolimus nor by TGF-?1, indicating an incomplete activation of TK-173 fibroblasts under culture conditions. Tacrolimus- and TGF-?1-induced Nox4 protein upregulation was confirmed by Western blotting, and was accompanied by a rise in intracellular H2O2 concentration. Si-RNA mediated knock-down of Nox4 expression prevented up-regulation of procollagen ?1(V) mRNA in tacrolimus-treated cells, but induced procollagen ?1(V) expression in control cells. Nox4 knock-down had no significant effect on the other genes tested. TGF-? is a key molecule in fibrosis, and the constant activation of aberrant receptor signaling by tacrolimus might contribute to the long-term development of interstitial kidney fibrosis in immunosuppressed patients. Nox4 levels possibly play a regulatory role in these processes.

Kern, Georg; Mair, Sabine M.; Noppert, Susie-Jane; Jennings, Paul; Schramek, Herbert; Rudnicki, Michael; Mueller, Gerhard A.; Mayer, Gert; Koppelstaetter, Christian

2014-01-01

35

Ovol2, a mammalian homolog of Drosophila ovo: gene structure, chromosomal mapping, and aberrant expression in blind-sterile mice.  

PubMed

The ovo gene family consists of evolutionarily conserved genes including those cloned from Caenorhabditis elegans, Drosophila melanogaster, mouse, and human. Here we report the isolation and characterization of mouse Ovol2 (also known as movol2 or movo2) and provide evidence supporting the existence of multiple Ovol2 transcripts. These transcripts are produced by alternative promoter usage and alternative splicing and encode long and short OVOL2 protein isoforms, whose sequences differ from those previously reported. Mouse and human OVOL2 genes are expressed in overlapping tissues including testis, where Ovol2 expression is developmentally regulated and correlates with the meiotic/postmeiotic stages of spermatogenesis. Mouse Ovol2 maps to chromosome 2 in a region containing blind-sterile (bs), a spontaneous mutation that causes spermatogenic defects and germ cell loss. No mutation has been detected in the coding region of Ovol2 from bs mice, but Ovol2 transcription was dramatically reduced in testes from these mice, suggesting that Ovol2 is expressed in male germ cells. PMID:12213202

Li, Baoan; Dai, Qian; Li, Ling; Nair, Mahalakshmi; Mackay, Douglas R; Dai, Xing

2002-09-01

36

Ovol2, a Mammalian Homolog of Drosophila ovo: Gene Structure, Chromosomal Mapping, and Aberrant Expression in Blind-Sterile Mice  

PubMed Central

The ovo gene family consists of evolutionarily conserved genes including those cloned from Caenorhabditis elegans, Drosophila melanogaster, mouse, and human. Here we report the isolation and characterization of mouse Ovol2 (also known as movol2 or movo2) and provide evidence supporting the existence of multiple Ovol2 transcripts. These transcripts are produced by alternative promoter usage and alternative splicing and encode long and short OVOL2 protein isoforms, whose sequences differ from those previously reported. Mouse and human OVOL2 genes are expressed in overlapping tissues including testis, where Ovol2 expression is developmentally regulated and correlates with the meiotic/post-meiotic stages of spermatogenesis. Mouse Ovol2 maps to chromosome 2 in a region containing blind-sterile (bs), a spontaneous mutation that causes spermatogenic defects and germ cell loss. No mutation has been detected in the coding region of Ovol2 from bs mice, but Ovol2 transcription was dramatically reduced in testes from these mice, suggesting that Ovol2 is expressed in male germ cells.

Li, Baoan; Dai, Qian; Li, Ling; Nair, Mahalakshmi; Mackay, Douglas R.; Dai, Xing

2010-01-01

37

Aberrant brain microRNA target and miRISC gene expression in the anx/anx anorexia mouse model.  

PubMed

The anorexia mouse model, anx/anx, carries a spontaneous mutation not yet identified and homozygous mutants are characterized by anorexia-cachexia, hyperactivity, and ataxia. In order to test if the microRNA function was altered in these mice, hypothalamus and cortex transcriptomes were evaluated and the data was analyzed taking into account the presence of microRNA target sites. Subsequent validation of the expression of a subset of miRISC coding genes and microRNA targets was performed by TaqMan real time PCR. In anx/anx hypothalamus we found that predicted microRNA targets were preferentially upregulated in a linearly dependent manner according to the number of microRNA target sites in each mRNA (p=10(-139)). Conversely, we observed that in anx/anx cortex mRNAs predicted to be targeted by microRNAs were preferentially downregulated (p<10(-74)), suggesting a de-regulation of genes targeted by microRNAs in two brain areas in anx/anx mice. A closer look to the mRNA transcriptome allowed us to identify upregulation of five miRISC genes, including Dgcr8 and Fmr1, and Ago2, which were later confirmed by real time PCR. The results suggest alteration of microRNA machinery expression in anx/anx mice and are consistent with its involvement in inflammatory/cancer-associated anorexia-cachexia. The data also support the previously reported link between microRNA machinery and ataxia. Further functional studies and the cloning of the anx gene should be pursued in order to elucidate the causality of microRNA machinery and microRNA target de-regulation, its relationship with the anx/anx phenotype and to propose this mouse as a model for microRNA research. PMID:22310387

Mercader, Josep M; González, Juan R; Lozano, Juan José; Bak, Mads; Kauppinen, Sakari; Sumoy, Lauro; Dierssen, Mara; Fernández-Aranda, Fernando; Visa, Joana; Gratacòs, Mònica; Estivill, Xavier

2012-04-15

38

Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene  

PubMed Central

Cancers arise through accumulating genetic and epigenetic alterations, considered relevant for phenotype and approaches to targeting new therapies. We investigated a unique collection of endometrial cancer precursor samples and clinically annotated primary and metastatic lesions for two evolutionary and functionally related transcription factors, CCCTC-binding factor (zinc finger protein) (CTCF) and its paralogue CTCF-like factor, also denoted Brother of the Regulator of Imprinted Sites (CTCFL/BORIS). CTCF, a chromatin modeling- and transcription factor, is normally expressed in a ubiquitous fashion, while CTCFL/BORIS is restricted to the testis. In cancer, CTCF is thought to be a tumor suppressor, while CTCFL/BORIS has been suggested as an oncogene. CTCF mutations were identified in 13 %, with CTCF hotspot frameshift mutations at p.T204, all observed solely in the endometrioid subtype, but with no association with outcome. Interestingly, CTCFL/BORIS was amongst the top ranked genes differentially expressed between endometrioid and non-endometrioid tumors, and increasing mRNA level of CTCFL/BORIS was highly significantly associated with poor survival. As aberrant CTCFL/BORIS expression might relate to loss of methylation, we explored methylation status in clinical samples from complex atypical hyperplasia, through primary tumors to metastatic lesions, demonstrating a pattern of DNA methylation loss during disease development and progression in line with the increase in CTCFL/BORIS mRNA expression observed. Thus, CTCF and CTCFL/BORIS are found to diverge in the different subtypes of endometrial cancer, with CTCFL/BORIS activation through demethylation from precursors to metastatic lesions. We thus propose, CTCFL/BORIS as an Epi-driver gene in endometrial cancer, suggesting a potential for future vaccine development.

Hoivik, Erling A.; Kusonmano, Kanthida; Halle, Mari K.; Berg, Anna; Wik, Elisabeth; Werner, Henrica M. J.; Petersen, Kjell; Oyan, Anne M.; Kalland, Karl-Henning; Krakstad, Camilla; Trovik, Jone; Widschwendter, Martin; Salvesen, Helga B.

2014-01-01

39

Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene.  

PubMed

Cancers arise through accumulating genetic and epigenetic alterations, considered relevant for phenotype and approaches to targeting new therapies. We investigated a unique collection of endometrial cancer precursor samples and clinically annotated primary and metastatic lesions for two evolutionary and functionally related transcription factors, CCCTC-binding factor (zinc finger protein) (CTCF) and its paralogue CTCF-like factor, also denoted Brother of the Regulator of Imprinted Sites (CTCFL/BORIS). CTCF, a chromatin modeling- and transcription factor, is normally expressed in a ubiquitous fashion, while CTCFL/BORIS is restricted to the testis. In cancer, CTCF is thought to be a tumor suppressor, while CTCFL/BORIS has been suggested as an oncogene. CTCF mutations were identified in 13%, with CTCF hotspot frameshift mutations at p.T204, all observed solely in the endometrioid subtype, but with no association with outcome. Interestingly, CTCFL/BORIS was amongst the top ranked genes differentially expressed between endometrioid and non-endometrioid tumors, and increasing mRNA level of CTCFL/BORIS was highly significantly associated with poor survival. As aberrant CTCFL/BORIS expression might relate to loss of methylation, we explored methylation status in clinical samples from complex atypical hyperplasia, through primary tumors to metastatic lesions, demonstrating a pattern of DNA methylation loss during disease development and progression in line with the increase in CTCFL/BORIS mRNA expression observed. Thus, CTCF and CTCFL/BORIS are found to diverge in the different subtypes of endometrial cancer, with CTCFL/BORIS activation through demethylation from precursors to metastatic lesions. We thus propose, CTCFL/BORIS as an Epi-driver gene in endometrial cancer, suggesting a potential for future vaccine development. PMID:24658009

Hoivik, Erling A; Kusonmano, Kanthida; Halle, Mari K; Berg, Anna; Wik, Elisabeth; Werner, Henrica M J; Petersen, Kjell; Oyan, Anne M; Kalland, Karl-Henning; Krakstad, Camilla; Trovik, Jone; Widschwendter, Martin; Salvesen, Helga B

2014-02-28

40

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

41

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

42

Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression  

PubMed Central

Abstract Langerhans cell sarcoma is a rare and aggressive high grade hematopoietic neoplasm with a dismal prognosis. It has a unique morphological and immunotypic profile with a CD1a/ langerin/S100?+?phenotype. T cell lineage markers except for CD4 in Langerhans cell sarcoma have not been documented previously. We report a case of 86?year-old male of Caucasian descent who presented with an enlarging right neck mass over 2?months with an underlying unknown cause of anemia. Computed tomography scan of the neck, chest and abdomen revealed generalized lymphadenopathy and mild splenomegaly suspicious for lymphoma. Diagnostic core biopsy performed on right neck mass revealed a possible T cell lymphoma with expression of T cell lineage specific marker CD3 but conclusive diagnosis could not be made due to insufficient core biopsy sample. Further excisional biopsy performed on a left inguinal node showed a hematopoietic neoplasm with features of Langerhans cell sarcoma with a focal cytoplasmic CD3 expression in 30-40% of the tumor cells. PCR for T cell receptor (TCR) gene rearrangement failed to demonstrate a clonal gene rearrangement in the tumor cells arguing against a T cell lineage transdifferentiation, suggesting an aberrant CD3 expression. To the best of our knowledge, this case represents the first report of Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression. Virtual slides http://www.diagnosticpathology.diagnomx.eu/vs/2065486371761991

2012-01-01

43

Molecular mechanisms for aberrant expression of the human breast cancer specific gene 1 in breast cancer cells: control of transcription by DNA methylation and intronic sequences  

Microsoft Academic Search

Breast cancer specific gene 1 (BCSG1), also referred as synuclein ?, is the third member of a neuronal protein family synuclein. BCSG1 is not expressed in normal breast tissues but highly expressed in advanced infiltrating breast carcinomas. When over expressed, BCSG1 significantly stimulates breast cancer metastasis. To elucidate the molecular mechanisms underlying the abnormal transcription of BCSG1 in breast cancer

AiPing Lu; Anu Gupta; Cong Li; Thomas E Ahlborn; YongSheng Ma; Eric Y Shi; Jingwen Liu; J Liu

2001-01-01

44

Susceptibility to Heat Stress and Aberrant Gene Expression Patterns in Holocarboxylase Synthetase-deficient Drosophila melanogaster are Caused by Decreased Biotinylation of Histones, not of Carboxylases12  

PubMed Central

Previously we discovered that holocarboxylase synthetase (HCS) is a chromatin-associated protein in Drosophila melanogaster, and that HCS deficiency alters chromatin structure and gene expression patterns, leading to decreased heat tolerance. The effects of HCS deficiency were attributed to decreased biotinylation of histones. However, HCS is known to mediate biotinylation of carboxylases in cytoplasm and mitochondria in addition to mediating biotinylation of histones. A challenge posed by the genetic analysis of HCS is to distinguish between the effects of decreased biotinylation of carboxylases from the effects of decreased histone biotinylation in the gene expression patterns and phenotypes observed in HCS-deficient flies. Here, we tested whether 3-methylcrotonyl-CoA carboxylase (MCC) mutant flies exhibit gene expression patterns and heat susceptibility similar to that in HCS-deficient Drosophila. Biotin transporter (SMVT) mutants were used to investigate effects of cellular biotin depletion on gene expression and heat susceptibility. Deficiencies of MCC and SMVT in mutant flies were confirmed by real-time PCR, streptavidin blotting of holocarboxylases, and analysis of MCC activities; expression of HCS and biotinylation of histones were not altered in MCC and SMVT mutants. Gene expression patterns in MCC and SMVT mutants were different from that seen with HCS-deficient flies, as judged by the abundance of mRNA coding for defective chorion 1, chitin binding peritrophin-A, dopamine receptor 2, and yolk protein 2. MCC mutants exhibited increased resistance to heat stress compared with wild-type flies. We conclude that gene expression patterns and phenotypes in HCS-deficient flies in previous studies are caused by decreased biotinylation of histones rather than MCC.

Camporeale, Gabriela; Zempleni, Janos; Eissenberg, Joel C.

2007-01-01

45

Susceptibility to heat stress and aberrant gene expression patterns in holocarboxylase synthetase-deficient Drosophila melanogaster are caused by decreased biotinylation of histones, not of carboxylases.  

PubMed

Previously, we discovered that holocarboxylase synthetase (HCS) is a chromatin-associated protein in Drosophila melanogaster and that HCS deficiency alters chromatin structure and gene expression patterns, leading to decreased heat tolerance. The effects of HCS deficiency were attributed to decreased biotinylation of histones. However, HCS is known to mediate biotinylation of carboxylases in cytoplasm and mitochondria in addition to mediating biotinylation of histones. A challenge posed by the genetic analysis of HCS is to distinguish between the effects of decreased biotinylation of carboxylases from the effects of decreased histone biotinylation in the gene expression patterns and phenotypes observed in HCS-deficient flies. Here, we tested whether 3-methylcrotonyl-CoA carboxylase (MCC) mutant flies exhibit gene expression patterns and heat susceptibility similar to that in HCS-deficient Drosophila. Biotin transporter [sodium-dependent multivitamin transporter (SMVT)] mutants were used to investigate effects of cellular biotin depletion on gene expression and heat susceptibility. Deficiencies of MCC and SMVT in mutant flies were confirmed by real-time PCR, streptavidin blotting of holocarboxylases, and analysis of MCC activities; expression of HCS and biotinylation of histones were not altered in MCC and SMVT mutants. Gene expression patterns in MCC and SMVT mutants were different from that seen with HCS-deficient flies, as judged by the abundance of mRNA coding for defective chorion 1, chitin-binding peritrophin-A, dopamine receptor 2, and yolk protein 2. MCC mutants exhibited increased resistance to heat stress compared with wild-type flies. We conclude that gene expression patterns and phenotypes in HCS-deficient flies in previous studies are caused by decreased biotinylation of histones rather than MCC. PMID:17374649

Camporeale, Gabriela; Zempleni, Janos; Eissenberg, Joel C

2007-04-01

46

Mice with targeted disruption of p8 gene show increased sensitivity to lipopolysaccharide and DNA microarray analysis of livers reveals an aberrant gene expression response  

Microsoft Academic Search

BACKGROUND: p8 is a DNA-binding protein induced in many tissues in response to LPS treatment. Hence, p8 could be a mediator of LPS-associated effects or, on the contrary, p8 expression may be part of the protective mechanism of the tissues in response to LPS. Finally, p8 expression in response to LPS could also be a simple epiphenomenon. METHODS: To investigate

Sophie Vasseur; Albrecht Hoffmeister; Andrés Garcia-Montero; Marc Barthet; Laure Saint-Michel; Patrice Berthézène; Fritz Fiedler; Daniel Closa; Jean Charles Dagorn; Juan Lucio Iovanna

2003-01-01

47

High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting, and of CPT1A and CPT1C that regulate fatty acid metabolism.  

PubMed

The diagnosis of glioblastoma is still based on tumor histology, but emerging molecular diagnosis is becoming an important part of glioblastoma classification. Besides the well-known cell cycle-related circuitries that are associated with glioblastoma onset and development, new insights may be derived by looking at pathways involved in regulation of epigenetic phenomena and cellular metabolism, which may both be highly deregulated in cancer cells. We evaluated if in glioblastoma patients the high grade of malignancy could be associated with aberrant expression of some genes involved in regulation of epigenetic phenomena and lipid metabolism. We measured the mRNA levels of ZFP57, TRIM28, CPT1A, CPT1B, and CPT1C in a cohort of 80 patients divided in two groups: grade II and grade IV. We evidenced that high grade glioblastoma is associated with increased level of ZFP57, a protein involved in gene imprinting, and aberrant expression of CPT1A and CPT1C, regulators of fatty acid oxidation. Our study may pave the way to identify new markers that could be potentially useful for diagnosis and/or prognosis of glioblastoma. PMID:24618825

Cirillo, Alessandra; Di Salle, Anna; Petillo, Orsolina; Melone, Mariarosa Ab; Grimaldi, Giovanna; Bellotti, Alfredo; Torelli, Giovanni; De' Santi, Maria Serena; Cantatore, Giovanna; Marinelli, Alfredo; Galderisi, Umberto; Peluso, Gianfranco

2014-06-01

48

Identification of Aberrantly Expressed miRNAs in Gastric Cancer  

PubMed Central

The noncoding components of the genome, including miRNA, can contribute to pathogenesis of gastric cancer. Their expression has been profiled in many human cancers, but there are a few published studies in gastric cancer. It is necessary to identify novel aberrantly expressed miRNAs in gastric cancer. In this study, the expression profile of 1891 miRNAs was analyzed using a miRCURY array LNA miRNA chip from three gastric cancer tissues and three normal tissues. The expression levels of 4 miRNAs were compared by real-time PCR between cancerous and normal tissues. We found that 31 miRNAs are upregulated in gastric cancer (P < 0.05) and 10 miRNAs have never been reported by other studies; 30 miRNA are downregulated (P < 0.05) in gastric cancer tissues. Gene ontology analysis revealed that those dysregulated miRNAs mainly take part in regulating cell proliferation. The levels of has-miR-105, -213?, -514b, and -548n were tested by real-time PCR and have high levels in cancerous tissues. Here, we report a miRNA profile of gastric cancer and provide new perspective to understand this malignant disease. This novel information suggests the potential roles of these miRNAs in the diagnosis, prognosis biomarkers, or therapy targets of gastric cancer.

Liu, Dan; Hu, Xiaowei; Zhou, Hongfeng; Shi, Guangyue; Wu, Jin

2014-01-01

49

miRNA Gene Promoters Are Frequent Targets of Aberrant DNA Methylation in Human Breast Cancer  

PubMed Central

miRNAs are important regulators of gene expression that are frequently deregulated in cancer, with aberrant DNA methylation being an epigenetic mechanism involved in this process. We previously identified miRNA promoter regions active in normal mammary cell types and here we analyzed which of these promoters are targets of aberrant DNA methylation in human breast cancer cell lines and breast tumor specimens. Using 5-methylcytosine immunoprecipitation coupled to miRNA tiling microarray hybridization, we performed comprehensive evaluation of DNA methylation of miRNA gene promoters in breast cancer. We found almost one third (55/167) of miRNA promoters were targets for aberrant methylation in breast cancer cell lines. Breast tumor specimens displayed DNA methylation of majority of these miRNA promoters, indicating that these changes in DNA methylation might be clinically relevant. Aberrantly methylated miRNA promoters were, similar to protein coding genes, enriched for promoters targeted by polycomb in normal cells. Detailed analysis of selected miRNA promoters revealed decreased expression of miRNA linked to increased promoter methylation for mir-31, mir-130a, let-7a-3/let-7b, mir-155, mir-137 and mir-34b/mir-34c genes. The proportion of miRNA promoters we found aberrantly methylated in breast cancer is several fold larger than that observed for protein coding genes, indicating an important role of DNA methylation in miRNA deregulation in cancer.

Vrba, Lukas; Munoz-Rodriguez, Jose L.; Stampfer, Martha R.; Futscher, Bernard W.

2013-01-01

50

V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia  

Microsoft Academic Search

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immuno- globulin variable heavy chain gene (VH) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognos- tic impact of the individual parameters is unknown. In the current study, we ana- lyzed VH mutation status by polymerase chain reaction and sequencing (n 300), genomic

Alexander Krober; Till Seiler; Axel Benner; Lars Bullinger; Elsbeth Bruckle; Peter Lichter; Hartmut Dohner; Stephan Stilgenbauer

2010-01-01

51

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

2011-01-01

52

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes  

PubMed Central

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie-Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann-Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming-Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F. A.; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; McPherson, John D.; Gibbs, Richard A.; Grimmond, Sean M.

2012-01-01

53

Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes  

Microsoft Academic Search

Epigenetic chromatin modification is a major regulator of eukary- otic gene expression, and aberrant epigenetic silencing of gene expression contributes to tumorigenesis. Histone modifications include acetylation, phosphorylation, and methylation, resulting in a combination of histone marks known collectively as the histone code. The chromatin marks at a given promoter determine, in part, whether specific promoters are in an open\\/active conformation

Yi Huang; Eriko Greene; Tracy Murray Stewart; Andrew C. Goodwin; Stephen B. Baylin; Patrick M. Woster; Robert A. Casero

2007-01-01

54

Gene Fusions Associated with Recurrent Amplicons Represent a Class of Passenger Aberrations in Breast Cancer12  

PubMed Central

Application of high-throughput transcriptome sequencing has spurred highly sensitive detection and discovery of gene fusions in cancer, but distinguishing potentially oncogenic fusions from random, “passenger” aberrations has proven challenging. Here we examine a distinctive group of gene fusions that involve genes present in the loci of chromosomal amplifications—a class of oncogenic aberrations that are widely prevalent in breast cancers. Integrative analysis of a panel of 14 breast cancer cell lines comparing gene fusions discovered by high-throughput transcriptome sequencing and genome-wide copy number aberrations assessed by array comparative genomic hybridization, led to the identification of 77 gene fusions, of which more than 60% were localized to amplicons including 17q12, 17q23, 20q13, chr8q, and others. Many of these fusions appeared to be recurrent or involved highly expressed oncogenic drivers, frequently fused with multiple different partners, but sometimes displaying loss of functional domains. As illustrative examples of the “amplicon-associated” gene fusions, we examined here a recurrent gene fusion involving the mediator of mammalian target of rapamycin signaling, RPS6KB1 kinase in BT-474, and the therapeutically important receptor tyrosine kinase EGFR in MDA-MB-468 breast cancer cell line. These gene fusions comprise a minor allelic fraction relative to the highly expressed full-length transcripts and encode chimera lacking the kinase domains, which do not impart dependence on the respective cells. Our study suggests that amplicon-associated gene fusions in breast cancer primarily represent a by-product of chromosomal amplifications, which constitutes a subset of passenger aberrations and should be factored accordingly during prioritization of gene fusion candidates.

Kalyana-Sundaram, Shanker; Shankar, Sunita; DeRoo, Scott; Iyer, Matthew K; Palanisamy, Nallasivam; Chinnaiyan, Arul M; Kumar-Sinha, Chandan

2012-01-01

55

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

2013-10-01

56

Dysregulation of microRNA expression drives aberrant DNA hypermethylation in basal-like breast cancer  

PubMed Central

Basal-like breast cancers frequently express aberrant DNA hypermethylation associated with concurrent silencing of specific genes secondary to DNMT3b overexpression and DNMT hyperactivity. DNMT3b is known to be post-transcriptionally regulated by microRNAs. The objective of the current study was to determine the role of microRNA dysregulation in the molecular mechanism governing DNMT3b overexpression in primary breast cancers that express aberrant DNA hypermethylation. The expression of microRNAs (miRs) that regulate (miR-29a, miR-29b, miR-29c, miR-148a and miR-148b) or are predicted to regulate DNMT3b (miR-26a, miR-26b, miR-203 and miR-222) were evaluated among 70 primary breast cancers (36 luminal A-like, 13 luminal B-like, 5 HER2-enriched, 16 basal-like) and 18 normal mammoplasty tissues. Significantly reduced expression of miR-29c distinguished basal-like breast cancers from other breast cancer molecular subtypes. The expression of aberrant DNA hypermethylation was determined in a subset of 33 breast cancers (6 luminal A-like, 6 luminal B-like, 5 HER2-enriched and 16 basal-like) through examination of methylation-sensitive biomarker gene expression (CEACAM6, CDH1, CST6, ESR1, GNA11, MUC1, MYB, TFF3 and SCNN1A), 11/33 (33%) cancers exhibited aberrant DNA hypermethylation including 9/16 (56%) basal-like cancers, but only 2/17 (12%) non-basal-like cancers (luminal A-like, n=1; HER2-enriched, n=1). Breast cancers with aberrant DNA hypermethylation express diminished levels of miR-29a, miR-29b, miR-26a, miR-26b, miR-148a and miR-148b compared to cancers lacking aberrant DNA hypermethylation. A total of 7/9 (78%) basal-like breast cancers with aberrant DNA hypermethylation exhibit diminished levels of ?6 regulatory miRs. The results show that i) reduced expression of miR-29c is characteristic of basal-like breast cancers, ii) miR and methylation-sensitive gene expression patterns identify two subsets of basal-like breast cancers, and iii) the subset of basal-like breast cancers with reduced expression of multiple regulatory miRs express aberrant DNA hypermethylation. Together, these findings strongly suggest that the molecular mechanism governing the DNMT3b-mediated aberrant DNA hypermethylation in primary breast cancer involves the loss of post-transcriptional regulation of DNMT3b by regulatory miRs.

SANDHU, RUPNINDER; RIVENBARK, ASHLEY G.; MACKLER, RANDI M.; LIVASY, CHAD A.; COLEMAN, WILLIAM B.

2014-01-01

57

Aberrantly methylated genes in human papillary thyroid cancer and their association with BRAF/RAS mutation  

PubMed Central

Cancer arises through accumulation of epigenetic and genetic alteration. Aberrant promoter methylation is a common epigenetic mechanism of gene silencing in cancer cells. We here performed genome-wide analysis of DNA methylation of promoter regions by Infinium HumanMethylation27 BeadChip, using 14 clinical papillary thyroid cancer samples and 10 normal thyroid samples. Among the 14 papillary cancer cases, 11 showed frequent aberrant methylation, but the other three cases showed no aberrant methylation at all. Distribution of the hypermethylation among cancer samples was non-random, which implied existence of a subset of preferentially methylated papillary thyroid cancer. Among 25 frequently methylated genes, methylation status of six genes (HIST1H3J, POU4F2, SHOX2, PHKG2, TLX3, HOXA7) was validated quantitatively by pyrosequencing. Epigenetic silencing of these genes in methylated papillary thyroid cancer cell lines was confirmed by gene re-expression following treatment with 5-aza-2?-deoxycytidine and trichostatin A, and detected by real-time RT-PCR. Methylation of these six genes was validated by analysis of additional 20 papillary thyroid cancer and 10 normal samples. Among the 34 cancer samples in total, 26 cancer samples with preferential methylation were significantly associated with mutation of BRAF/RAS oncogene (P = 0.04, Fisher's exact test). Thus, we identified new genes with frequent epigenetic hypermethylation in papillary thyroid cancer, two subsets of either preferentially methylated or hardly methylated papillary thyroid cancer, with a concomitant occurrence of oncogene mutation and gene methylation. These hypermethylated genes may constitute potential biomarkers for papillary thyroid cancer.

Kikuchi, Yasuko; Tsuji, Eiichi; Yagi, Koichi; Matsusaka, Keisuke; Tsuji, Shingo; Kurebayashi, Junichi; Ogawa, Toshihisa; Aburatani, Hiroyuki; Kaneda, Atsushi

2013-01-01

58

Kr?ppel-Like Factor 9 Loss-of-Expression in Human Endometrial Carcinoma Links Altered Expression of Growth-Regulatory Genes with Aberrant Proliferative Response to Estrogen1  

PubMed Central

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, differentiation, and apoptosis. Deregulated expression of a number of Sp proteins has been associated with multiple types of human tumors, but a role for KLF9 in endometrial cancer development and/or progression is unknown. Here, we evaluated KLF9 expression in endometrial tumors and adjacent uninvolved endometrium of women with endometrial carcinoma. KLF9 mRNA and protein levels were lower in endometrial tumors coincident with decreased expression of family member KLF4 and growth-regulators FBJ murine osteosarcoma viral oncogene homolog (FOS) and myelocytomatosis viral oncogene homolog (MYC) and with increased expression of telomerase reverse transcriptase (TERT) and the chromatin-modifying enzymes DNA methyltransferase 1 (DNMT1) and histone deacetylase 3 (HDAC3). Expression of estrogen receptor alpha (ESR1) and the tumor-suppressor phosphatase and tensin homolog deleted in chromosome 10 (PTEN) did not differ between tumor and normal tissue. The functional relevance of attenuated KLF9 expression in endometrial carcinogenesis was further evaluated in the human endometrial carcinoma cell line Ishikawa by siRNA targeting. KLF9 depletion resulted in loss of normal cellular response to the proliferative effects of estrogen concomitant with reductions in KLF4 and MYC and with enhancement of TERT and ESR1 gene expression. Silencing of KLF4 did not mimic the effects of silencing KLF9 in Ishikawa cells. We suggest that KLF9 loss-of-expression accompanying endometrial carcinogenesis may predispose endometrial epithelial cells to mechanisms of escape from estrogen-mediated growth regulation, leading to progression of established neoplasms.

Simmons, Christian D.; Pabona, John Mark P.; Heard, Melissa E.; Friedman, Theodore M.; Spataro, Michael T.; Godley, Amy L.; Simmen, Frank A.; Burnett, Alexander F.; Simmen, Rosalia C.M.

2011-01-01

59

Clustering gene expression patterns  

Microsoft Academic Search

Recent advances in biotechnology allow researchers to measure expression levels for thousands of genes simultaneously, across different conditions and over time. Analysis of data produced by such experiments offers potential insight into gene function and regulatory mechanisms. A key step in the analysis of gene expression data is the detection of groups of genes that manifest similar expression patterns. The

Amir Ben-Dor; Zohar Yakhinit; Zohar Yakhini

1999-01-01

60

Aberrant DNA methylation of microRNA genes in human breast cancer - a critical appraisal.  

PubMed

Aberrant DNA methylation of regulatory sequences is a well-documented mechanism of functional deletion of genes with anti-tumourigenic properties including microRNAs. This review discusses the publications describing aberrant methylation of microRNA genes in human breast cancer cells. Among the anti-tumourigenic properties of epigenetically inactivated microRNA genes, the inhibition of proliferation and of epithelial-to-mesenchymal transition (EMT) are the best studied. Several studies are conceptually very interesting and present a comprehensive functional characterization of anti-tumorigenic microRNAs. The link between microRNA expression and gene methylation is not addressed directly by all studies and a number of studies are limited in their strength by not including primary breast cancer specimens or by analysing very small sets of primary human specimens. The publications cover a wide range of DNA methylation detection techniques, often making direct comparison of results challenging. Despite the identification and thorough characterization of many interesting candidates and functionally important microRNA genes affected by DNA methylation, the translation of microRNA gene methylation as a new biomarker into the daily routine practice has not yet worked out. PMID:24509818

Lehmann, Ulrich

2014-06-01

61

Aberrantly expressed lncRNAs in primary varicose great saphenous veins.  

PubMed

Long non-coding RNAs (lncRNAs) are key regulatory molecules involved in a variety of biological processes and human diseases. However, the pathological effects of lncRNAs on primary varicose great saphenous veins (GSVs) remain unclear. The purpose of the present study was to identify aberrantly expressed lncRNAs involved in the prevalence of GSV varicosities and predict their potential functions. Using microarray with 33,045 lncRNA and 30,215 mRNA probes, 557 lncRNAs and 980 mRNAs that differed significantly in expression between the varicose great saphenous veins and control veins were identified in six pairs of samples. These lncRNAs were sub-grouped and mRNAs expressed at different levels were clustered into several pathways with six focused on metabolic pathways. Quantitative real-time PCR replication of nine lncRNAs was performed in 32 subjects, validating six lncRNAs (AF119885, AK021444, NR_027830, G36810, NR_027927, uc.345-). A coding-non-coding gene co-expression network revealed that four of these six lncRNAs may be correlated with 11 mRNAs and pathway analysis revealed that they may be correlated with another 8 mRNAs associated with metabolic pathways. In conclusion, aberrantly expressed lncRNAs for GSV varicosities were here systematically screened and validated and their functions were predicted. These findings provide novel insight into the physiology of lncRNAs and the pathogenesis of varicose veins for further investigation. These aberrantly expressed lncRNAs may serve as new therapeutic targets for varicose veins. The Human Ethnics Committee of Shanghai East Hospital, Tongji University School of Medicine approved the study (NO.: 2011-DF-53). PMID:24497937

Li, Xiang; Jiang, Xiao-Yan; Ge, Jin; Wang, Jing; Chen, Guo-Jun; Xu, Liang; Xie, Duan-Yang; Yuan, Tian-You; Zhang, Da-Sheng; Zhang, Hong; Chen, Yi-Han

2014-01-01

62

Identification of 27 5' CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers.  

PubMed

Aberrantly methylated DNA fragments were searched for in human pancreatic cancers, using the genome scanning technique: methylation-sensitive-representational difference analysis (MS-RDA). MS-RDA isolated 111 DNA fragments derived from CpG islands (CGIs), and 35 of them were from CGIs in the 5' regions of known genes. Methylation-specific PCR (MSP) of the CGIs in seven pancreatic cancer cell lines and two pancreatic ductal epithelial cell lines showed that 27 CGIs in the 5' regions were aberrantly methylated in at least one of the cancer cell lines. Quantitative reverse-transcription-PCR analysis showed that downstream genes of all the CGIs were either not expressed or only very weakly expressed in cancer cell lines with the aberrant methylation. In the pancreatic ductal epithelial cell lines, 18 genes were expressed at various levels, and nine genes were not expressed at all. Treatment of a cancer cell line with a demethylating agent, 5-aza-2'-deoxycytidine, restored the expression of 13 genes, RASGRF2, ADAM23, NEF3, NKX2-8, HAND1, EGR4, PRG2, FBN2, CDH2, TLL1, NPTX1, NTSR1 and THBD, showing their silencing by methylation of their 5' CGIs. MSP of 24 primary pancreatic cancers showed that all these genes, except for THBD, were methylated in at least one cancer. Some of those were suggested to be potentially involved in pancreatic cancer development and progression. PMID:15467763

Hagihara, Atsushi; Miyamoto, Kazuaki; Furuta, Junichi; Hiraoka, Nobuyoshi; Wakazono, Kuniko; Seki, Shuichi; Fukushima, Shoji; Tsao, Ming-Sound; Sugimura, Takashi; Ushijima, Toshikazu

2004-11-11

63

Analysis of the expression of putatively imprinted genes in bovine peri-implantation embryos  

Microsoft Academic Search

The application of assisted reproductive technologies (ART) has been shown to induce changes in the methylation of the embryonic genome, leading to aberrant gene expression, including that of imprinted genes. Aberrant methylation and gene expression has been linked to the large offspring syndrome (LOS) in bovine embryos resulting in increased embryonic morbidity and mortality. In the bovine, limited numbers of

P. Y. Tveden-Nyborg; N. I. Alexopoulos; M. A. Cooney; A. J. French; R. T. Tecirlioglu; M. K. Holland; P. D. Thomsen; N. T. D’Cruz

2008-01-01

64

MicroRNA Gene Expression Deregulation in Human Breast Cancer  

Microsoft Academic Search

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leuke- mias, where miRNA signatures were associated with specific clinicobiological features. Here, we

Marilena V. Iorio; Manuela Ferracin; Chang-Gong Liu; Angelo Veronese; Riccardo Spizzo; Silvia Sabbioni; Massimo Pedriali; Muller Fabbri; Manuela Campiglio; Sylvie Menard; Juan P. Palazzo; Anne Rosenberg; Piero Musiani; Stefano Volinia; Italo Nenci; George A. Calin; Patrizia Querzoli; Massimo Negrini; Carlo M. Croce

2005-01-01

65

Characterization of EGFR family gene aberrations in cholangiocarcinoma.  

PubMed

Cholangiocarcinoma (CCA) is a highly lethal malignancy of the biliary tract with very few treatment options. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER2) have been considered as potential therapeutic targets in CCA. In the present study, we attempted to clarify the clinicopathological significance of all EGFR family members, EGFR, HER2, HER3 and HER4, across the full spectrum of CCAs. Immunohistochemistry and FISH were performed to validate expressions and genetic aberrations of these molecules retrospectively in 175 CCA patients. EGFR, HER3 and HER4 were overexpressed in 20 (30.8%), 8 (12.3%) and 41 (63.1%) of the 65 intrahepatic cholangiocarcinomas (IHCCs), and in 23 (20.9%), 13 (11.8%) and 62 (56.4%) of the 110 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, among which the rate was 4.5% (5/110). A significant association was identified between EGFR amplification and EGFR overexpression (P=0.002). Similarly, HER2 amplification was strongly associated with HER2 overexpression (P<0.001). Multivariate analysis suggested that EGFR overexpression is an independent prognostic factor in IHCC, but not in EHCC cases [HR (95% CI): 3.689 (1.253-10.587), P=0.018]. Notably, for the first time, we demonstrated HER4 expression is a prognostic factor in EGFR-negative IHCC patients. In vitro data further suggested a tumor-suppressor role of HER4 in CCA. siRNA knockdown of HER4 significantly increased RBE cell migration and invasion. By contrast, HER4 overexpression decreased proliferation of HuCCT-1 cells and their migratory and invasive capacity. In summary, our results revealed expression of the EGFR family members in CCA development and progression. CCAs differentially express HER2 protein based on tumor location. HER4 expression status allows stratification of CCA patients into different survival categories. PMID:24927194

Yang, Xiaoqing; Wang, Weishan; Wang, Chunni; Wang, Lin; Yang, Muyi; Qi, Mei; Su, Hong; Sun, Xiubin; Liu, Zhiyan; Zhang, Juan; Qin, Xiaomin; Han, Bo

2014-08-01

66

Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes.  

PubMed

Epigenetic chromatin modification is a major regulator of eukaryotic gene expression, and aberrant epigenetic silencing of gene expression contributes to tumorigenesis. Histone modifications include acetylation, phosphorylation, and methylation, resulting in a combination of histone marks known collectively as the histone code. The chromatin marks at a given promoter determine, in part, whether specific promoters are in an open/active conformation or closed/repressed conformation. Dimethyl-lysine 4 histone H3 (H3K4me2) is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by the lysine-specific demethylase 1 (LSD1), a homologue of polyamine oxidases, may broadly repress gene expression. We now report that novel biguanide and bisguanidine polyamine analogues are potent inhibitors of LSD1. These analogues inhibit LSD1 in human colon carcinoma cells and affect a reexpression of multiple, aberrantly silenced genes important in the development of colon cancer, including members of the secreted frizzle-related proteins (SFRPs) and the GATA family of transcription factors. Furthermore, we demonstrate by chromatin immunoprecipitation analysis that the reexpression is concurrent with increased H3K4me2 and acetyl-H3K9 marks, decreased H3K9me1 and H3K9me2 repressive marks. We thus define important new agents for reversing aberrant repression of gene transcription. PMID:17463086

Huang, Yi; Greene, Eriko; Murray Stewart, Tracy; Goodwin, Andrew C; Baylin, Stephen B; Woster, Patrick M; Casero, Robert A

2007-05-01

67

The transglutaminase 2 gene is aberrantly hypermethylated in glioma  

Microsoft Academic Search

Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein\\/protein crosslinking. Because extracellular\\u000a TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We\\u000a 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,\\u000a and

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

2011-01-01

68

Aberrant methylation of multiple imprinted genes in embryos of tamoxifen-treated male rats.  

PubMed

Genomic imprinting is an epigenetic phenomenon known to regulate fetal growth and development. Studies from our laboratory have demonstrated that treatment of adult male rats with tamoxifen increased postimplantation loss around mid gestation. Further studies demonstrated the aberrant expression of transcripts of several imprinted genes in the resorbing embryos at days 11 and 13 of gestation including IGF2. In addition, decreased methylation at the Igf2-H19 imprint control region was observed in spermatozoa and in resorbing embryos sired by tamoxifen-treated males. In this study, methylation analysis of the imprinted genes, which were found to be differentially expressed, was done using EpiTYPER in the spermatozoa of tamoxifen-treated rats and in postimplantation embryos sired by tamoxifen-treated rats. Differentially methylated regions (DMRs) for most imprinted genes have not been identified in the rats. Hence, initial experiments were performed to identify the putative DMRs in the genes selected for the study. Increased methylation at CpG islands present in the putative DMRs of a number of imprinted genes was observed in the resorbing embryos sired by tamoxifen-treated male rats. This increase in methylation is associated with the downregulation of most of these genes at the transcript level in resorbing embryos. No change in the methylation status of these genes was observed in spermatozoa. These observations suggest that a deregulation of mechanisms protecting unmethylated alleles from a wave of de novo methylation occurs following implantation. PMID:23740079

Kedia-Mokashi, Neelam A; Kadam, Leena; Ankolkar, Mandar; Dumasia, Kushaan; Balasinor, N H

2013-08-01

69

A network-based, integrative approach to identify genes with aberrant co-methylation in colorectal cancer.  

PubMed

Epigenetic changes, including aberrations in DNA methylation, are a common hallmark of many cancers. The identification and interpretation of epigenetic changes associated with cancers may benefit from integration with protein interactomes. Based on the assumption that genes implicated in a specific tumor phenotype will show high aberrant co-methylation patterns with their interacting partners, we propose an integrated approach to uncover cancer-associated genes by integrating a DNA methylome with an interactome. Aberrant co-methylated interactions were first identified in the specific cancer, and genes were then prioritized based on their enrichment in aberrant co-methylation. By applying this to a large-scale colorectal cancer (CRC) dataset, the proposed method increases the power to capture known genes. More importantly, genes possessing high aberrant co-methylation patterns, located at the topological center of the original protein-protein interaction network (PPIN), affect several cancer-associated pathways and form hotspots that are frequently hijacked in cancer. Additionally, the top-ranked candidate genes may also be useful as an indicator of CRC diagnosis and prognosis. Five fold cross-validation of the top-ranked genes in diagnosis reveals that it can achieve an area under the receiver operating characteristic (ROC) curve ranging from 82.2% to 98.4% in three independent datasets. Five of these genes form a core repressive module. CCNA1 and ESR1 in particular are evidently silenced by promoter hypermethylation in CRC cell lines and tissues, whose re-expression markedly suppresses tumor cell survival and clonogenicity. These results show that the network-centric method could identify novel disease biomarkers and model how oncogenic lesions mediate epigenetic changes, providing important insights into tumorigenesis. PMID:24317156

Li, Yongsheng; Xu, Juan; Ju, Huanyu; Xiao, Yun; Chen, Hong; Lv, Junying; Shao, Tingting; Bai, Jing; Zhang, Yunpeng; Wang, Li; Wang, Xishan; Ren, Huan; Li, Xia

2014-02-01

70

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

71

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

2012-12-01

72

Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids.  

PubMed

Uterine fibroids are the most common benign tumour afflicting women of reproductive age. Despite the large healthcare burden caused by fibroids, there is only limited understanding of the molecular mechanisms that drive fibroid pathophysiology. Although a large number of genes are differentially expressed in fibroids compared with myometrium, it is likely that most of these differences are a consequence of the fibroid presence and are not causal. The aim of this study was to investigate the expression and regulation of NR2F2 and CTNNB1 based on their potential causal role in uterine fibroid pathophysiology. We used real-time quantitative RT-PCR, western blotting and immunohistochemistry to describe the expression of NR2F2 and CTNNB1 in matched human uterine fibroid and myometrial tissues. Primary myometrial and fibroid smooth muscle cell cultures were treated with progesterone and/or retinoic acid (RA) and sonic hedgehog (SHH) conditioned media to investigate regulatory pathways for these proteins. We showed that NR2F2 and CTNNB1 are aberrantly expressed in fibroid tissue compared with matched myometrium, with strong blood vessel-specific localisation. Although the SHH pathway was shown to be active in myometrial and fibroid primary cultures, it did not regulate NR2F2 or CTNNB1 mRNA expression. However, progesterone and RA combined regulated NR2F2 mRNA, but not CTNNB1, in myometrial but not fibroid primary cultures. In conclusion, we demonstrate aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids compared with normal myometrium, consistent with the hypothesis that these factors may play a causal role uterine fibroid development. PMID:23704310

Zaitseva, Marina; Holdsworth-Carson, Sarah J; Waldrip, Luke; Nevzorova, Julia; Martelotto, Luciano; Vollenhoven, Beverley J; Rogers, Peter A W

2013-08-01

73

Aberrant expression of interferon regulatory factor 3 in human lung cancer  

SciTech Connect

We analyzed the subcellular distributions and gene structures of interferon regulatory factor 3 (IRF3) transcription factor in 50 cases of human primary lung cancer. The immunohistochemical analyses revealed substantially aberrant IRF3 expression specific to the cancer lesions (2 and 6 tumors with nuclear staining, and 4 and 5 tumors with negative staining, in adenocarcinoma and squamous cell carcinoma, respectively), while the morphologically normal region around the tumors exhibited only cytoplasmic staining. In addition, we determined the sequence of the entire IRF3 coding region, and found two novel variants with the amino acid changes (S{sup 175}(AGC) {yields} R{sup 175}(CGC) and A{sup 208}(GCC) {yields} D{sup 208}(GAC)). The R{sup 175} variant was also detected in a morphologically normal region around the nuclear staining squamous cell carcinoma, and exhibited almost the same functions as the wild type IRF3. On the other hand, the D{sup 208} variant, found in the negative staining squamous cell carcinoma cases, reduced the nuclear translocation in response to I{kappa}B kinase {epsilon} stimulation, as compared to the wild type IRF3, but the same variant was detected in the surrounding morphologically normal region. The aberrant expression of IRF3 and the novel D{sup 208} variant may provide clues to elucidate the etiology of primary lung cancer.

Tokunaga, Takayuki [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan) [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Naruke, Yuki; Shigematsu, Sayuri; Kohno, Tomoko; Yasui, Kiyoshi; Ma, Yuhua; Chua, Koon Jiew [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Katayama, Ikuo; Nakamura, Takashi [Department of Radiology and Cancer Biology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Department of Radiology and Cancer Biology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Hishikawa, Yoshitaka; Koji, Takehiko [Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Department of Developmental and Reconstructive Medicine, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Yatabe, Yasushi [Department of Pathology and Clinical Oncology, Aichi Cancer Research Institute, Nagoya 464-8681 (Japan)] [Department of Pathology and Clinical Oncology, Aichi Cancer Research Institute, Nagoya 464-8681 (Japan); Nagayasu, Takeshi [Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)] [Division of Surgical Oncology, Department of Translational Medical Science, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Fujita, Takashi [Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan)] [Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507 (Japan); Matsuyama, Toshifumi, E-mail: tosim@nagasaki-u.ac.jp [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan) [Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Science, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); The Global Center of Excellence Program at Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); and others

2010-06-25

74

High frequency of aberrant p16(INK4A) expression in human breast cancer.  

PubMed Central

The product of the CDKN2/MTS1 gene, p16(INK4A) (16), inhibits phosphorylation of the retinoblastoma protein, pRB, and thus acts as a negative cell cycle regulator. It is inactivated in a wide range of human malignancies, including breast cancer. Using an immunohistochemical approach, we studied the expression of both p16 and pRB in 104 archival breast tumors, including 63 ductal, 33 lobular, and 8 mixed carcinomas. All specimens except one were evaluable for pRB expression, but only 87 were interpretable for p16 expression, reflecting the lower abundance and greater lability of this protein. Only six tumors showed abnormal RB expression. However, 43 carcinomas (49%) were completely (35) or focally (8) negative for p16. Abnormal p16 expression did not significantly correlate with several histopathological parameters. These findings provide evidence that aberrant p16(INK4A) expression is one of the most common abnormalities in human breast cancer. Images Figure 1

Geradts, J.; Wilson, P. A.

1996-01-01

75

Gene Expression Mural: Visualizing Gene Expression Databases  

Microsoft Academic Search

The Gene Expression Mural is a tool designed for managing the vast amount of information produced by the rapidly growing field of Bioinformatics. The advantages of this tool are that it not only provides an overview of many experiments for an entire genome, but also promotes discovery with its zooming and navigation capabilities. A \\

Mathew Clement; Margaret Ellis; Josh Steele; Yuying Tian; Chris North

76

Aberrant crypt foci: detection, gene abnormalities, and clinical usefulness.  

PubMed

Human aberrant crypt foci (ACF) were first identified as lesions consisting of large thick crypts in colonic mucosa of surgical specimens after staining with methylene blue. Previously we succeeded in identifying ACF by using magnifying endoscopy and analyzed the number, size, and dysplastic features of ACF in normal controls and patients with adenoma or cancer patients. On the basis of these analyses, we strongly suggested that ACF, particularly dysplastic ACF, are precursor lesions of the adenoma-carcinoma sequence in humans. In most sporadic ACF, K-ras mutations were positive, but APC mutations were negative irrespective of nondysplastic or dysplastic features. Conversely, in most ACF from familial adenomatous polyposis patients, APC mutations were positive but K-ras mutations were negative. These results may suggest that the molecular mechanism of sporadic colon carcinogenesis is not necessarily the same as that of familial adenomatous polyposis. It was shown that ACF acquired resistance to apoptosis induced by bile salts, whereas normal colonic epithelial cells are turning over consistently by apoptosis. This apoptosis resistance was closely associated with glutathione S-transferase P1-1 expression. One of the most important clinical applications of ACF observation with magnifying endoscopy is its use as a target lesion for chemoprevention. Because ACF are tiny lesions, they should be eradicated during a short time by administration of chemopreventive agents. In fact, we performed an open chemopreventive trial of sulindac and found that the number of ACF was reduced markedly in 2 months. We currently are proceeding with a randomized double-blind trial targeting ACF. PMID:16012995

Takayama, Tetsuji; Miyanishi, Koji; Hayashi, Tsuyoshi; Kukitsu, Takehiro; Takanashi, Kunihiro; Ishiwatari, Hirotoshi; Kogawa, Takahiro; Abe, Tomoyuki; Niitsu, Yoshiro

2005-07-01

77

Expression of the Pluripotency Transcription Factor OCT4 in the Normal and Aberrant Mammary Gland  

PubMed Central

Breast cancers with lactating features, some of which are associated with pregnancy and lactation, are often poorly differentiated, lack estrogen receptor, progesterone receptor, and HER2 expression and have high mortality. Very little is known about the molecular mechanisms that drive uncontrolled cell proliferation in these tumors and confer lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell self-renewal genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and compare it with that observed during normal lactation, using rare specimens of human lactating breast. In accordance with previous literature, the normal resting breast (from non-pregnant, non-lactating women) showed minimal OCT4 nuclear expression (0.9%). However, this increased in the normal lactating breast (11.4%), with further increase in lactating adenomas, lactating carcinomas, and pregnancy-associated breast cancer (30.7–48.3%). OCT4 was expressed in the epithelium and at lower levels in the stroma, and was co-localized with NANOG. Comparison of normal non-tumorigenic hBSCs with OCT4-overexpressing tumorigenic breast cell lines (OTBCs) demonstrated upregulation of OCT4, SOX2, and NANOG in both systems, but OTBCs expressed OCT4 at significantly higher levels than SOX2 and NANOG. Similar to hBSCs, OTBCs displayed multi-lineage differentiation potential, including the ability to differentiate into functional lactocytes synthesizing milk proteins both in vitro and in vivo. Based on these findings, we propose a hypothesis of normal and malignant transformation in the breast, which centers on OCT4 and its associated gene network. Although minimal expression of these embryonic genes can be seen in the breast in its resting state throughout life, a controlled program of upregulation of this gene network may be a potential regulator of the normal remodeling of the breast toward a milk-secretory organ during pregnancy and lactation. Deregulation of this gene network either within or outside pregnancy and lactation may lead to aberrant breast cell proliferation and malignant transformation, suggesting a role of these genes in both normal lactation and breast oncogenesis.

Hassiotou, Foteini; Hepworth, Anna R.; Beltran, Adriana S.; Mathews, Michelle M.; Stuebe, Alison M.; Hartmann, Peter E.; Filgueira, Luis; Blancafort, Pilar

2013-01-01

78

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

79

Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations.  

PubMed

We previously identified a rearrangement of mixed-lineage leukemia (MLL) gene (also known as ALL-1, HRX, and HTRX1), consisting of an in-frame partial tandem duplication (PTD) of exons 5 through 11 in the absence of a partner gene, occurring in approximately 4%-7% of patients with acute myeloid leukemia (AML) and normal cytogenetics, and associated with a poor prognosis. The mechanism by which the MLL PTD contributes to aberrant hematopoiesis and/or leukemia is unknown. To examine this, we generated a mouse knockin model in which exons 5 through 11 of the murine Mll gene were targeted to intron 4 of the endogenous Mll locus. Mll(PTD/WT) mice exhibit an alteration in the boundaries of normal homeobox (Hox) gene expression during embryogenesis, resulting in axial skeletal defects and increased numbers of hematopoietic progenitor cells. Mll(PTD/WT) mice overexpress Hoxa7, Hoxa9, and Hoxa10 in spleen, BM, and blood. An increase in histone H3/H4 acetylation and histone H3 lysine 4 (Lys4) methylation within the Hoxa7 and Hoxa9 promoters provides an epigenetic mechanism by which this overexpression occurs in vivo and an etiologic role for MLL PTD gain of function in the genesis of AML. PMID:16981007

Dorrance, Adrienne M; Liu, Shujun; Yuan, Weifeng; Becknell, Brian; Arnoczky, Kristy J; Guimond, Martin; Strout, Matthew P; Feng, Lan; Nakamura, Tatsuya; Yu, Li; Rush, Laura J; Weinstein, Michael; Leone, Gustavo; Wu, Lizhao; Ferketich, Amy; Whitman, Susan P; Marcucci, Guido; Caligiuri, Michael A

2006-10-01

80

TGF-{beta}-stimulated aberrant expression of class III {beta}-tubulin via the ERK signaling pathway in cultured retinal pigment epithelial cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer TGF-{beta} induces aberrant expression of {beta}III in RPE cells via the ERK pathway. Black-Right-Pointing-Pointer TGF-{beta} increases O-GlcNAc modification of {beta}III in RPE cells. Black-Right-Pointing-Pointer Mature RPE cells have the capacity to express a neuron-associated gene by TGF-{beta}. -- Abstract: The class III {beta}-tubulin isotype ({beta}{sub III}) is expressed exclusively by neurons within the normal human retina and is not present in normal retinal pigment epithelial (RPE) cells in situ or in the early phase of primary cultures. However, aberrant expression of class III {beta}-tubulin has been observed in passaged RPE cells and RPE cells with dedifferentiated morphology in pathologic epiretinal membranes from idiopathic macular pucker, proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). Transforming growth factor-{beta} (TGF-{beta}) has been implicated in dedifferentiation of RPE cells and has a critical role in the development of proliferative vitreoretinal diseases. Here, we investigated the potential effects of TGF-{beta} on the aberrant expression of class III {beta}-tubulin and the intracellular signaling pathway mediating these changes. TGF-{beta}-induced aberrant expression and O-linked-{beta}-N-acetylglucosamine (O-GlcNac) modification of class III {beta}-tubulin in cultured RPE cells as determined using Western blotting, RT-PCR and immunocytochemistry. TGF-{beta} also stimulated phosphorylation of ERK. TGF-{beta}-induced aberrant expression of class III {beta}-tubulin was significantly reduced by pretreatment with U0126, an inhibitor of ERK phosphorylation. Our findings indicate that TGF-{beta} stimulated aberrant expression of class III {beta}-tubulin via activation of the ERK signaling pathway. These data demonstrate that mature RPE cells have the capacity to express a neuron-associated gene in response to TGF-{beta} stimulation and provide useful information towards understanding the pathogenesis of proliferative vitreoretinal diseases.

Chung, Eun Jee [Department of Ophthalmology, National Health Insurance Corporation Ilsan Hospital, Gyeonggi-do (Korea, Republic of)] [Department of Ophthalmology, National Health Insurance Corporation Ilsan Hospital, Gyeonggi-do (Korea, Republic of); Chun, Ji Na; Jung, Sun-Ah [Konyang University Myunggok Medical Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of)] [Konyang University Myunggok Medical Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of); Cho, Jin Won [Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749 (Korea, Republic of)] [Department of Biology, Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Lee, Joon H., E-mail: joonhlee@konyang.ac.kr [Konyang University Myunggok Medical Research Institute, Kim's Eye Hospital, Konyang University College of Medicine, Seoul (Korea, Republic of)

2011-11-18

81

Aberrations of the Tumor Suppressor p53 and Retinoblastoma Genes in Human Hepatocellular Carcinomas1  

Microsoft Academic Search

Aberrations of the p53 gene in 43 primary hepatocellular carcinomas (HCCs) were examined by single-strand conformation polymorphism analysis of polymerase chain reaction products. Of these hepatocellular carcinomas, 22 were advanced HCCs, and 21 were early HCCs. Structural abnormalities of the p53 gene were observed in eight of the 22 advanced HCCs, but in none of the early HCCs. Of the

Yoshinori Murakami; Kenshi Hayashi; Setsuo Hirohashi; Takao Sekiya

82

Aberrant DNA methylation of the PDGF gene in homocysteine?mediated VSMC proliferation and its underlying mechanism.  

PubMed

It is well established that homocysteine (Hcy) is an independent risk factor for atherosclerosis (AS), which is characterized by vascular smooth muscle cell (VSMC) proliferation. However, the molecular mechanism underlying AS in VSMCs is yet to be elucidated. The aim of this study was to investigate the potential involvement of aberrant DNA methylation of the platelet?derived growth factor (PDGF) gene in Hcy?mediated VSMC proliferation and its underlying mechanism. Cultured human VSMCs were treated with varying concentrations of Hcy. VSMC proliferation, PDGF mRNA and protein expression and PDGF promoter demethylation showed a dose?dependent increase with Hcy concentration, suggesting an association among them. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase, indicating that VSMC proliferation was increased under Hcy treatment. Furthermore, S?adenosylhomocysteine (SAH) levels were observed to increase and those of S?adenosylmethionine (SAM) were observed to decrease. The consequent decrease in the ratio of SAM/SAH may partially explain the hypomethylation of PDGF with Hcy treatment. Folate treatment exhibited an antagonistic effect against Hcy?induced VSMC proliferation, aberrant PDGF methylation and PDGF expression. These data suggest that Hcy may stimulate VSMC proliferation through the PDGF signaling pathway by affecting the epigenetic regulation of PDGF through the demethylation of its promoter region. These findings may provide novel insight into the molecular association between aberrant PDGF gene demethylation and the proliferation of VSMCs in Hcy?associated AS. PMID:24841643

Han, Xue-Bo; Zhang, Hui-Ping; Cao, Cheng-Jian; Wang, Yan-Hua; Tian, Jue; Yang, Xiao-Ling; Yang, An-Ning; Wang, Jie; Jiang, Yi-Deng; Xu, Hua

2014-08-01

83

Aberrant DNA Methylation of Matrix Remodeling and Cell Adhesion Related Genes in Pterygium  

PubMed Central

Background Pterygium is a common ocular surface disease characterized by abnormal epithelial and fibrovascular proliferation, invasion, and matrix remodeling. This lesion, which migrates from the periphery to the center of the cornea, impairs vision and causes considerable irritation. The mechanism of pterygium formation remains ambiguous, and current treatment is solely surgical excision, with a significant risk of recurrence after surgery. Here, we investigate the role of methylation in DNA sequences that regulate matrix remodeling and cell adhesion in pterygium formation. Methodology/Principal Findings Pterygium and uninvolved conjunctiva samples were obtained from the same eye of patients undergoing surgery. The EpiTYPER Sequenom technology, based on differential base cleavage and bisulfite sequencing was used to evaluate the extent of methylation of 29 matrix and adhesion related genes. In pterygium, three CpG sites at ?268, ?32 and ?29 bp upstream of transglutaminase 2 (TGM-2) transcription initiation were significantly hypermethylated (p<0.05), whereas hypomethylation was detected at CpGs +484 and +602 bp downstream of matrix metalloproteinase 2 (MMP-2) transcription start site, and ?809, ?762, ?631 and ?629 bp upstream of the CD24 transcription start site. RT-qPCR, western blot and immunofluorescent staining showed that transcript and protein expression were reduced for TGM-2 and increased for MMP-2 and CD24. Inhibition of methylation in cultured conjunctival epithelial cells increased these transcripts. Conclusions/Significance We found regions of aberrant DNA methylation which were consistent with alteration of TGM-2, MMP-2, and CD24 transcript and protein expression, and that inhibition of methylation in cultured cells can increase the expression of these genes. Since these genes were related to cell adhesion and matrix remodeling, dysregulation may lead to fibroblastic and neovascular changes and pterygium formation. These results have implications for the prognostication of pterygium in clinical practice, for example, detection of epigenetic changes may have a role in predicting post surgical recurrence of aggressive lesions.

Riau, Andri K.; Wong, Tina T.; Finger, Sharon N.; Chaurasia, Shyam S.; Hou, Ai Hua; Chen, Silin; Yu, Shang Juan; Tong, Louis

2011-01-01

84

Aberrant expression of redox protein Ape1 in colon cancer stem cells  

PubMed Central

Ape1 is an important redox protein, essential for specific cytokine-induced signal transduction. Ape1 signaling is also important in regulating the growth of cancer cells, including colon cancer cells. The present study investigated whether Ape1 signaling plays a role in the regulation of colon cancer stem cell (CCSC) growth. The results showed that Ape1 was aberrantly expressed in CCSCs, as determined by quantitative (q)PCR assay. A laser confocal microscopy assay demonstrated that the Ape1 protein was mainly distributed in the nuclei, but not the cytoplasm, of the CSCs. Treatment of CCSCs with Ape1 redox inhibitor (E3330) significantly affected growth in vitro. In colon cancer xenograft mice, in vivo administration of E3330 enhanced tumor responses to the chemotherapeutic drug, 5-fluorouracil (5-FU). Furthermore, the combination of E3330 and 5-FU evidently increased the cytotoxicity of 5-FU in CSC growth. In the qPCR assay, the CCSCs were demonstrated to express the dominant ATP-binding cassette sub-family G member 2 (ABC-G2), but not the multidrug resistance 1, genes. Thus, we hypothesized that drug resistance in CCSCs is mediated by ABC-G2. Since CSCs are involved in cancer metastasis, the Ape1 inhibitor may be a potential agent in the inhibition of colon cancer growth and metastasis.

LOU, DEBAO; ZHU, LINA; DING, HUAWEI; DAI, HAI-YAN; ZOU, GANG-MING

2014-01-01

85

Comparison of methods to identify aberrant expression patterns in individual patients: augmenting our toolkit for precision medicine  

PubMed Central

Background Patient-specific aberrant expression patterns in conjunction with functional screening assays can guide elucidation of the cancer genome architecture and identification of therapeutic targets. Since most statistical methods for expression analysis are focused on differences between experimental groups, the performance of approaches for patient-specific expression analyses are currently less well characterized. A comparison of methods for the identification of genes that are dysregulated relative to a single sample in a given set of experimental samples, to our knowledge, has not been performed. Methods We systematically evaluated several methods including variations on the nearest neighbor based outlying degree method, as well as the Zscore and a robust variant for their suitability to detect patient-specific events. The methods were assessed using both simulations and expression data from a cohort of pediatric acute B lymphoblastic leukemia patients. Results We first assessed power and false discovery rates using simulations and found that even under optimal conditions, high effect sizes (>4 unit differences) were necessary to have acceptable power for any method (>0.9) though high false discovery rates (>0.1) were pervasive across simulation conditions. Next we introduced a technical factor into the simulation and found that performance was reduced for all methods and that using weights with the outlying degree could provide performance gains depending on the number of samples and genes affected by the technical factor. In our use case that highlights the integration of functional assays and aberrant expression in a patient cohort (the identification of gene dysregulation events associated with the targets from a siRNA screen), we demonstrated that both the outlying degree and the Zscore can successfully identify genes dysregulated in one patient sample. However, only the outlying degree can identify genes dysregulated across several patient samples. Conclusion Our results show that outlying degree methods may be a useful alternative to the Zscore or Rscore in a personalized medicine context especially in small to medium sized (between 10 and 50 samples) expression datasets with moderate to high sample-to-sample variability. From these results we provide guidelines for detection of aberrant expression in a precision medicine context.

2013-01-01

86

Multi-gene fluorescence in situ hybridization to detect cell cycle gene copy number aberrations in young breast cancer patients.  

PubMed

Breast cancer is a disease of cell cycle, and the dysfunction of cell cycle checkpoints plays a vital role in the occurrence and development of breast cancer. We employed multi-gene fluorescence in situ hybridization (M-FISH) to investigate gene copy number aberrations (CNAs) of 4 genes (Rb1, CHEK2, c-Myc, CCND1) that are involved in the regulation of cell cycle, in order to analyze the impact of gene aberrations on prognosis in the young breast cancer patients. Gene copy number aberrations of these 4 genes were more frequently observed in young breast cancer patients when compared with the older group. Further, these CNAs were more frequently seen in Luminal B type, Her2 overexpression, and tiple-negative breast cancer (TNBC) type in young breast cancer patients. The variations of CCND1, Rb1, and CHEK2 were significantly correlated with poor survival in the young breast cancer patient group, while the amplification of c-Myc was not obviously correlated with poor survival in young breast cancer patients. Thus, gene copy number aberrations (CNAs) of cell cycle-regulated genes can serve as an important tool for prognosis in young breast cancer patients. PMID:24621502

Li, Chunyan; Bai, Jingchao; Hao, Xiaomeng; Zhang, Sheng; Hu, Yunhui; Zhang, Xiaobei; Yuan, Weiping; Hu, Linping; Cheng, Tao; Zetterberg, Anders; Lee, Mong-Hong; Zhang, J

2014-04-15

87

Aberrant expression of HLA-DR antigen on valvular fibroblasts from patients with active rheumatic carditis.  

PubMed Central

Immunofluorescence and immunoperoxidase staining was used to investigate the expression of Class II major histocompatibility antigens in myocardial tissue of 16 patients with acute rheumatic carditis. Aberrant expression of HLA-DR was examined using monoclonal anti-Ia antibodies and was detected on the valvular fibroblasts of those valves with ongoing active carditis. Sections of myocardial and valvular tissue from normal controls or from patients dying of other cardiac diseases did not express HLA-DR. The aberrant expression of HLA-DR on valvular fibroblasts could be important in triggering autoimmune destruction in that these cells could present self-antigens to sensitized T-lymphocytes which could initiate autoantibody production or direct destruction of local tissue. Images Fig. 2

Amoils, B; Morrison, R C; Wadee, A A; Marcus, R; Ninin, D; King, P; Sareli, P; Levin, S; Rabson, A R

1986-01-01

88

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

89

Aberrant Promoter Hypermethylation of the Death-Associated Protein Kinase Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens  

Microsoft Academic Search

Loss of expression of the death-associated protein (DAP)-kinase gene by aberrant promoter methylation may play an important role in cancer development and progression. The purpose of this investigation was to determine the commonality for inactivation of the DAP-kinase gene in adenocarcinomas induced in mice by chronic exposure to mainstream cigarette smoke, the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyr- idyl)-1-butanone (NNK) and vinyl carbamate,

Leah C. Pulling; Brian R. Vuillemenot; Julie A. Hutt; Theodora R. Devereux; Steven A. Belinsky

2004-01-01

90

An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer  

PubMed Central

Background Genomics has substantially changed our approach to cancer research. Gene expression profiling, for example, has been utilized to delineate subtypes of cancer, and facilitated derivation of predictive and prognostic signatures. The emergence of technologies for the high resolution and genome-wide description of genetic and epigenetic features has enabled the identification of a multitude of causal DNA events in tumors. This has afforded the potential for large scale integration of genome and transcriptome data generated from a variety of technology platforms to acquire a better understanding of cancer. Results Here we show how multi-dimensional genomics data analysis would enable the deciphering of mechanisms that disrupt regulatory/signaling cascades and downstream effects. Since not all gene expression changes observed in a tumor are causal to cancer development, we demonstrate an approach based on multiple concerted disruption (MCD) analysis of genes that facilitates the rational deduction of aberrant genes and pathways, which otherwise would be overlooked in single genomic dimension investigations. Conclusions Notably, this is the first comprehensive study of breast cancer cells by parallel integrative genome wide analyses of DNA copy number, LOH, and DNA methylation status to interpret changes in gene expression pattern. Our findings demonstrate the power of a multi-dimensional approach to elucidate events which would escape conventional single dimensional analysis and as such, reduce the cohort sample size for cancer gene discovery.

2010-01-01

91

Gene Expression Profiling in Familial Adenomatous Polyposis Adenomas and Desmoid Disease  

Microsoft Academic Search

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

Nikola A Bowden; Amanda Croft; Rodney J Scott

2007-01-01

92

Association of a d-Alanyl-d-Alanine Carboxypeptidase Gene with the Formation of Aberrantly Shaped Cells during the Induction of Viable but Nonculturable Vibrio parahaemolyticus  

PubMed Central

Vibrio parahaemolyticus is a halophilic Gram-negative bacterium that causes human gastroenteritis. When the viable but nonculturable (VBNC) state of this bacterium was induced by incubation at 4°C in Morita minimal salt solution containing 0.5% NaCl, the rod-shaped cells became coccoid, and various aberrantly shaped intermediates were formed in the initial stage. This study examined the factors that influence the formation of these aberrantly shaped cells. The proportion of aberrantly shaped cells was not affected in a medium containing d-cycloserine (50 ?g/ml) but was lower in a medium containing cephalosporin C (10 ?g/ml) than in the control medium without antibiotics. The proportion of aberrantly shaped cells was higher in a culture medium that contained 0.5% NaCl than in culture media containing 1.0 or 1.5% NaCl. The expression of 15 of 17 selected genes associated with cell wall synthesis was enhanced, and the expression of VP2468 (dacB), which encodes d-alanyl-d-alanine carboxypeptidase, was enhanced the most. The proportion of aberrantly shaped cells was significantly lower in the dacB mutant strain than in the parent strain, but the proportion was restored in the presence of the complementary dacB gene. This study suggests that disturbance of the dynamics of cell wall synthesis by enhanced expression of the VP2468 gene is associated with the formation of aberrantly shaped cells in the initial stage of induction of VBNC V. parahaemolyticus cells under specific conditions.

Hung, Wei-cheng; Jane, Wann-Neng

2013-01-01

93

Aberrant DNA methylation at genes associated with a stem cell-like phenotype in cholangiocarcinoma tumours  

PubMed Central

Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterised. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium’s HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly epigenetically regulated in this tumour type. Using a linear model for microarray data we identified 1610 differentially methylated autosomal CpG sites with 809 CpG sites (representing 603 genes) being hypermethylated and 801 CpG sites (representing 712 genes) being hypomethylated in cholangiocarcinoma versus adjacent normal tissues (false discovery rate ? 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12 and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors.

Dai, Wei; Siddiq, Afshan; Walley, Andrew J; Limpaiboon, Temduang; Brown, Robert

2013-01-01

94

SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers  

PubMed Central

We identify a gene, SLC5A8, and show it is a candidate tumor suppressor gene whose silencing by aberrant methylation is a common and early event in human colon neoplasia. Aberrant DNA methylation has been implicated as a component of an epigenetic mechanism that silences genes in human cancers. Using restriction landmark genome scanning, we performed a global search to identify genes that would be aberrantly methylated at high frequency in human colon cancer. From among 1,231 genomic NotI sites assayed, site 3D41 was identified as methylated in 11 of 12 colon cancers profiled. Site 3D41 mapped to exon 1 of SLC5A8, a transcript that we assembled. In normal colon mucosa we found that SLC5A8 exon 1 is unmethylated and SLC5A8 transcript is expressed. In contrast, SLC5A8 exon 1 proved to be aberrantly methylated in 59% of primary colon cancers and 52% of colon cancer cell lines. SLC5A8 exon 1 methylated cells were uniformly silenced for SLC5A8 expression, but reactivated expression on treatment with a demethylating drug, 5-azacytidine. Transfection of SLC5A8 suppressed colony growth in each of three SLC5A8-deficient cell lines, but showed no suppressive effect in any of three SLC5A8-proficient cell lines. SLC5A8 exon 1 methylation is an early event, detectable in colon adenomas, and in even earlier microscopic colonic aberrant crypt foci. Structural homology and functional testing demonstrated that SLC5A8 is a member of the family of sodium solute symporters, which are now added as a class of candidate colon cancer suppressor genes.

Li, Hui; Myeroff, Lois; Smiraglia, Dominic; Romero, Michael F.; Pretlow, Theresa P.; Kasturi, Lakshmi; Lutterbaugh, James; Rerko, Ronald M.; Casey, Graham; Issa, Jean-Pierre; Willis, Joseph; Willson, James K. V.; Plass, Christoph; Markowitz, Sanford D.

2003-01-01

95

Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD.  

PubMed

Basement membrane abnormalities have often been observed in kidney cysts of polycystic kidney disease (PKD) patients and animal models. There is an abnormal deposition of extracellular matrix molecules, including laminin-?3,?3,?2 (laminin-332), in human autosomal dominant PKD (ADPKD). Knockdown of PKD1 paralogs in zebrafish leads to dysregulated synthesis of the extracellular matrix, suggesting that altered basement membrane assembly may be a primary defect in ADPKD. In this study, we demonstrate that laminin-332 is aberrantly expressed in cysts and precystic tubules of human autosomal recessive PKD (ARPKD) kidneys as well as in the kidneys of PCK rats, an orthologous ARPKD model. There was aberrant expression of laminin-?2 as early as postnatal day 2 and elevated laminin-332 protein in postnatal day 30, coinciding with the formation and early growth of renal cysts in PCK rat kidneys. We also show that a kidney cell line derived from Oak Ridge polycystic kidney mice, another model of ARPKD, exhibited abnormal lumen-deficient and multilumen structures in Matrigel culture. These cells had increased proliferation rates and altered expression levels of laminin-332 compared with their rescued counterparts. A function-blocking polyclonal antibody to laminin-332 significantly inhibited their abnormal proliferation rates and rescued their aberrant phenotype in Matrigel culture. Furthermore, abnormal laminin-332 expression in cysts originating from collecting ducts and proximal tubules as well as in precystic tubules was observed in a human end-stage ADPKD kidney. Our results suggest that abnormal expression of laminin-332 contributes to the aberrant proliferation of cyst epithelial cells and cyst growth in genetic forms of PKD. PMID:24370592

Vijayakumar, Soundarapandian; Dang, Suparna; Marinkovich, M Peter; Lazarova, Zelmira; Yoder, Bradley; Torres, Vicente E; Wallace, Darren P

2014-03-15

96

Male Germ Cell Gene Expression  

Microsoft Academic Search

Formation of the male gamete occurs in sequential mitotic, meiotic, and postmeiotic phases. Many germ cell-specific transcripts are produced during this process. Their expression is develop- mentally regulated and stage specific. Some of these transcripts are product of genes that are male germ cell-specific homologs of genes expressed in somatic cells, while some are expressed from unique genes unlike any

EDWARD M. EDDY

2010-01-01

97

High resolution analysis of genomic aberrations by metaphase and array comparative genomic hybridization identifies candidate tumour genes in lung cancer cell lines.  

PubMed

Tumours develop from clonally expanded population of cells harbouring aberrations of oncogenes and tumour suppressor genes. In this study, metaphase and array comparative genomic hybridization showed good correlation of aberration profiles in lung adenocarcinoma cell lines from patients with different tobacco exposure. Recurrent DNA gains were found at chromosomes 1, 7, 8, 17, 20, and deletions at 1, 3, 8, 9, 10, 12, 17, 18, 19. Candidate tumour loci and encompassed genes at 7p21 (AGR2), 8q21(TPD52), 20q13 (ZNF217, WFDC2, EEF1A2) and 10p15 (KLF6) were analyzed by dual colour FISH for genomic changes and quantitative PCR for expression changes. Results indicated that EEF1A2 and KLF6 were strong candidates of oncogene and tumour suppressor genes, respectively. This study illustrates, a practical strategy for identifying candidate cancer genes from microarray data. PMID:16517066

Zhu, Hong; Lam, David Chi Leung; Han, Kam Chu; Tin, Vicky Pui Chi; Suen, Wai Sing; Wang, Elaine; Lam, Wah Kit; Cai, Wei Wen; Chung, Lap Ping; Wong, Maria Pik

2007-01-01

98

Aberrant immunoglobulin and c-myc gene rearrangements in patients with nonmalignant monoclonal cryoglobulinemia  

SciTech Connect

The status of the immunoglobulin (Ig) genes was investigated in patients with idiopathic nonmalignant monoclonal IgG cryoglobulinemia (NCG). In NCG, monoclonal antibodies are synthesized at an accelerated rate by nonmalignant B lymphocytes. In order to determine whether this high production rate is related to a clonal B cell expansion, the rearrangement of the Ig genes was investigated by Southern blot analysis of genomic, /sup 32/P-labelled, DNA extracted from the peripheral blood lymphocytes of four NCG patients. In three of four (VI, BR, and CH) clonal expansion of B cells was detected using probes specific for the genes. BamHI digestion of DNA from VI and BR produced three rearranged fragments which cohybridized with two of the probes. This finding suggested the presence of additional nonsecretory B cell clones and/or disruption of the gene segments spanned by and detected with the probes. In addition, the possibility of aberrant gene rearrangements was supported by noting the alteration of the c-myc gene locus in genomic DNA from peripheral blood leukocytes of VI and CH. Northern blot analysis of RNA isolated from peripheral blood B cells of VI and CH demonstrated aberrant transcripts of the c-myc gene, showing an active role of the altered c-myc locus. Detection of c-myc rearrangement in NCG patients clearly shows that this event may not be a final step in malignant B cell transformation.

Perl, A.; Wang, N.; Williams, J.M.; Hunt, M.J.; Rosenfeld, S.I.; Condemi, J.J.; Packman, C.H.; Abraham, G.N.

1987-11-15

99

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

100

Reversibility of Aberrant Global DNA and Estrogen Receptor-? Gene Methylation Distinguishes Colorectal Precancer from Cancer  

PubMed Central

Alterations in the global methylation of DNA and in specific regulatory genes are two epigenetic alterations found in cancer. However, the significance of epigenetic changes for diagnosis and/or prognosis of colorectal cancer have not been established, although it has been extensively investigated. Recently we have identified a new type of cancer cell called precancerous stem cells (pCSCs) and proposed that cancer may arise from a lengthy development process of tumor initiating cells (TICs) ? pCSCs ? cancer stem cells (CSCs) ? cancer, which is in parallel to histological changes of hyperplasia (TICs) ? precancer (pCSCs) ? carcinoma (CSCs/cancer cells), accompanied by clonal evolutionary epigenetic and genetic alterations. In this study, we investigated whether aberrant DNA methylation can be used as a biomarker for the differentiation between premalignant and malignant lesions in the colorectum. The profile of global DNA and estrogen receptor (ER)-? gene methylation during cancer development was determined by analysis of 5-methylcytosine (5-MeC) using immunohistochemical (IHC) staining, dot blot analysis or a quantitative gene methylation assay (QGMA). Herein we show that global DNA hypomethylation and ER-? gene hypermethylation are progressively enhanced from hyperplastic polyps (HPs) ? adenomatous polyps (APs) ? adenomatous carcinoma (AdCa). The aberrant methylation can be completely reversed in APs, but not in AdCa by a nonsteroidal anti-inflammatory drug (NSAID) celecoxib, which is a selective inhibitor of cyclooxygenase-2 (Cox-2), suggesting that the epigenetic alterations between colorectal precancer (AP) and cancer (AdCa) are fundamentally different in response to anti-cancer therapy. In normal colorectal mucosa, while global DNA methylation was not affected by aging, ER-? gene methylation was significantly increased with aging. However, this increase did not reach the level observed in colorectal APs. Taken together, reversibility of aberrant global DNA and ER-? gene methylation distinguishes colorectal precancer from cancer.

Shen, Rulong; Tao, Lianhui; Xu, Yiqing; Chang, Shi; Van Brocklyn, James; Gao, Jian-Xin

2009-01-01

101

Linking Gene Expression Patterns to Therapeutic Groups in Breast Cancer1  

Microsoft Academic Search

A major objective of current cancer research is to develop a detailed molecular characterization of tumor cells and tissues that is linked to clinical information. Toward this end, we have identified approximately one-quarter of all genes that were aberrantly expressed in a breast cancer cell line using differential display. The cancer cells lost the expression of many genes involved in

Katherine J. Martin; Brian M. Kritzman; Laura M. Price; Brian Koh; Chi-Pong Kwan; Xiaohong Zhang; Alan Mackay; Michael J. O'Hare; Carolyn M. Kaelin; George L. Mutter; Arthur B. Pardee; Ruth Sager

2000-01-01

102

Analysis of the Rice Mutant dwarf and gladius leaf 1. Aberrant Katanin-Mediated Microtubule Organization Causes Up-Regulation of Gibberellin Biosynthetic Genes Independently of Gibberellin Signaling  

PubMed Central

Molecular genetic studies of plant dwarf mutants have indicated that gibberellin (GA) and brassinosteroid (BR) are two major factors that determine plant height; dwarf mutants that are caused by other defects are relatively rare, especially in monocot species. Here, we report a rice (Oryza sativa) dwarf mutant, dwarf and gladius leaf 1 (dgl1), which exhibits only minimal response to GA and BR. In addition to the dwarf phenotype, dgl1 produces leaves with abnormally rounded tip regions. Positional cloning of DGL1 revealed that it encodes a 60-kD microtubule-severing katanin-like protein. The protein was found to be important in cell elongation and division, based on the observed cell phenotypes. GA biosynthetic genes are up-regulated in dgl1, but the expression of BR biosynthetic genes is not enhanced. The enhanced expression of GA biosynthetic genes in dgl1 is not caused by inappropriate GA signaling because the expression of these genes was repressed by GA3 treatment, and degradation of the rice DELLA protein SLR1 was triggered by GA3 in this mutant. Instead, aberrant microtubule organization caused by the loss of the microtubule-severing function of DGL1 may result in enhanced expression of GA biosynthetic genes in that enhanced expression was also observed in a BR-deficient mutant with aberrant microtubule organization. These results suggest that the function of DGL1 is important for cell and organ elongation in rice, and aberrant DGL1-mediated microtubule organization causes up-regulation of gibberellin biosynthetic genes independently of gibberellin signaling.

Komorisono, Masahiko; Ueguchi-Tanaka, Miyako; Aichi, Ikuko; Hasegawa, Yasuko; Ashikari, Motoyuki; Kitano, Hidemi; Matsuoka, Makoto; Sazuka, Takashi

2005-01-01

103

Alpharetroviral Vector-mediated Gene Therapy for X-CGD: Functional Correction and Lack of Aberrant Splicing  

PubMed Central

Comparative integrome analysis has revealed that the most neutral integration pattern among retroviruses is attributed to alpharetroviruses. We chose X-linked chronic granulomatous disease (X-CGD) as model to evaluate the potential of self-inactivating (SIN) alpharetroviral vectors for gene therapy of monogenic diseases. Therefore, we combined the alpharetroviral vector backbone with the elongation factor-1? short promoter, both considered to possess a low genotoxic profile, to drive transgene (gp91phox) expression. Following efficient transduction transgene expression was sustained and provided functional correction of the CGD phenotype in a cell line model at low vector copy number. Further analysis in a murine X-CGD transplantation model revealed gene-marking of bone marrow cells and oxidase positive granulocytes in peripheral blood. Transduction of human X-CGD CD34+ cells provided functional correction up to wild-type levels and long-term expression upon transplantation into a humanized mouse model. In contrast to lentiviral vectors, no aberrantly spliced transcripts containing cellular exons fused to alpharetroviral sequences were found in transduced cells, implying that the safety profile of alpharetroviral vectors may extend beyond their neutral integration profile. Taken together, this highlights the potential of this SIN alpharetroviral system as a platform for new candidate vectors for future gene therapy of hematopoietic disorders.

Kaufmann, Kerstin B.; Brendel, Christian; Suerth, Julia D.; Mueller-Kuller, Uta; Chen-Wichmann, Linping; Schwable, Joachim; Pahujani, Shweta; Kunkel, Hana; Schambach, Axel; Baum, Christopher; Grez, Manuel

2013-01-01

104

Alpharetroviral vector-mediated gene therapy for X-CGD: functional correction and lack of aberrant splicing.  

PubMed

Comparative integrome analysis has revealed that the most neutral integration pattern among retroviruses is attributed to alpharetroviruses. We chose X-linked chronic granulomatous disease (X-CGD) as model to evaluate the potential of self-inactivating (SIN) alpharetroviral vectors for gene therapy of monogenic diseases. Therefore, we combined the alpharetroviral vector backbone with the elongation factor-1? short promoter, both considered to possess a low genotoxic profile, to drive transgene (gp91(phox)) expression. Following efficient transduction transgene expression was sustained and provided functional correction of the CGD phenotype in a cell line model at low vector copy number. Further analysis in a murine X-CGD transplantation model revealed gene-marking of bone marrow cells and oxidase positive granulocytes in peripheral blood. Transduction of human X-CGD CD34+ cells provided functional correction up to wild-type levels and long-term expression upon transplantation into a humanized mouse model. In contrast to lentiviral vectors, no aberrantly spliced transcripts containing cellular exons fused to alpharetroviral sequences were found in transduced cells, implying that the safety profile of alpharetroviral vectors may extend beyond their neutral integration profile. Taken together, this highlights the potential of this SIN alpharetroviral system as a platform for new candidate vectors for future gene therapy of hematopoietic disorders. PMID:23207695

Kaufmann, Kerstin B; Brendel, Christian; Suerth, Julia D; Mueller-Kuller, Uta; Chen-Wichmann, Linping; Schwäble, Joachim; Pahujani, Shweta; Kunkel, Hana; Schambach, Axel; Baum, Christopher; Grez, Manuel

2013-03-01

105

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

106

Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer.  

PubMed Central

Expression of nuclear factor-kappaB (NF-kappaB)/Rel transcription factors has recently been found to promote cell survival, inhibiting the induction of apoptosis. In most cells other than B lymphocytes, NF-kappaB/Rel is inactive, sequestered in the cytoplasm. For example, nuclear extracts from two human untransformed breast epithelial cell lines expressed only very low levels of NF-kappaB. Unexpectedly, nuclear extracts from two human breast tumor cell lines displayed significant levels of NF-kappaB/Rel. Direct inhibition of this NF-kappaB/ Rel activity in breast cancer cells induced apoptosis. High levels of NF-kappaB/Rel binding were also observed in carcinogen-induced primary rat mammary tumors, whereas only expectedly low levels were seen in normal rat mammary glands. Furthermore, multiple human breast cancer specimens contained significant levels of nuclear NF-kappaB/Rel subunits. Thus, aberrant nuclear expression of NF-kappaB/Rel is associated with breast cancer. Given the role of NF-kappaB/Rel factors in cell survival, this aberrant activity may play a role in tumor progression, and represents a possible therapeutic target in the treatment of these tumors.

Sovak, M A; Bellas, R E; Kim, D W; Zanieski, G J; Rogers, A E; Traish, A M; Sonenshein, G E

1997-01-01

107

Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features  

PubMed Central

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins ?H2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2?, Ap2?, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2? protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

Guler, Gulnur; Himmetoglu, Cigdem; Jimenez, Rafael E.; Geyer, Susan M.; Wang, Wenle P.; Costinean, Stefan; Pilarski, Robert T.; Morrison, Carl; Suren, Dinc; Liu, Jianhua; Chen, Jingchun; Kamal, Jyoti; Shapiro, Charles L.

2013-01-01

108

Aberrant promoter methylation of multiple genes in sputum from individuals exposed to smoky coal emissions  

PubMed Central

Summary Aberrant methylation in the promoter region of cancer-related genes leads to gene transcriptional inactivation and plays an integral role in lung tumorigenesis. Recent studies demonstrated that promoter methylation was detected not only in lung tumors from patients with lung cancer but also in sputum of smokers without the disease, suggesting the potential for aberrant gene promoter methylation in sputum as a predictive marker for lung cancer. In the present study, we investigated promoter methylation of 4 genes frequently detected in lung tumors, including p16, MGMT, RASSF1A and DAPK genes, in sputum samples obtained from 107 individuals, including 34 never-smoking females and 73 mostly smoking males, who had no evidence of lung cancer but who were exposed to smoky coal emission in Xuan Wei County, China, where lung cancer rate is more than 6 times the Chinese national average rate. Forty nine of the individuals showed evidence of chronic bronchitis while the remaining 58 individuals showed no such a symptom. Promoter methylation of p16, MGMT, RASSF1A and DAPK was detected in 51.4% (55/107), 17.8% (19/107), 29.9% (32/107), and 15.9% (17/107) of the sputum samples from these individuals, respectively. There were no differences in promoter methylation frequencies of any of these genes according to smoking status or gender of the subjects or between individuals with chronic bronchitis and those without evidence of such a symptom. Therefore, individuals exposed to smoky coal emissions in this region harbored in their sputum frequent promoter methylation of these genes that have been previously found in lung tumors and implicated in lung cancer development.

Liu, Yang; Lan, Qing; Shen, Min; Mumford, Judy; Keohavong, Phouthone

2010-01-01

109

Expression divergence between duplicate genes  

Microsoft Academic Search

A general picture of the role of expression divergence in the evolution of duplicate genes is emerging, thanks to the availability of completely sequenced genomes and functional genomic data, such as microarray data. It is now clear that expression divergence, regulatory-motif divergence and coding-sequence divergence all increase with the age of duplicate genes, although their exact interrelationships remain to be

Wen-Hsiung Li; Jing Yang; Xun Gu

2005-01-01

110

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

111

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

112

Evolutionary biclustering of gene expressions  

Microsoft Academic Search

With the advent of microarray technology it has been possible to measure thousands of expression values of genes in a single experiment. Biclustering or simultaneous clustering of both genes and conditions is challenging particularly for the analysis of high-dimensional gene expression data in information retrieval, knowledge discovery, and data mining. The objective here is to find sub-matrices, i.e., maximal subgroups

Haider Banka; Sushmita Mitra

2006-01-01

113

Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: Mechanism, function, and implication for a potential novel therapeutic target.  

PubMed

Treatment for high-risk pediatric and adult acute B cell lymphoblastic leukemia (B-ALL) remains challenging. Exploring novel pathways in B-ALL could lead to new therapy. Our previous study has shown that stem cell factor SALL4 is aberrantly expressed in B-ALL, but its functional roles and the mechanism that accounts for its upregulation in B-ALL remain unexplored. To address this question, we first surveyed the existing B-ALL cell lines and primary patient samples for SALL4 expression. We then selected the B-ALL cell lines with the highest SALL4 expression for functional studies. RNA interference was used to downregulate SALL4 expression in these cell lines. When compared with control cells, SALL4 knockdown cells exhibited decreased cell proliferation, increased apoptosis in vitro, and decreased engraftment in a xenotransplant model in vivo. Gene expression analysis showed that in SALL4 knockdown B-ALL cells, multiple caspase members involved in cell apoptosis pathway were upregulated. Next, we explored the mechanisms of aberrant SALL4 expression in B-ALL. We found that hypomethylation of the SALL4 CpG islands was correlated with its high expression. Furthermore, treatment of low SALL4-expressing B-ALL cell lines with DNA methylation inhibitor led to demethylation of the SALL4 CpG and increased SALL4 expression. In summary, to our knowledge, we are the first to show that the aberrant expression of SALL4 in B-ALL is associated with hypomethylation, and that SALL4 plays a key role in B-ALL cell survival and could be a potential novel target in B-ALL treatment. PMID:24463278

Ueno, Shikiko; Lu, Jiayun; He, Jie; Li, Ailing; Zhang, Xiaoxian; Ritz, Jerome; Silberstein, Leslie E; Chai, Li

2014-04-01

114

Aberrant histone modification in endometriosis.  

PubMed

Accumulating evidence suggests that epigenetic aberrations play definite roles in the pathogenesis of endometriosis. These include aberrations in genomic DNA methylation, microRNA expression, and histone modification. The aberrant histone modification status and the aberrant expression of histone deacetylases, which regulate histone acetylation, in endometriosis are the focus of this review. Herein, we summarize the recent studies in the following areas: (i) hyperacetylation of histones located in the promoter lesions of G-protein-coupled estrogen receptor 1, steroidogenic factor-1, and hypoxia-inducible factor-1 alpha genes and (ii) hypoacetylation of histones located in the promoter lesions of estrogen receptor alpha, homeobox A10, CCAAT/enhancer-binding protein alpha, p16(INK4a), p21(Waf1/Cip1), p27(Kip1), checkpoint kinase 2, death receptor 6, and E-cadherin genes. Further research from the viewpoint of epigenetics may lead to the identification of the candidate molecules that are aberrantly expressed in endometriosis and may help elucidate the pathogenesis of this disease. In addition, epigenetic drugs (including histone deacetylase inhibitors) show promise for the treatment of endometriosis by amending the expression of these epigenetically dysregulated genes. PMID:24896345

Nasu, Kaei; Kawano, Yukie; Kai, Kentaro; Aoyagi, Yoko; Abe, Wakana; Okamoto, Mamiko; Narahara, Hisashi

2014-01-01

115

Monoallelic gene expression in mammals  

Microsoft Academic Search

Three systems of monoallelic gene expression in mammals are known, namely, X-chromosome inactivation, imprinting, and allelic\\u000a exclusion. In all three systems, monoallelic expression is regulated epigenetically and is frequently directed by long non-coding\\u000a RNAs (ncRNAs). This review briefs all three systems of monoallelic gene expression in mammals focusing on chromatin modifications,\\u000a spatial chromosome organization in the nucleus, and the functioning

Irina S. Zakharova; Alexander I. Shevchenko; Suren M. Zakian

2009-01-01

116

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

117

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

PubMed

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. PMID:22621904

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

2012-07-01

118

Aberrant cytoplasmic expression of the p16 protein in breast cancer is associated with accelerated tumour proliferation.  

PubMed Central

The p16 protein plays an important role in the transition of cells into the G1 phase of the cell cycle. We have studied the prevalence of p16 protein expression in breast carcinomas in a prospective series of 368 invasive and 52 non-invasive malignancies, as well as in 88 locally recurring tumours and three tumour cell lines. p16 protein expression was evaluated immunohistochemically on paraffin sections using monoclonal and polyclonal anti-p16 antibodies, and by immunoblotting of tumour cell suspensions. Tumour cell lines were also subjected to polymerase chain reaction-single strand polymorphism (PCR-SSCP) analysis and direct DNA sequencing. The results were compared with established prognostic parameters, DNA flow cytometry and p53 protein expression. In 33 (9%) invasive and two (4%) intraductal carcinomas, a cytoplasmic accumulation of the p16 protein was seen. These cases were characterized by poor histological grade of differentiation, loss of of oestrogen receptors and progesterone receptors and frequent overexpression of the p53 protein. In addition, breast carcinomas with aberrant p16 expression demonstrated a high proliferative activity, with median S-phase fractions 74% higher than in the control group and the median Ki67 fractions elevated to 75%. A genetic alteration of the p16 gene was not detectable in three analysed cell lines with cytoplasmic p16 expression applying PCR-SSCP and direct DNA sequencing. These results indicate that cytoplasmic accumulation of the p16 protein identifies a subset of highly malignant breast carcinomas with accelerated tumour proliferation and other unfavourable parameters in breast cancer. The described protein accumulation is apparently not caused by an alteration of the p16 gene. Images Figure 1 Figure 4

Emig, R.; Magener, A.; Ehemann, V.; Meyer, A.; Stilgenbauer, F.; Volkmann, M.; Wallwiener, D.; Sinn, H. P.

1998-01-01

119

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

120

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

2013-11-01

121

Imprinted gene expression in hybrids: perturbed mechanisms and evolutionary implications.  

PubMed

Diverse mechanisms contribute to the evolution of reproductive barriers, a process that is critical in speciation. Amongst these are alterations in gene products and in gene dosage that affect development and reproductive success in hybrid offspring. Because of its strict parent-of-origin dependence, genomic imprinting is thought to contribute to the aberrant phenotypes observed in interspecies hybrids in mammals and flowering plants, when the abnormalities depend on the directionality of the cross. In different groups of mammals, hybrid incompatibility has indeed been linked to loss of imprinting. Aberrant expression levels have been reported as well, including imprinted genes involved in development and growth. Recent studies in humans emphasize that genetic diversity within a species can readily perturb imprinted gene expression and phenotype as well. Despite novel insights into the underlying mechanisms, the full extent of imprinted gene perturbation still remains to be determined in the different hybrid systems. Here we review imprinted gene expression in intra- and interspecies hybrids and examine the evolutionary scenarios under which imprinting could contribute to hybrid incompatibilities. We discuss effects on development and reproduction and possible evolutionary implications. PMID:24619185

Wolf, J B; Oakey, R J; Feil, R

2014-08-01

122

TRPM8 ion channel is aberrantly expressed and required for preventing replicative senescence in pancreatic adenocarcinoma  

PubMed Central

Pancreatic adenocarcinoma is mostly fatal and generally resistant to conventional treatments, such that effective therapies with tolerable side effects are desperately needed. Ion channels including the transient receptor potential (TRP) channels have been implicated in human malignancies, but their roles in pancreatic cancer were mostly unknown. Recent identification of the melastatin-subfamily members of the TRP family of ion channels, and their functions in pancreatic epithelia and adenocarcinoma, is expected to provide a new perspective to understanding the mechanism underlying pancreatic tumorigenesis. In this report, we present the clinical and pathological features of a mini-series of patients with pancreatic adenocarcinoma, which aberrantly exhibits immunoreactivity against the TRPM8 channel. We have recently demonstrated the proliferative role of TRPM8 channel in pancreatic cancer cells. Here, we present evidence that RNA interference-mediated silencing of TRPM8 induces replicative senescence in pancreatic adenocarcinoma cells. This suggests that the aberrantly expressed TRPM8 channel may contribute to pancreatic tumorigenesis by preventing oncogene-induced senescence, and targeted inhibition of TRPM8 may enhance tumor sensitivity to therapeutics. Based on these observations, we hypothesize that the TRPM8 ion channel plays a crucial role in the growth and progression of pancreatic neoplasia during tumorigenesis. We propose that TRPM8 can be exploited as a clinical biomarker and as a therapeutic target for developing personalized therapy in pancreatic adenocarcinoma.

Yee, Nelson S.; Brown, Robert D.; Lee, Min Sun; Zhou, Weiqiang; Jensen, Chris; Gerke, Henning; Yee, Rosemary K.

2012-01-01

123

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

2013-06-01

124

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

2011-12-01

125

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

126

Book Review: Plant Gene Expression  

NSDL National Science Digital Library

Whereas many important biological discoveries have been made using plants, subsequent progress in some areas of plant research has fallen behind that in other organisms for which funding and in vitro assays are more readily available. Gene expression is one such field in which importance continues to grow because many potential plant biotechnology–based solutions to global problems depend on regulating the expression of specific genes. Previous limitations to exploring gene expression in plants have been partially mitigated by recent advances in genomics, genetics, and transformation techniques. The book Regulation of Gene Expression in Plants: The Role of Transcript Structure and Processing, edited by Carole L. Bassett, summarizes our current understanding of plant gene expression, with an emphasis on transcriptional and posttranscriptional regulation. The topics covered in six chapters include differences in messenger RNA (mRNA) structure caused by variations in transcription start and polyadenylation sites, alternative splicing, regulation by small RNAs, and mRNA transport and degradation. The chapters vary in depth, quality, and the degree to which the emphasis is placed on plants rather than eukaryotes in general. However, this slim volume is a useful review of gene expression in plants. The question of whether or not all differences in mRNA structure have functional importance remains open.

Alan Rose (University of California Davis;Molecular and Cellular Biology REV)

2007-05-22

127

Aberrant Expression and Secretion of Heat Shock Protein 90 in Patients with Bullous Pemphigoid  

PubMed Central

The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses and its inhibition has proven successful in different mouse models of autoimmune diseases, including epidermolysis bullosa acquisita. Here, we investigated expression levels and secretory responses of Hsp90 in patients with bullous pemphigoid (BP), the most common subepidermal autoimmune blistering skin disease. In comparison to healthy controls, the following observations were made: (i) Hsp90 was highly expressed in the skin of BP patients, whereas its serum levels were decreased and inversely associated with IgG autoantibody levels against the NC16A immunodominant region of the BP180 autoantigen, (ii) in contrast, neither aberrant levels of circulating Hsp90 nor any correlation of this protein with serum autoantibodies was found in a control cohort of autoimmune bullous disease patients with pemphigus vulgaris, (iii) Hsp90 was highly expressed in and restrictedly released from peripheral blood mononuclear cells of BP patients, and (iv) Hsp90 was potently induced in and restrictedly secreted from human keratinocyte (HaCaT) cells by BP serum and isolated anti-BP180 NC16A IgG autoantibodies, respectively. Our results reveal an upregulated Hsp90 expression at the site of inflammation and an autoantibody-mediated dysregulation of the intracellular and extracellular distribution of this chaperone in BP patients. These findings suggest that Hsp90 may play a pathophysiological role and represent a novel potential treatment target in BP.

Tukaj, Stefan; Kleszczynski, Konrad; Vafia, Katerina; Groth, Stephanie; Meyersburg, Damian; Trzonkowski, Piotr; Ludwig, Ralf J.; Zillikens, Detlef; Schmidt, Enno; Fischer, Tobias W.; Kasperkiewicz, Michael

2013-01-01

128

Immunohistochemical expression of aberrant Notch-1 signaling in vitiligo: an implication for pathogenesis.  

PubMed

The etiopathogenetic mechanisms leading to pigment loss in vitiligo are not fully understood. Notch signaling is required for development and maintenance of melanocyte lineage and acts as a key component among keratinocyte-melanocyte interactions. The current study aimed to investigate the possible role of Notch signaling and its effect on the whole melanocyte lineage in vitiligo and correlating it with the different clinicopathologic parameters. Using immunohistochemical technique, Notch-1 expression was evaluated in 50 lesional and 20 perilesional biopsies of patients with vitiligo in comparison with 20 normal skin biopsies as a control group. Lesional biopsies were stained with human melanoma black-45 and tyrosinase-related protein-2 to demonstrate the melanocyte lineage. Membranous and/or nuclear expression of Notch-1 was in favor of control and perilesional skin, whereas cytoplasmic expression appeared only in vitiliginous lesions (P < .05). Membranous and/or nuclear expression of Notch-1 was significantly associated with epidermal human melanoma black-45 positivity (P = .01) and percentage of expression in both epidermis (P = .02) and hair follicles (P = .03) of lesional skin. Cytoplasmic pattern of Notch-1 expression in epidermis was significantly found in lesions with white hair (P = .04) and in cases with marked keratinocyte vacuolization (P = .03). Segmental and acrofacial vitiligo were associated with mild to moderate Notch-1 intensity, whereas generalized vitiligo was associated with strong intensity of expression (P = .02). In conclusion, Notch-1 signaling is inactivated in vitiligo with consequent loss of epidermal and/or follicular active melanocytes. Aberrant Notch signaling in vitiliginous white hair and acral and segmental vitiligo may be the cause of their treatment resistance. PMID:24560443

Seleit, Iman; Bakry, Ola Ahmed; Abdou, Asmaa Gaber; Dawoud, Noha Mohammed

2014-06-01

129

Differentially Expressed Genes in Hormone Refractory Prostate Cancer  

PubMed Central

Differential gene expression between the androgen sensitive human prostate cancer cell line LNCaP and an insensitive clonal variant, LNCaP-r, was demonstrated by suppression subtractive hybridization. Twenty-one sequences were identified of which 9 are homologous to known genes, 11 are represented by expressed sequence tags (ESTs), and 1 is novel. We present data for 5 of 7 sequences confirmed to be differentially expressed by Northern blot analysis and semiquantitative RT-PCR. Only one gene, fibronectin (FN), was highly overexpressed (>60-fold) in LNCaP-r cells, consistent with previously reported overexpression of FN in prostate cancer. Four sequences were down-regulated in LNCaP-r cells, including an inactive variant of the E2 ubiquitin conjugating enzyme (UEV-1), a novel metalloproteinase-related collagenase (PM5), and a potential tumor suppressor gene (breast basic conserved gene, BBC1). UEV-1 is multifunctional, regulates the cell cycle via cdk1, has homology to MMS2 and likewise functions as a DNA protection protein, and also has homology to TSG101. Aberrant splice variants of TSG101 occur frequently in both breast and prostate cancer, but its mechanism of action is unknown. FN, BBC1, and UEV-1 localize to regions of chromosomal aberration (2q3.4, 16q24.3, and 20q13.2, respectively) associated with advanced prostate cancer and thus may be highly relevant to disease progression.

Stubbs, Andrew P.; Abel, Paul D.; Golding, Matthew; Bhangal, Gurjeet; Wang, Qin; Waxman, Jonathan; Stamp, Gordon W.H.; Lalani, El-Nasir

1999-01-01

130

Shared gene expression in distinct neurons expressing common selector genes  

PubMed Central

Expression of the mec-3/unc-86 selector gene complex induces the differentiation of the touch receptor neurons (TRNs) of Caenorhabditis elegans. These genes are also expressed in another set of embryonically derived mechanosensory neurons, the FLP neurons, but these cells do not share obvious TRN traits or proteins. We have identified ?300 genes in each cell type that are up-regulated at least threefold using DNA microarrays. Twenty-three percent of these genes are up-regulated in both cells. Surprisingly, some of the common genes had previously been identified as TRN-specific. Although the FLP neurons contain low amounts of the mRNAs for these TRN genes, they do not have detectable proteins. These results suggest that transcription control is relatively inexact but that these apparent errors of transcription are tolerated and do not alter cell fate. Previous studies showed that loss of the EGL-44 and EGL-46 transcription factors cause the FLP neurons to acquire TRN-like traits. Here, we show that similar changes occur (e.g., the expression of both the TRN mRNAs and proteins) when the FLP neurons ectopically express the auxiliary transcription factor ALR-1 (Aristaless related), which ensures, but does not direct, TRN differentiation. Thus, the FLP neurons can acquire a TRN-like fate but use multiple levels of regulation to ensure they do not. Our data indicate that expression of common master regulators in different cell types can result in inappropriate expression of effector genes. This misexpression makes these cells vulnerable to influences that could cause them to acquire alternative fates.

Topalidou, Irini; Chalfie, Martin

2011-01-01

131

Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy.  

PubMed

Dysregulation of homologous recombination (HR) DNA repair has been implicated in breast carcinogenesis and chemosensitivity. Here, we investigated the methylation status of sixteen HR genes and analyzed their association with tumor subtypes and responses to neoadjuvant chemotherapy. Core specimens were obtained before neoadjuvant chemotherapy from sixty cases of primary breast cancer of the following four subgroups: luminal breast cancer (LBC) with pathological complete response (pCR), LBC with stable disease, triple-negative breast cancer (TNBC) with pCR and TNBC with poor response. The aberrant DNA methylation status of the following HR related-genes was analyzed using bisulfite-pyrosequencing: BRCA1, BRCA2, BARD1, MDC1, RNF8, RNF168, UBC13, ABRA1, PALB2, RAD50, RAD51, RAD51C, MRE11, NBS1, CtIP and ATM. Among the genes analyzed, only the incidence of BRCA1 and RNF8 methylation was significantly higher in TNBC than that in LBC. Whereas the incidence of BRCA1 methylation was tended to be higher in pCR cases than in poor-response cases in TNBC, that of RNF8 was significantly lower in pCR cases than in poor-response cases. Our results indicate that the methylation status of HR genes was not generally associated with TNBC subtype or chemosensitivity although hypermethylation of BRCA1 is associated with TNBC subtype and may impact chemosensitivity. PMID:24581343

Watanabe, Yoshiyuki; Maeda, Ichiro; Oikawa, Ritsuko; Wu, Wenwen; Tsuchiya, Kyoko; Miyoshi, Yasuo; Itoh, Fumio; Tsugawa, Ko-ichiro; Ohta, Tomohiko

2013-12-01

132

Ke 6 gene. Sequence and organization and aberrant regulation in murine polycystic kidney disease.  

PubMed

Ke 6 gene is a newly identified gene located in the major histocompatibility complex and is a candidate steroid dehydrogenase gene because of structural homology and regulatory similarities with mammalian steroid dehydrogenases. We report here the complete nucleotide sequence and intron-exon organization of the Ke 6 gene and cloning of the alternatively spliced Ke 6b transcript. We find that Ke 6 gene expression is down-regulated in pcy mice which is a murine model of polycystic kidney disease (PKD). Thus far, Ke 6 gene expression is down-regulated in all murine models of PKD we have examined. Abnormal steroid metabolism as a possible cause of PKD is discussed. PMID:7559658

Maxwell, M M; Nearing, J; Aziz, N

1995-10-20

133

Systems Biophysics of Gene Expression  

PubMed Central

Gene expression is a process central to any form of life. It involves multiple temporal and functional scales that extend from specific protein-DNA interactions to the coordinated regulation of multiple genes in response to intracellular and extracellular changes. This diversity in scales poses fundamental challenges to the use of traditional approaches to fully understand even the simplest gene expression systems. Recent advances in computational systems biophysics have provided promising avenues to reliably integrate the molecular detail of biophysical process into the system behavior. Here, we review recent advances in the description of gene regulation as a system of biophysical processes that extend from specific protein-DNA interactions to the combinatorial assembly of nucleoprotein complexes. There is now basic mechanistic understanding on how promoters controlled by multiple, local and distal, DNA binding sites for transcription factors can actively control transcriptional noise, cell-to-cell variability, and other properties of gene regulation, including precision and flexibility of the transcriptional responses.

Vilar, Jose M.G.; Saiz, Leonor

2013-01-01

134

The Immunoconjugate "Icon" Targets Aberrantly Expressed Endothelial Tissue Factor Causing Regression of Endometriosis  

PubMed Central

Endometriosis is a major cause of chronic pain, infertility, medical and surgical interventions, and health care expenditures. Tissue factor (TF), the primary initiator of coagulation and a modulator of angiogenesis, is not normally expressed by the endothelium; however, prior studies have demonstrated that both blood vessels in solid tumors and choroidal tissue in macular degeneration express endothelial TF. The present study describes the anomalous expression of TF by endothelial cells in endometriotic lesions. The immunoconjugate molecule (Icon), which binds with high affinity and specificity to this aberrant endothelial TF, has been shown to induce a cytolytic immune response that eradicates tumor and choroidal blood vessels. Using an athymic mouse model of endometriosis, we now report that Icon largely destroys endometriotic implants by vascular disruption without apparent toxicity, reduced fertility, or subsequent teratogenic effects. Unlike antiangiogenic treatments that can only target developing angiogenesis, Icon eliminates pre-existing pathological vessels. Thus, Icon could serve as a novel, nontoxic, fertility-preserving, and effective treatment for endometriosis.

Krikun, Graciela; Hu, Zhiwei; Osteen, Kevin; Bruner-Tran, Kaylon L.; Schatz, Frederick; Taylor, Hugh S.; Toti, Paolo; Arcuri, Felice; Konigsberg, William; Garen, Alan; Booth, Carmen J.; Lockwood, Charles J.

2010-01-01

135

Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer  

PubMed Central

Protein Phosphatase 2A (PP2A) is an important and ubiquitously expressed serine threonine phosphatase and regulates the function by dephosphorylating many critical cellular molecules like Akt, p53, c-Myc and ?-catenin. It plays a critical role in cellular processes, such as cell proliferation, signal transduction and apoptosis. Structurally, it is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. PP2A undergoes post-translational modifications (i.e. phosphorylation and methylation), which in turn, regulates its enzymatic activity. Aberrant expression, mutations and somatic alterations of the PP2A scaffold and regulatory subunits have been observed in various human malignancies, including lung, breast, skin and colon cancer, highlighting its role as a ‘tumor suppressor’. This review is focused on the structural complexity of serine/threonine phosphatase PP2A and summarizes its expression pattern in cancer. Additionally, the PP2A interacting and regulatory proteins and substrates are also discussed. Finally, the mouse models developed to understand the biological role of PP2A subunits in an in vivo model system are also reviewed in this article.

Seshacharyulu, Parthasarathy; Pandey, Poomy; Datta, Kaustubh; Batra, Surinder K.

2013-01-01

136

EGFR and MYC gene copy number aberrations are more common in squamous cell carcinoma than keratoacanthoma: a FISH study.  

PubMed

Epidermal growth factor receptor (EGFR) and MYC genomic aberrations have been described in cutaneous squamous cell carcinoma (SCC) but have not been widely investigated in keratoacanthoma (KA). EGFR and MYC were evaluated by fluorescence in situ hybridization and immunohistochemistry in 8 verrucae, 19 involuting KA (IKA), 23 classic KA (CKA), 6 atypical KA (AKA) and 19 SCC. Increased EGFR gene copy number was seen in 9 of 23 CKA and 14 of 19 SCC (p = 0.03). Increased MYC gene copy number was observed in 7 of 23 CKA and 17 of 19 SCC (p = 0.0001). MYC gene amplification was more common in SCC than CKA (p = 0.005), while EGFR gene amplification was rare and not significant. MYC protein overexpression was identified in 6 of 23 CKA and 14 of 19 SCC (p = 0.005). There was no statistical difference in EGFR protein overexpression in SCC and CKA (p = 0.06). EGFR and MYC aberrations were rare in IKA. AKA showed EGFR and MYC anomalies at an incidence intermediate between CKA and SCC. EGFR and MYC gene copy number aberrations are more common in SCC than KA. The incidence of aberrations parallels the degree of cytologic atypia in KA. PMID:23521519

Jacobs, Melissa S; Persons, Diane L; Fraga, Garth R

2013-05-01

137

Concomitant aberrant methylation of p15 and MGMT genes in acute myeloid leukemia: association with a particular immunophenotype of blast cells.  

PubMed

In this study, methylation-specific polymerase chain reaction (MS-PCR) was used to define the methylation status of the target promoter sequences of p15 and MGMT genes in the group of 21 adult patients with acute myeloid leukemia (AML). The incidence of aberrant hypermethylation of p15 gene (71 %) was higher comparing to MGMT gene (33 %), whereas concomitant methylation of both genes had 24 % of the patients. Although the incidence of cytogenetic abnormalities between the groups with a different methylation status of p15 and/or MGMT genes was not significantly different, we observed general trend of clustering of abnormalities with adverse prognosis into groups with concomitant hypermethylation of both genes and only p15 gene. Also, we showed that AML patients with concomitant methylation of p15/MGMT genes had a higher proportion of leukemic blast cells characterized with specific expression of individual leukocyte surface antigens (CD117(+)/CD7(+)/CD34(+)/CD15(-)), indicating leukemic cells as early myeloid progenitors. Although we could not prove that hypermethylation of p15 and/or MGMT genes is predictive parameter for response to therapy and overall survival, we noticed that AML patients with comethylated p15/MGMT genes or methylated p15 gene exhibited a higher frequency of early death, lower frequency of complete remissions as well as a trend for shorter overall survival. Assessing of the methylation status of p15 and MGMT genes may allow stratification of patients with AML into distinct groups with potentially different prognosis. PMID:22772967

Kraguljac Kurtovi?, Nada; Krajnovi?, Milena; Bogdanovi?, Andrija; Suvajdži?, Nada; Jovanovi?, Jelica; Dimitrijevi?, Bogomir; Colovi?, Milica; Krtolica, Koviljka

2012-12-01

138

Aberrant expression of IL-22 receptor 1 (IL-22R1) and autocrine IL-22 stimulation contribute to tumorigenicity in ALK-positive anaplastic large cell lymphoma  

PubMed Central

One of the characteristic features of anaplastic lymphoma kinase (ALK)-positive, anaplastic large cell lymphoma (ALK+ALCL) is the constitutive activation of STAT3, a defect believed to be important for the pathogenesis of these tumors. In this report, we describe the existence of an autocrine stimulatory loop involving interleukin-22 (IL-22) that contributes to STAT3 activation and tumorigenicity of ALK+ALCL. The IL-22 receptor, a heterodimer composed of IL-22R1 and IL-10R2, was expressed in all ALK+ALCL cell lines and tumors examined. The expression of IL-22R1 in ALK+ALCL is aberrant, since this protein is absent in benign lymphocytes. While ALK+ALCL cells produce endogenous IL-22, addition of recombinant IL-22 to ALK+ALCL cell lines significantly increased STAT3 activation, cell proliferation and colony formation in soft agar. Opposite biological effects were observed in cells treated with recombinant IL-22BP (a naturally-occurring IL-22 decoy) or IL-22 neutralizing antibody. NPM-ALK, the characteristic fusion gene oncoprotein expressed in ALK+ALCL, directly contributes to the aberrant expression of IL-22R1, since transfection of NPM-ALK in Jurkat cells induced IL-22R1 expression and IL-22-mediated STAT3 activation. To conclude, for the first time, we demonstrate the importance of the IL-22 autocrine pathway in a lymphoid malignancy, and reveal yet another novel function of NPM-ALK.

Bard, Jennifer Dien; Gelebart, Pascal; Anand, Mona; Amin, Hesham M.; Lai, Raymond

2012-01-01

139

Chromosome aberrations and HEY1-NCOA2 fusion gene in a mesenchymal chondrosarcoma  

PubMed Central

Mesenchymal chondrosarcomas are fast-growing tumors that account for 2–10% of primary chondrosarcomas. Cytogenetic information is restricted to 12 cases that did not show a specific aberration pattern. Recently, two fusion genes were described in mesenchymal chondrosarcomas: a recurrent HEY1-NCOA2 found in tumors that had not been cytogenetically characterized and an IRF2BP2-CDX1 found in a tumor carrying a t(1;5)(q42;q32) translocation as the sole chromosomal abnormality. Here, we present the cytogenetic and molecular genetic analysis of a mesenchymal chondrosarcoma in which the patient had two histologically indistinguishable tumor lesions, one in the neck and one in the thigh. An abnormal clone with the G-banding karyotype 46,XX,add(6)(q23),add(8)(p23),del(10)(p11),+12,?15[6] was found in the neck tumor whereas a normal karyotype, 46,XX, was found in the tumor of the thigh. RT-PCR and Sanger sequencing showed that exon 4 of HEY1 was fused to exon 13 of NCOA2 in the sample from the thigh lesion; we did not have spare material to perform a similar analysis of the neck tumor. Examining the published karyotypes we observed numerical or structural aberrations of chromosome 8 in the majority of the karyotyped mesenchymal chondrosarcomas. Chromosome 8 was also structurally affected in the present study. The pathogenetic mechanisms behind this nonrandom involvement are unknown, but the presence on 8q of two genes, HEY1 and NCOA2, now known to be involved in mesenchymal chondrosarcoma tumorigenesis is, of course, suggestive.

PANAGOPOULOS, IOANNIS; GORUNOVA, LUDMILA; BJERKEHAGEN, BODIL; BOYE, KJETIL; HEIM, SVERRE

2014-01-01

140

Chromosome aberrations and HEY1-NCOA2 fusion gene in a mesenchymal chondrosarcoma.  

PubMed

Mesenchymal chondrosarcomas are fast-growing tumors that account for 2-10% of primary chondrosarcomas. Cytogenetic information is restricted to 12 cases that did not show a specific aberration pattern. Recently, two fusion genes were described in mesenchymal chondrosarcomas: a recurrent HEY1-NCOA2 found in tumors that had not been cytogenetically characterized and an IRF2BP2-CDX1 found in a tumor carrying a t(1;5)(q42;q32) translocation as the sole chromosomal abnormality. Here, we present the cytogenetic and molecular genetic analysis of a mesenchymal chondrosarcoma in which the patient had two histologically indistinguishable tumor lesions, one in the neck and one in the thigh. An abnormal clone with the G-banding karyotype 46,XX,add(6)(q23),add(8)(p23),del(10)(p11),+12,-15[6] was found in the neck tumor whereas a normal karyotype, 46,XX, was found in the tumor of the thigh. RT-PCR and Sanger sequencing showed that exon 4 of HEY1 was fused to exon 13 of NCOA2 in the sample from the thigh lesion; we did not have spare material to perform a similar analysis of the neck tumor. Examining the published karyotypes we observed numerical or structural aberrations of chromosome 8 in the majority of the karyotyped mesenchymal chondrosarcomas. Chromosome 8 was also structurally affected in the present study. The pathogenetic mechanisms behind this nonrandom involvement are unknown, but the presence on 8q of two genes, HEY1 and NCOA2, now known to be involved in mesenchymal chondrosarcoma tumorigenesis is, of course, suggestive. PMID:24839999

Panagopoulos, Ioannis; Gorunova, Ludmila; Bjerkehagen, Bodil; Boye, Kjetil; Heim, Sverre

2014-07-01

141

An aberrant spliced transcript of focal adhesion kinase is exclusively expressed in human breast cancer  

PubMed Central

Purpose To clarify the roles of a new aberrantly spliced transcript of FAK that lacks exon 26 (denoted -26-exon FAK) in human breast cancers. Methods Transcripts of FAK expressed in 102 human breast tumor tissues and 52 corresponding normal tissues were analyzed by RT-PCR and DNA sequencing, as well as agarose gel electrophoresis. The cDNA of -26-exon FAK was cloned and expressed in MCF-10A cells, and then the kinase activity, cellular localization and migration capability of FAK were examined by western blotting, immunofluorescent staining and migration assays, respectively. The expression levels of FAK were analyzed by western blotting in MCF-7 cells treated with TNF-? or in MCF-10A cells upon serum deprivation. The MCF-10A cells transfected with a plasmid expressing -26-exon FAK were cultured in serum-free medium and cell apoptosis was analyzed by flow cytometry. Results The -26-exon FAK transcript was exclusively present in human breast tumor tissues and the encoded protein possessed the same kinase activity, cellular localization and cell migration-promoting ability as wild-type FAK. In MCF-7 cells treated with TNF-?, and in MCF-10A cells upon serum deprivation, the -26-exon FAK was resistant to proteolysis while wild-type FAK was largely cleaved. In addition, the -26-exon FAK, but not wild-type FAK, inhibited cell apoptosis. Conclusions The -26-exon FAK transcript, which is exclusively expressed in human breast tumor tissues, encodes a protein that possesses the same kinase activity and biological function as the wild-type FAK, but because it is resistant to the caspase-mediated cleavage that induces the proteolysis of the wild-type form, it ultimately prevents apoptosis.

2014-01-01

142

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

143

Aberrant c-erbB2 expression in cell clusters overlying focally disrupted breast myoepithelial cell layers: a trigger or sign for emergence of more aggressive cell clones?  

PubMed Central

Our recent studies revealed that cell clusters overlying focal myoepithelial cell layer disruption (FMCLD) had a significantly higher frequency of genetic instabilities and expression of invasion-related genes than their adjacent counterparts within the same duct. Our current study attempted to assess whether these cell clusters would also have elevated c-erbB2 expression. Human breast tumors (n=50) with a high frequency of FMCLD were analyzed with double immunohistochemistry, real-time RT-PCR, and chromogenic in situ hybridization for c-erbB2 protein and gene expression. Of 448 FMCLD detected, 404 (90.2%) were associated with cell clusters that had intense c-erbB2 immunoreactivities primarily in their cytoplasm, in contrast to their adjacent counterparts within the same duct, which had no or barely detectable c-erbB2 expression. These c-erbB2 positive cells were arranged as tongue-like projections, “puncturing” into the stroma, and about 20% of them were in direct continuity with tube-like structures that resembled blood vessels. Aberrant c-erbB2 expression was also seen in clusters of architecturally normal-appearing ducts that had distinct cytological abnormalities in both ME and epithelial cells, whereas not in their clear-cut normal counterparts. Molecular assays detected markedly higher c-erbB2 mRNA and gene amplification in cell clusters associated with FMCLD than in those associated with non-disrupted ME cell layers. Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant cerbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.

Zhang, Xichen; Hashemi, Shahreyar Shar; Yousefi, Morvarid; Ni, Jinsong; Wang, Qiuyue; Gao, Ling; Gong, Pengtao; Gao, Chunling; Sheng, Joy; Mason, Jeffrey; Man, Yan-gao

2008-01-01

144

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

145

Aberrant DNA methyltransferase expression in pancreatic ductal adenocarcinoma development and progression  

PubMed Central

Background Altered gene methylation, regulated by DNA methyltransferases (DNMT) 1, 3a and 3b, contributes to tumorigenesis. However, the role of DNMT in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods Expression of DNMT 1, 3a and 3b was detected in 88 Pancreatic ductal adenocarcinoma (PDAC) and 10 normal tissue samples by immunohistochemistry. Changes in cell viability, cell cycle distribution, and apoptosis of PDAC cell lines (Panc-1 and SW1990) were assessed after transfection with DNMT1 and 3b siRNA. Levels of CDKN1A, Bcl-2 and Bax mRNA were assessed by qRT-PCR, and methylation of the Bax gene promoter was assayed by methylation-specific PCR (MSP). Results DNMT1, 3a and 3b proteins were expressed in 46.6%, 23.9%, and 77.3% of PDAC tissues, respectively, but were not expressed in normal pancreatic tissues. There was a co-presence of DNMT3a and DNMT3b expression and an association of DNMT1 expression with alcohol consumption and poor overall survival. Moreover, knockdown of DNMT1 and DNMT3b expression significantly inhibited PDAC cell viability, decreased S-phase but increased G1-phase of the cell cycle, and induced apoptosis. Molecularly, expression of CDKN1A and Bax mRNA was upregulated, and the Bax gene promoter was demethylated. However, a synergistic effect of combined DNMT1 and 3b knockdown was not observed. Conclusion Expression of DNMT1, 3a and 3b proteins is increased in PDAC tissues, and DNMT1 expression is associated with poor prognosis of patients. Knockdown of DNMT1 and 3b expression arrests tumor cells at the G1 phase of the cell cycle and induces apoptosis. The data suggest that DNMT knockdown may be a novel treatment strategy for PDAC.

2013-01-01

146

?4 Integrin and Laminin 5 Are Aberrantly Expressed in Polycystic Kidney Disease  

PubMed Central

Extracellular matrix alterations have been suggested to be part of the early events occurring in Autosomal Dominant Polycystic Kidney Disease (ADPKD), a disease characterized by formation of renal cysts and progressive renal failure. Here we report that cDNA array analysis identified ?4 integrin aberrant expression in ADPKD cells. Furthermore, laminin 5 (Ln-5), the main ?6?4 integrin ligand, was also found to be abnormally expressed in ADPKD. Studies performed with ADPKD cyst-lining epithelial cells (CC) by comparison with normal tubular cells indicate that integrin ?6?4-Ln-5 interactions are involved in cellular events of potential importance for cystogenesis: 1) laminin 5 is a preferential adhesion substrate for CC, mainly through ?6?4 interaction, 2) CC increased haptotactic and chemotactic motility depends on the presence of Ln-5 and requires integrin ?3?1 cooperation, and 3) CC haptotactic or chemotactic migration is specifically increased by mAb-mediated ?4 integrin ligation, through an ?3?1 integrin-dependent and independent pathway, respectively. These results highlight the role of Ln-5 and ?6?4 integrin in adhesive and motility properties of cyst-lining epithelial cells, and further suggest that integrins and extracellular matrix modifications may be of general relevance to kidney epithelial cell cyst formation.

Joly, Dominique; Morel, Viviane; Hummel, Aurelie; Ruello, Antonella; Nusbaum, Patrick; Patey, Natacha; Noel, Laure-Helene; Rousselle, Patricia; Knebelmann, Bertrand

2003-01-01

147

Aberrant miRNA expression response to UV irradiation in human liver cancer cells.  

PubMed

microRNAs (miRNAs) are small, highly conserved, non-coding RNAs that regulate gene expression at the post?transcriptional level. The expression of these small RNA genes is tightly regulated during development, differentiation and apoptosis of normal cells, however, they are often deregulated in various types of cancer. miRNA expression is also affected by cellular stress, including radiation and chemotherapy. The present study monitored the expression levels of several miRNAs by using the stem-loop real-time polymerase chain reaction (PCR) in HepG2 cells following ultraviolet (UV) radiation. Our data demonstrated that UV irradiation is able to induce alterations in miRNA expression levels in HepG2 cells. Among them, miR-26a, miR-34a and miR-146a were significantly upregulated, while the expression of miR-21 was significantly downregulated. Bioinformatics analysis of these significantly regulated miRNAs was discussed. The results also indicated that miRNAs may be part of the innate response mechanism of the cells to radiation injury, which provides a rationale for miRNA replacement therapy by using specific miRNAs that may function as tumor suppressor genes in several types of cancer. PMID:24431000

Liang, Gaofeng; Li, Guangda; Wang, Yanyan; Lei, Wanjun; Xiao, Zhongdang

2014-03-01

148

Transgenic Arabidopsis Gene Expression System  

NASA Technical Reports Server (NTRS)

The Transgenic Arabidopsis Gene Expression System (TAGES) investigation is one in a pair of investigations that use the Advanced Biological Research System (ABRS) facility. TAGES uses Arabidopsis thaliana, thale cress, with sensor promoter-reporter gene constructs that render the plants as biomonitors (an organism used to determine the quality of the surrounding environment) of their environment using real-time nondestructive Green Fluorescent Protein (GFP) imagery and traditional postflight analyses.

Ferl, Robert; Paul, Anna-Lisa

2009-01-01

149

Ontogeny of erythroid gene expression  

PubMed Central

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.

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

2013-01-01

150

Zipf's Law in Gene Expression  

NASA Astrophysics Data System (ADS)

Using data from gene expression databases on various organisms and tissues, including yeast, nematodes, human normal and cancer tissues, and embryonic stem cells, we found that the abundances of expressed genes exhibit a power-law distribution with an exponent close to -1; i.e., they obey Zipf’s law. Furthermore, by simulations of a simple model with an intracellular reaction network, we found that Zipf’s law of chemical abundance is a universal feature of cells where such a network optimizes the efficiency and faithfulness of self-reproduction. These findings provide novel insights into the nature of the organization of reaction dynamics in living cells.

Furusawa, Chikara; Kaneko, Kunihiko

2003-02-01

151

DNA methylation and gene expression.  

PubMed

A large body of evidence demonstrates that DNA methylation plays a role in gene regulation in animal cells. Not only is there a correlation between gene transcription and undermethylation, but also transfection experiments clearly show that the presence of methyl moieties inhibits gene expression in vivo. Furthermore, gene activation can be induced by treatment of cells with 5-azacytidine, a potent demethylating agent. Methylation appears to influence gene expression by affecting the interactions with DNA of both chromatin proteins and specific transcription factors. Although methylation patterns are very stable in somatic cells, the early embryo is characterized by large alterations in DNA modification. New methodologies are now becoming available for studying methylation at this stage and in the germ line. During development, tissue-specific genes undergo demethylation in their tissue of expression. In tissue culture cells this process is highly specific and appears to involve an active mechanism which takes place in the absence of DNA replication. The X chromosome undergoes inactivation during development; this is accompanied by de novo methylation, which appears necessary to stably maintain its silent state. As opposed to the programmed changes in DNA methylation which occur in vivo, immortalized tissue culture cells demonstrate alterations in DNA modification which take place over a long time scale and which appear to be the result of selective pressures present during the growth of these cells in culture. PMID:1943996

Razin, A; Cedar, H

1991-09-01

152

Stimulation of the aberrant expression of a paraneoplastic antigen, recoverin, in small cell lung cancer cell lines.  

PubMed

Recoverin, a retina-specific Ca2+-binding protein, is one of the paraneoplastic antigens (PNAs) which are normally present in neurons, but can also be aberrantly expressed in malignant tumors localized outside the nervous system. In this study, we have analyzed 16 small cell lung carcinoma (SCLC) and 12 non-small cell lung carcinoma cell lines and found that none of them is capable of expressing recoverin in vitro. However, two small cell lung carcinoma lines, NCI-H69 and NCI-H82, became recoverin-positive after cultivation in the presence of butyrate. Recoverin expression in the butyrate-treated cells has been detected by immunoblotting with polyclonal (monospecific) antibodies against recoverin and confirmed by the analysis of recoverin mRNA expression. To our knowledge, this work is the first to demonstrate stimulation of the aberrant expression of recoverin in cancer cell lines in vitro. This result opens the way to investigation of the mechanisms underlying the aberrant expression of recoverin, as well as other paraneoplastic antigens, in tumor cells. PMID:15301870

Bazhin, Alexandr V; Savchenko, Marina S; Belousov, Eugene V; Jaques, Gabriele; Philippov, Pavel P

2004-09-01

153

Trichostatin A reverses skewed expression of CD154, interleukin-10, and interferon-? gene and protein expression in lupus T cells  

PubMed Central

In systemic lupus erythematosus (SLE), T helper cells exhibit increased and prolonged expression of cell-surface CD40 ligand (CD154), spontaneously overproduce interleukin-10 (IL-10), but underproduce interferon-gamma (IFN-?). We tested the hypothesis that the imbalance of these gene products reflects skewed expression of CD154, IL-10, and IFN-? genes. Here, we demonstrate that the histone deacetylase inhibitor, trichostatin A, significantly down-regulated CD154 and IL-10 and up-regulated IFN-? gene expression in SLE T cells. This reversal corrected the aberrant expression of these gene products, thereby enhancing IFN-? production and inhibiting IL-10 and CD154 expression. That trichostatin A can simultaneously reverse the skewed expression of multiple genes implicated in the immunopathogenesis of SLE suggests that this pharmacologic agent may be a candidate for the treatment of this autoimmune disease.

Mishra, Nilamadhab; Brown, Doris R.; Olorenshaw, Irene M.; Kammer, Gary M.

2001-01-01

154

Gene dysregulations driven by somatic copy number aberrations-biological and clinical implications in colon tumors: a paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology.  

PubMed

The majority of colorectal cancer (CRC) cases have chromosomal instability, in which the tumor genome is characterized by gross chromosomal aberrations such as gains in 20q, 13q, 8q, and 7, and losses in 4, 8p, 18q, and 17p. These somatic copy number changes (gains, losses, and somatic uniparental disomies) are crucial to CRC progression as they drive genes toward cancer-promoting (oncogenic or tumor suppressive) states. Numerous studies have shown that the loss of 18q or 8p is associated with poorer clinical outcome in CRCs. Either chromosomal arm may contain a tumor suppressor gene (or genes), whose deactivation by copy loss (loss of wild-type allele, decreased expression) can be crucial to the later stages of cancer progression. Our own integrated genomic analysis (single nucleotide polymorphism array, expression array) of more than 200 CRC tumor and normal samples indicates that the overall down-regulation of genes within the 8p or 18q arm is associated with lower survival rate. Among the often down-regulated, poor prognosis-associated 8p genes is MTUS1, whose gene product (a mitotic spindle-associated protein) was recently demonstrated to have a tumor suppressive property. Within 18q is ATP5A1, which codes for the catalytic a component of mitochondrial H(+)-ATP synthase. Like SMAD4 (also in 18q), the decreased expression of ATP5A1 appears to be a marker of unfavorable clinical outcome in CRCs. PMID:20709793

Bacolod, Manny D; Barany, Francis

2010-09-01

155

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

156

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

157

Ikaros gene expression and leukemia.  

PubMed

The Ikaros (Ik) protein, or LyF1, was initially described as a protein binding to regulatory sequences of a number of genes expressed in murine lymphoid cells. Ikaros is a critical regulator of normal hematopoietic stem cell differentiation, as evidenced by dramatic defects in the lymphoid compartments, in homozygous animals with gene inactivation. Because differential splicing produces multiple isoforms with potentially different functions, Ikaros provides a unique model to study how post-transcriptional mechanisms may be involved in neoplastic processes. Indeed, several groups including ours have underlined evidences that expression of different Ikaros isoforms vary among different types of leukemias. The predominance of short isoforms in certain subsets is intriguing. Here, additional observations reinforced the hypothesis that Ikaros expression may be deregulated in human leukemias. Whether this is a cause or a consequence of the leukemic process remains speculative. Other human diseases however, provide examples of abnormal post-transcriptional regulations that have been further characterized. PMID:11908734

Tonnelle, Cécile; Calmels, Boris; Maroc, Christine; Gabert, Jean; Chabannon, Christian

2002-01-01

158

Analysis of Microarray Gene Expression Data  

Microsoft Academic Search

Microarrays provide the biological research community with tremendously rich, sensitive and detailed information on gene expression profiles. Gene expression profiling and gene expression patterns have been found useful for solving a wide variety of important biological and biomedical problems, including the study of metabolic pathways, inference of the functions of unknown genes, diagnosis of diseased states, as well as facilitating

Tuan D. Pham; Christine Wells; Denis I. Crane

2006-01-01

159

Chromosome aberrations in solid tumors  

Microsoft Academic Search

Chromosome aberrations in human solid tumors are hallmarks of gene deregulation and genome instability. This review summarizes current knowledge regarding aberrations, discusses their functional importance, suggests mechanisms by which aberrations may form during cancer progression and provides examples of clinical advances that have come from studies of chromosome aberrations.

Colin Collins; Frank McCormick; Donna G Albertson; Joe W. Gray

2003-01-01

160

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

161

Dynamic modeling of gene expression data  

Microsoft Academic Search

We describe the time evolution of gene expression levels by using a time translational matrix to predict future expression levels of genes based on their expression levels at some initial time. We deduce the time translational matrix for previously published DNA microarray gene expression data sets by modeling them within a linear framework by using the characteristic modes obtained by

Neal S. Holter; Amos Maritan; Marek Cieplak; Nina V. Fedoroff; Jayanth R. Banavar

2001-01-01

162

Altered Expression of MGMT in High-Grade Gliomas Results from the Combined Effect of Epigenetic and Genetic Aberrations  

PubMed Central

MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy.

Ramalho-Carvalho, Joao; Pires, Malini; Lisboa, Susana; Graca, Ines; Rocha, Patricia; Barros-Silva, Joao Diogo; Savva-Bordalo, Joana; Mauricio, Joaquina; Resende, Mario; Teixeira, Manuel R.; Honavar, Mrinalini; Henrique, Rui; Jeronimo, Carmen

2013-01-01

163

Altered expression of MGMT in high-grade gliomas results from the combined effect of epigenetic and genetic aberrations.  

PubMed

MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy. PMID:23505468

Ramalho-Carvalho, João; Pires, Malini; Lisboa, Susana; Graça, Inês; Rocha, Patrícia; Barros-Silva, João Diogo; Savva-Bordalo, Joana; Maurício, Joaquina; Resende, Mário; Teixeira, Manuel R; Honavar, Mrinalini; Henrique, Rui; Jerónimo, Carmen

2013-01-01

164

Aberrant expression of immunoglobulin mRNA in bovine leukemia virus-infected cattle.  

PubMed

Our objective was to determine whether bovine leukemia virus (BLV) integration and expression affect the expression of host genes that function in immune responses and cell proliferation. Freshly isolated mlgM+ cells obtained from BLV-infected cows with persistent lymphocytosis (PL) expressed increased Ig-mu mRNA and decreased mRNA for Ig-lambda relative to infected and uninfected animals that had normal peripheral lymphocyte counts. In contrast, there was no correlation between BLV-infection status and expression of major histocompatibility complex (Mhc) Class I or Class II genes. The induction of BLV expression in mlgM+ cells from animals with PL did not affect significantly the levels of Mhc Class I, Class II, Ig-mu or Ig-lambda mRNA. Phorbol ester-induced c-fos mRNA expression was greater in the BLV-infected cell line BL3 degrees than the uninfected parental cell line BL3 degrees. However, the level of c-fos expression did not appear different compared with its induction in peripheral blood B cells from seronegative animals and animals with PL. We conclude that the BLV early and late phase proteins have no effect on Ig or Mhc mRNA levels, but that freshly isolated mlgM+ cells from PL animals constitutively express increased Ig-mu and decreased Ig-lambda mRNA. These data suggest that the increase in Ig-mu and mlgM on B cells from PL cows is related to a differentiation state rather than trans-activation by BLV. PMID:8941971

Teutsch, M R; Lewin, H A

1996-09-01

165

Discovering Connected Patterns in Gene Expression Arrays  

Microsoft Academic Search

Clustering methods have been extensively used for gene expression data analysis to detect groups of related genes. The clusters provide useful information to analyze gene function, gene regulation and cellular patterns. Most existing clustering algorithms, though, discover only coherent gene expression patterns, and do not handle connected patterns. Coherent and connected patterns correspond to globular and arbitrary shaped clusters, respectively,

Noha A. Yousri; Mohamed A. Ismail; Mohamed S. Kamel

2007-01-01

166

Gene Expression in Trypanosomatid Parasites  

PubMed Central

The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa.

Martinez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C.; Florencio-Martinez, Luis E.; Manning-Cela, Rebeca G.; Figueroa-Angulo, Elisa E.

2010-01-01

167

Gene expression in trypanosomatid parasites.  

PubMed

The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa. PMID:20169133

Martínez-Calvillo, Santiago; Vizuet-de-Rueda, Juan C; Florencio-Martínez, Luis E; Manning-Cela, Rebeca G; Figueroa-Angulo, Elisa E

2010-01-01

168

Regulators of gene expression as biomarkers for prostate cancer  

PubMed Central

Recent technological advancements in gene expression analysis have led to the discovery of a promising new group of prostate cancer (PCa) biomarkers that have the potential to influence diagnosis and the prediction of disease severity. The accumulation of deleterious changes in gene expression is a fundamental mechanism of prostate carcinogenesis. Aberrant gene expression can arise from changes in epigenetic regulation or mutation in the genome affecting either key regulatory elements or gene sequences themselves. At the epigenetic level, a myriad of abnormal histone modifications and changes in DNA methylation are found in PCa patients. In addition, many mutations in the genome have been associated with higher PCa risk. Finally, over- or underexpression of key genes involved in cell cycle regulation, apoptosis, cell adhesion and regulation of transcription has been observed. An interesting group of biomarkers are emerging from these studies which may prove more predictive than the standard prostate specific antigen (PSA) serum test. In this review, we discuss recent results in the field of gene expression analysis in PCa including the most promising biomarkers in the areas of epigenetics, genomics and the transcriptome, some of which are currently under investigation as clinical tests for early detection and better prognostic prediction of PCa.

Willard, Stacey S; Koochekpour, Shahriar

2012-01-01

169

Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene  

PubMed Central

Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), and microhomology-mediated replication-dependent recombination (MMRDR) have all been put forward as mechanisms to explain DNA rearrangements associated with genomic disorders. However, many nonrecurrent rearrangements in humans remain unexplained. To further investigate the mutation mechanisms of these copy number variations (CNVs), we performed breakpoint mapping analysis for 62 clinical cases with intragenic deletions in the human DMD gene (50 cases) and other known disease-causing genes (one PCCB, one IVD, one DBT, three PAH, one STK11, one HEXB, three DBT, one HRPT1, and one EMD cases). While repetitive elements were found in only four individual cases, three involving DMD and one HEXB gene, microhomologies (2–10 bp) were observed at breakpoint junctions in 56% and insertions ranging from 1 to 48 bp were seen in 16 of the total 62 cases. Among these insertions, we observed evidence for tandem repetitions of short segments (5–20 bp) of reference sequence proximal to the breakpoints in six individual DMD cases (six repeats in one, four repeats in three, two repeats in one, and one repeat in one case), strongly indicating attempts by the replication machinery to surpass the stalled replication fork. We provide evidence of a novel template slippage event during replication rescue. With a deeper insight into the complex process of replication and its rescue during origin failure, brought forward by recent studies, we propose a hypothesis based on aberrant firing of replication origins to explain intragenic nonrecurrent rearrangements within genes, including the DMD gene.

Ankala, Arunkanth; Kohn, Jordan N.; Hegde, Anisha; Meka, Arjun; Ephrem, Chin Lip Hon; Askree, Syed H.; Bhide, Shruti; Hegde, Madhuri R.

2012-01-01

170

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

171

Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium.  

PubMed

Long non-coding RNAs (lncRNAs) have emerged recently as key regulatory molecules with diverse roles at almost every level of the regulation of gene expression. The roles of these RNAs in the pathogenesis of cystic fibrosis (CF); a lethal multisystem, autosomal recessive disorder have yet to be explored. Our aim was to examine the expression profile of lncRNA, in the airway epithelium of people with CF. We examined the expression of 30,586 lncRNAs by microarray (Human LncRNA Array v3.0, Arraystar, Inc.), in vivo in bronchial cells isolated from endobronchial brushings obtained from CF and non-CF individuals. In total, we identified 1,063 lncRNAs with differential expression between CF and non-CF individuals (fold change ?3, p?0.001). The microarray also contained probes for ?26,109 protein coding transcripts, of which 720 were differentially expressed between CF and non-CF brush samples (fold change ?3, p?0.001). Confirmation of a selection of differentially expressed coding mRNA and lncRNA transcripts such as XIST and TLR8 was achieved using qRT-PCR. Gene ontology bioinformatics analysis highlighted that many processes over-represented in the CF bronchial epithelium are related to inflammation. These data show a significantly altered lncRNA and mRNA expression profile in CF bronchial cells in vivo. Dysregulation of some of these lncRNAs may play important roles in the chronic infection and inflammation that exists in the lungs of people with CF. This article is part of a directed issue entitled: Cystic fibrosis: from o-mics to cell biology, physiology, and therapeutic advances. PMID:24631641

McKiernan, Paul J; Molloy, Kevin; Cryan, Sally A; McElvaney, Noel G; Greene, Catherine M

2014-07-01

172

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

173

Aberrant silencing of the endocrine peptide gene tachykinin-1 in gastric cancer  

SciTech Connect

Tachykinin-1 (TAC1) is the precursor protein for neuroendocrine peptides, including substance P, and is centrally involved in gastric secretion, motility, mucosal immunity, and cell proliferation. Here we report aberrant silencing of TAC1 in gastric cancer (GC) by promoter hypermethylation. TAC1 methylation and mRNA expression in 47 primary GCs and 41 noncancerous gastric mucosae (NLs) were analyzed by utilizing real-time quantitative PCR-based assays. TAC1 methylation was more prevalent in GCs than in NLs: 21 (45%) of 47 GCs versus 6 (15%) of 41 NLs (p < 0.01). Microsatellite instability was also associated with TAC1 methylation in GCs. There was no significant association between TAC1 methylation and age, gender, stage, histological differentiation, or the presence of Helicobacter pylori. TAC1 mRNA was markedly downregulated in GCs relative to NLs. 5-Aza-2'-deoxycytidine-induced demethylation of the TAC1 promoter resulted in TAC1 mRNA upregulation. Further studies are indicated to elucidate the functional involvement of TAC1 in gastric carcinogenesis.

David, Stefan; Kan, Takatsugu; Cheng, Yulan; Agarwal, Rachana; Jin, Zhe [Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, 1503 E. Jefferson Street Office 108, Baltimore, MA 21287 (United States); Mori, Yuriko [Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, 1503 E. Jefferson Street Office 108, Baltimore, MA 21287 (United States)], E-mail: ymori3@jhmi.edu

2009-01-16

174

Gene expression in diabetic nephropathy  

Microsoft Academic Search

Diabetic nephropathy (DN) is a common complication of diabetes types 1 and 2. One of the hallmarks of DN is the development\\u000a of mesangial expansion, which occurs through accumulation of extracellular matrix (ECM) components. Altered local gene expression\\u000a of humoral factors (eg, transforming growth factor-â, connective tissue growth factor, and platelet-derived growth factor) can lead to increased\\u000a production of ECM

Daniela Hohenadel; Fokko J. van der Woude

2004-01-01

175

Gene expression in Chromobacterium violaceum  

Microsoft Academic Search

The repertoire of 4,431 open reading frames (ORFs), eight rRNA operons and 98 tRNA genes of Chromobacterium viola- ceum must be expressed in a regulated manner for successful adapta- tion to a wide variety of environmental conditions. To accomplish this feat, the organism relies on protein machineries involved in transcription, RNA processing and translation. Analysis of the C. violaceum genome

Rosane Silva; Júlia R. Araripe; Edson Rondinelli; Turán P. Ürményi

2004-01-01

176

Classification of genes based on gene expression analysis  

SciTech Connect

Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

Angelova, M., E-mail: maia.angelova@unn.ac.uk; Myers, C., E-mail: chris.myers@unn.ac.uk; Faith, J., E-mail: joe.faith@unn.ac.u [Northumbria University (United Kingdom)

2008-05-15

177

Classification of genes based on gene expression analysis  

NASA Astrophysics Data System (ADS)

Systems biology and bioinformatics are now major fields for productive research. DNA microarrays and other array technologies and genome sequencing have advanced to the point that it is now possible to monitor gene expression on a genomic scale. Gene expression analysis is discussed and some important clustering techniques are considered. The patterns identified in the data suggest similarities in the gene behavior, which provides useful information for the gene functionalities. We discuss measures for investigating the homogeneity of gene expression data in order to optimize the clustering process. We contribute to the knowledge of functional roles and regulation of E. coli genes by proposing a classification of these genes based on consistently correlated genes in expression data and similarities of gene expression patterns. A new visualization tool for targeted projection pursuit and dimensionality reduction of gene expression data is demonstrated.

Angelova, M.; Myers, C.; Faith, J.

2008-05-01

178

Gene Expression Studies in Mosquitoes  

PubMed Central

Research on gene expression in mosquitoes is motivated by both basic and applied interests. Studies of genes involved in hematophagy, reproduction, olfaction, and immune responses reveal an exquisite confluence of biological adaptations that result in these highly-successful life forms. The requirement of female mosquitoes for a bloodmeal for propagation has been exploited by a wide diversity of viral, protozoan and metazoan pathogens as part of their life cycles. Identifying genes involved in host-seeking, blood feeding and digestion, reproduction, insecticide resistance and susceptibility/refractoriness to pathogen development is expected to provide the bases for the development of novel methods to control mosquito-borne diseases. Advances in mosquito transgenesis technologies, the availability of whole genome sequence information, mass sequencing and analyses of transcriptomes and RNAi techniques will assist development of these tools as well as deepen the understanding of the underlying genetic components for biological phenomena characteristic of these insect species.

Chen, Xlao-Guang; Mathur, Geetika; James, Anthony A.

2009-01-01

179

Epigenetic manipulation of gene expression  

PubMed Central

Cell biologists have been afforded extraordinary new opportunities for experimentation by the emergence of powerful technologies that allow the selective manipulation of gene expression. Currently, RNA interference is very much in the limelight; however, significant progress has also been made with two other approaches. Thus, antisense oligonucleotide technology is undergoing a resurgence as a result of improvements in the chemistry of these molecules, whereas designed transcription factors offer a powerful and increasingly convenient strategy for either up- or down-regulation of targeted genes. This mini-review will highlight some of the key features of these three approaches to gene regulation, as well as provide pragmatic guidance concerning their use in cell biological experimentation based on our direct experience with each of these technologies. The approaches discussed here are being intensely pursued in terms of possible therapeutic applications. However, we will restrict our comments primarily to the cell culture situation, only briefly alluding to fundamental differences between utilization in animals versus cells.

Juliano, Rudy L.; Dixit, Vidula R.; Kang, Hyunmin; Kim, Tai Young; Miyamoto, Yuko; Xu, Dong

2005-01-01

180

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

181

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

2013-12-01

182

Critical Role for Aberrant CpG Island Methylation in the Evolution and Progression of Breast Cancer: Characterization of Known Genes and Identification of Novel Genes.  

National Technical Information Service (NTIS)

CpG island methylation is an epigenetic modification of DNA associated with the silencing of gene transcription. The hypothesis of this proposal is that breast cancers develop along different pathways, some involving aberrant CpG island methylation for ge...

S. Belinsky

2001-01-01

183

Critical Role for Aberrant CpG Island Methylation in the Evolution and Progression of Breast Cancer: Characterization of Known Genes and Identification of Novel Genes.  

National Technical Information Service (NTIS)

CpG island methylation is an epigenetic modification of DNA associated with the silencing of gene transcription. The hypothesis of this proposal is that breast cancers develop along different pathways, some involving aberrant CpG island methylation for ge...

S. A. Belinsky

2000-01-01

184

Aberration of FHIT Gene is Associated with Increased Tumor Proliferation and Decreased Apoptosis--Clinical Evidence in Lung and Head and Neck Carcinomas  

Microsoft Academic Search

Background: Human FHIT (fragile histidine triad) gene is highly conserved gene homologous to a group of genes identified in prokaryotes and eukaryotes. Loss of FHIT function may be important in the development and\\/or progression of various types of cancer. Materials and Methods: We undertook a clinical study to analyze the relation between aberrant function of FHIT gene, tumor cell proliferation,

Kresimir Pavelic; Simun Krizanac; TamaraCacev; Marijana Popovic Hadzija; SenkaRadosevic; Ivana Crnic; Sonja Levanat; SanjaKapitanovic

2001-01-01

185

Harnessing Gene Expression Networks to Prioritize Candidate Epileptic Encephalopathy Genes  

PubMed Central

We apply a novel gene expression network analysis to a cohort of 182 recently reported candidate Epileptic Encephalopathy genes to identify those most likely to be true Epileptic Encephalopathy genes. These candidate genes were identified as having single variants of likely pathogenic significance discovered in a large-scale massively parallel sequencing study. Candidate Epileptic Encephalopathy genes were prioritized according to their co-expression with 29 known Epileptic Encephalopathy genes. We utilized developing brain and adult brain gene expression data from the Allen Human Brain Atlas (AHBA) and compared this to data from Celsius: a large, heterogeneous gene expression data warehouse. We show replicable prioritization results using these three independent gene expression resources, two of which are brain-specific, with small sample size, and the third derived from a heterogeneous collection of tissues with large sample size. Of the nineteen genes that we predicted with the highest likelihood to be true Epileptic Encephalopathy genes, two (GNAO1 and GRIN2B) have recently been independently reported and confirmed. We compare our results to those produced by an established in silico prioritization approach called Endeavour, and finally present gene expression networks for the known and candidate Epileptic Encephalopathy genes. This highlights sub-networks of gene expression, particularly in the network derived from the adult AHBA gene expression dataset. These networks give clues to the likely biological interactions between Epileptic Encephalopathy genes, potentially highlighting underlying mechanisms and avenues for therapeutic targets.

Oliver, Karen L.; Lukic, Vesna; Thorne, Natalie P.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Bahlo, Melanie

2014-01-01

186

Signals from chloroplasts converge to regulate nuclear gene expression.  

PubMed

Plastid-to-nucleus retrograde signaling coordinates nuclear gene expression with chloroplast function and is essential for the photoautotrophic life-style of plants. Three retrograde signals have been described, but little is known of their signaling pathways. We show here that GUN1, a chloroplast-localized pentatricopeptide-repeat protein, and ABI4, an Apetala 2 (AP2)-type transcription factor, are common to all three pathways. ABI4 binds the promoter of a retrograde-regulated gene through a conserved motif found in close proximity to a light-regulatory element. We propose a model in which multiple indicators of aberrant plastid function in Arabidopsis are integrated upstream of GUN1 within plastids, which leads to ABI4-mediated repression of nuclear-encoded genes. PMID:17395793

Koussevitzky, Shai; Nott, Ajit; Mockler, Todd C; Hong, Fangxin; Sachetto-Martins, Gilberto; Surpin, Marci; Lim, Jason; Mittler, Ron; Chory, Joanne

2007-05-01

187

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

188

Disruption of imprinted gene expression and DNA methylation status in porcine parthenogenetic fetuses and placentas.  

PubMed

Parthenogenetically activated oocytes cannot develop to term in mammals due to the lack of paternal gene expression and failed X chromosome inactivation (XCI). To further characterize porcine parthenogenesis, the expression of 18 imprinted genes was compared between parthenogenetic (PA) and normally fertilized embryos (Con) using quantitative real-time PCR (qRT-PCR). The results revealed that maternally expressed genes were over-expressed, whereas paternally expressed genes were significantly reduced in PA fetuses and placentas. The results of bisulfite sequencing PCR (BSP) demonstrated that PRE-1 and Satellite were hypermethylated in both Con and PA fetuses and placentas, while XIST DMRs were hypomethylated only in PA samples. Taken together, these results suggest that the aberrant methylation profile of XIST DMRs and abnormal imprinted gene expression may be responsible for developmental failure and impaired growth in porcine parthenogenesis. PMID:24979339

Wang, Dongxu; Chen, Xianju; Song, Yuning; Lv, Qinyan; Lai, Liangxue; Li, Zhanjun

2014-09-01

189

Expression of centrosome-associated gene products is linked to tetraploidization in mantle cell lymphoma.  

PubMed

In mantle cell lymphoma (MCL), a blastoid variant with a striking tendency to harbor chromosome numbers in the tetraploid range has been identified. Centrosome aberrations have recently been implicated in the induction of aneuploidy in many human malignancies including MCL by malsegregation of chromosomes during anaphase of mitosis. Recently, we showed that centrosome aberrations occur more frequently in tetraploid MCL as compared to their diploid counterparts. To test the hypothesis of an association between tetraploidization and expression of genes coding for centrosomal proteins in MCL, tumor RNA of 33 MCL samples was hybridized to custom-made cDNA microarrays, representing 4,628 distinct human gene-specific fragments, with particular enrichment for cancer-relevant (n = 2,440) and centrosome-associated genes (n = 359). Notably, 4 of the 6 most significant genes (CAMKK2, PCNT2, TUBGCP3, TUBGCP4) discriminating between diploid and near-tetraploid MCL code for centrosomal proteins. As confirmed by quantitative RT-PCR analysis, calcium/calmodulin-dependent protein kinase II (CAMKK2), pericentrin (PCNT2) and gamma-tubulin complex associated protein 3 (TUBGCP3) were all found to be significantly higher expressed in near-tetraploid than in diploid MCL samples. In conclusion, we describe a comprehensive expression signature of a set of genes associated with tetraploidization in MCL. The high expression level of centrosome-associated gene products in blastoid MCL matches the description of more frequent centrosome aberrations in this MCL variant. PMID:17236200

Neben, Kai; Ott, German; Schweizer, Silja; Kalla, Jörg; Tews, Björn; Katzenberger, Tiemo; Hahn, Meinhard; Rosenwald, Andreas; Ho, Anthony D; Müller-Hermelink, Hans Konrad; Lichter, Peter; Krämer, Alwin

2007-04-15

190

Noise in eukaryotic gene expression  

NASA Astrophysics Data System (ADS)

Transcription in eukaryotic cells has been described as quantal, with pulses of messenger RNA produced in a probabilistic manner. This description reflects the inherently stochastic nature of gene expression, known to be a major factor in the heterogeneous response of individual cells within a clonal population to an inducing stimulus. Here we show in Saccharomyces cerevisiae that stochasticity (noise) arising from transcription contributes significantly to the level of heterogeneity within a eukaryotic clonal population, in contrast to observations in prokaryotes, and that such noise can be modulated at the translational level. We use a stochastic model of transcription initiation specific to eukaryotes to show that pulsatile mRNA production, through reinitiation, is crucial for the dependence of noise on transcriptional efficiency, highlighting a key difference between eukaryotic and prokaryotic sources of noise. Furthermore, we explore the propagation of noise in a gene cascade network and demonstrate experimentally that increased noise in the transcription of a regulatory protein leads to increased cell-cell variability in the target gene output, resulting in prolonged bistable expression states. This result has implications for the role of noise in phenotypic variation and cellular differentiation.

Blake, William J.; KÆrn, Mads; Cantor, Charles R.; Collins, J. J.

2003-04-01

191

Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer  

Microsoft Academic Search

Introduction  microRNA (miRNA) are short, noncoding RNA that negatively regulate gene expression and may play a causal role in invasive\\u000a breast cancer. Since many genetic aberrations of invasive disease are detectable in early stages, we hypothesized that miRNA\\u000a expression dysregulation and the predicted changes in gene expression might also be found in early breast neoplasias.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Expression profiling of 365 miRNA by

Bethany N Hannafon; Paola Sebastiani; Antonio de las Morenas; Jining Lu; Carol L Rosenberg

2011-01-01

192

Aberrant Epigenetic and Genetic Marks Are Seen in Myelodysplastic Leukocytes and Reveal Dock4 as a Candidate Pathogenic Gene on Chromosome 7q*  

PubMed Central

Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34+ stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region.

Zhou, Li; Opalinska, Joanna; Sohal, Davendra; Yu, Yiting; Mo, Yongkai; Bhagat, Tushar; Abdel-Wahab, Omar; Fazzari, Melissa; Figueroa, Maria; Alencar, Cristina; Zhang, Jinghang; Kambhampati, Suman; Parmar, Simrit; Nischal, Sangeeta; Hueck, Christoph; Suzuki, Masako; Freidman, Ellen; Pellagatti, Andrea; Boultwood, Jacqueline; Steidl, Ulrich; Sauthararajah, Yogen; Yajnik, Vijay; Mcmahon, Christine; Gore, Steven D.; Platanias, Leonidas C.; Levine, Ross; Melnick, Ari; Wickrema, Amittha; Greally, John M.; Verma, Amit

2011-01-01

193

Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.  

PubMed

Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region. PMID:21532034

Zhou, Li; Opalinska, Joanna; Sohal, Davendra; Yu, Yiting; Mo, Yongkai; Bhagat, Tushar; Abdel-Wahab, Omar; Fazzari, Melissa; Figueroa, Maria; Alencar, Cristina; Zhang, Jinghang; Kambhampati, Suman; Parmar, Simrit; Nischal, Sangeeta; Hueck, Christoph; Suzuki, Masako; Freidman, Ellen; Pellagatti, Andrea; Boultwood, Jacqueline; Steidl, Ulrich; Sauthararajah, Yogen; Yajnik, Vijay; McMahon, Christine; Gore, Steven D; Platanias, Leonidas C; Levine, Ross; Melnick, Ari; Wickrema, Amittha; Greally, John M; Verma, Amit

2011-07-15

194

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

PubMed Central

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.

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

2014-01-01

195

Whole-body gene expression pattern registration in Platynereis larvae  

PubMed Central

Background Digital anatomical atlases are increasingly used in order to depict different gene expression patterns and neuronal morphologies within a standardized reference template. In evo-devo, a discipline in which the comparison of gene expression patterns is a widely used approach, such standardized anatomical atlases would allow a more rigorous assessment of the conservation of and changes in gene expression patterns during micro- and macroevolutionary time scales. Due to its small size and invariant early development, the annelid Platynereis dumerilii is particularly well suited for such studies. Recently a reference template with registered gene expression patterns has been generated for the anterior part (episphere) of the Platynereis trochophore larva and used for the detailed study of neuronal development. Results Here we introduce and evaluate a method for whole-body gene expression pattern registration for Platynereis trochophore and nectochaete larvae based on whole-mount in situ hybridization, confocal microscopy, and image registration. We achieved high-resolution whole-body scanning using the mounting medium 2,2’-thiodiethanol (TDE), which allows the matching of the refractive index of the sample to that of glass and immersion oil thereby reducing spherical aberration and improving depth penetration. This approach allowed us to scan entire whole-mount larvae stained with nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate (NBT/BCIP) in situ hybridization and counterstained fluorescently with an acetylated-tubulin antibody and the nuclear stain 4’6-diamidino-2-phenylindole (DAPI). Due to the submicron isotropic voxel size whole-mount larvae could be scanned in any orientation. Based on the whole-body scans, we generated four different reference templates by the iterative registration and averaging of 40 individual image stacks using either the acetylated-tubulin or the nuclear-stain signal for each developmental stage. We then registered to these templates the expression patterns of cell-type specific genes. In order to evaluate the gene expression pattern registration, we analyzed the absolute deviation of cell-center positions. Both the acetylated-tubulin- and the nuclear-stain-based templates allowed near-cellular-resolution gene expression registration. Nuclear-stain-based templates often performed significantly better than acetylated-tubulin-based templates. We provide detailed guidelines and scripts for the use and further expansion of the Platynereis gene expression atlas. Conclusions We established whole-body reference templates for the generation of gene expression atlases for Platynereis trochophore and nectochaete larvae. We anticipate that nuclear-staining-based image registration will be applicable for whole-body alignment of the embryonic and larval stages of other organisms in a similar size range.

2012-01-01

196

Implantation failure in mice with a disruption in Phospholipase C beta 1 gene: lack of embryonic attachment, aberrant steroid hormone signalling and defective endocannabinoid metabolism.  

PubMed

Phospholipase C beta 1 (PLC?1) is a downstream effector of G-protein-coupled receptor signalling and holds central roles in reproductive physiology. Mice with a disruption in the Plc?1 gene are infertile with pleiotropic reproductive defects, the major reproductive block in females being implantation failure. Here, PLC?1 was demonstrated at the luminal and glandular epithelia throughout the pre- and peri-implantation period, with transient stromal expression during 0.5-1.5 days post coitum (dpc). Examination of implantation sites at 4.5 dpc showed that in females lacking functional PLC?1 (knock-out (KO) females), embryos failed to establish proper contact with the uterine epithelium. Proliferating luminal epithelial cells were evident in KO implantation sites, indicating failure to establish a receptive uterus. Real-time PCR demonstrated that KO implantation sites had aberrant ovarian steroid signalling, with high levels of estrogen receptor ?, lactoferrin and amphiregulin mRNA, while immunohistochemistry revealed very low levels of estrogen receptor ? protein, possibly due to rapid receptor turnover. KO implantation sites expressed markedly less fatty acid amide hydrolase and monoacylglycerol lipase, indicating that endocannabinoid metabolism was also affected. Collectively, our results show that PLC?1 is essential for uterine preparation for implantation, and that defective PLC?1-mediated signalling during implantation is associated with aberrant ovarian steroid signalling and endocannabinoid metabolism. PMID:23295235

Filis, Panayiotis; Kind, Peter C; Spears, Norah

2013-05-01

197

Decreased expression and aberrant methylation of Gadd45G is associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma.  

PubMed

The growth arrest DNA damage-inducible gene (Gadd45) family, which is composed of Gadd45A, Gadd45B, and Gadd45G, is involved in DNA damage response and cell growth arrest. The present study was to detect the role of Gadd45 gene family in esophageal cancer and the relationship of Gadd45G methylation to a series of pathological parameters in a large esophageal squamous cell carcinoma (ESCC) sample, in order to elucidate more information on the role of Gadd45 gene family with regard to the pathogenesis of ESCC. Frequent silencing of Gadd45G but not Gadd45A and Gadd45B were found in esophageal cancer cell lines and the silencing of Gadd45G may be reversed by 5-Aza-dC or TSA treatment in Eca109 cell line. The aberrant proximal promoter methylation of Gadd45G induces silencing of Gadd45G expression in Eca109 cell line. Gadd45A mRNA and protein expression in ESCC tumor tissues was significantly different compared to corresponding normal tissues. Decreased mRNA and protein expression of Gadd45G was observed in ESCC tumor tissues and was associated with Gadd45G proximal promoter methylation. Gadd45A or Gadd45B expression was not correlated with ESCC patients survival, while Gadd45G methylation status and protein expression were independently associated with ESCC patients' survival. These data indicated that Gadd45G may be a functional tumor suppressor and its inactivation through proximal promoter methylation may play an important role in ESCC carcinogenesis and reactivation of Gadd45G gene may has therapeutic potential and may be used as a prognostic marker for ESCC patients. PMID:23793925

Guo, Wei; Zhu, Tienian; Dong, Zhiming; Cui, Lei; Zhang, Minghui; Kuang, Gang

2013-12-01

198

Control of expression of silk protein genes  

Microsoft Academic Search

At least three silk genes are specifically expressed in the posterior, and five other genes in middle, silk glands. The products of genes active in PSG include fibroin, L-chain fibroin and P25 protein. PSG genes as well as the Ser-1 gene, differing in structure, exhibit a striking degree of homology of their 5? flanking sequences. This suggests the presence of

Krystyna Grzelak

1995-01-01

199

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

200

Stochastic Gene Expression Model Base Gene Regulatory Networks  

NASA Astrophysics Data System (ADS)

Gene regulatory networks consist of a number of genes and their interactions which regulate expressions of the genes. Along with the development of gene regulatory network studies, computer simulations have become a valuable tool to evaluate complex relationships between genes. Due to the stochastic nature of gene expressions, various stochastic approaches have attracted increasing interest. In this study, we build gene regulatory networks based on a stochastic gene expression model with delicate assumptions such as transcription, translation, DNA-protein, protein-protein associations and time delay for protein activation. Two simple in-silico gene regulatory network models are constructed and monitored their expression profiles reflecting the inhibition and activation of the gene regulations.

Kim, Haseong; Gelenbe, Erol

201

A comparative analysis of chromosomal aberrations in cultured human lymphocytes due to fluoroquinolone drugs at different expression periods.  

PubMed

Fluoroquinolones (FQ) are broad-spectrum antibacterial agents widely used for the treatment of infections with various types of gram negative and gram positive bacteria. Specifically, gatifloxacin (GFX) is under development as a component in a new antituberculosis fixed-dose drug combination. In the context of this project, GFX was also tested for genotoxic activity in human peripheral lymphocytes, and the induction of chromosomal aberrations by GFX in PHA-M stimulated cultured human lymphocytes, investigated under conditions of conventional and increased expression times, was further compared to the analogous effects induced by some other second- and third-generation FQ antibacterial agents, namely ofloxacin (OFX), ciprofloxacin (CFX) and sparfloxacin (SFX). OFX did not induce any significant chromosomal aberrations in human lymphocytes. CFX and SFX exhibited slight to moderate clastogenic potential at cytotoxic concentrations (150, 175, 200 and 225 microg/ml), and GFX, a third-generation FQ, induced a clear, concentration-dependent increase in the frequency of chromosomal aberrations at cytotoxic concentrations (150, 200 and 250 microg/ml). These effects were not apparent when metaphases were analysed at the conventionally used sampling time of 24 h, but only after prolongation of the expression time between treatment and harvesting to a sampling time of 36 h (4 h exposure and 32 h expression period). Also, an increased incidence of numerical aberrations (polyploidy and endoreduplication) was seen with GFX at non-cytotoxic concentrations (12.5, 25, 50 and 75 microg/ml). These effects can be attributed to the slight cross-reactivity of FQs between their inhibitory activity towards their intended targets, the prokaryotic type II topoisomerase enzymes DNA gyrase and topoisomerase IV, and the analogous mammalian enzyme topoisomerase II. We have also observed the formation of polycentrics, i.e., chromosomes with five to six centromeres, a rarely reported structural aberration, in GFX-treated cells. The significance of these observations with respect to the conventional conduct of such studies and to the interpretation of the effects is discussed. PMID:20049419

Anupama, M; Seiler, J P; Murthy, P B

2010-05-01

202

Aberrant expression of the neuronal transcription factor FOXP2 in neoplastic plasma cells.  

PubMed

FOXP2 mutation causes a severe inherited speech and language defect, while the related transcription factors FOXP1, FOXP3 and FOXP4 are implicated in cancer. FOXP2 mRNA and protein expression were characterised in normal human tissues, haematological cell lines and multiple myeloma (MM) patients' samples. FOXP2 mRNA and protein were absent in mononuclear cells from different anatomical sites, lineages and stages of differentiation. However, FOXP2 mRNA and protein was detected in several lymphoma (8/20) and all MM-derived cell lines (n = 4). FOXP2 mRNA was expressed in bone marrow samples from 96% of MM patients (24/25), 66.7% of patients with the pre-neoplastic plasma cell proliferation monoclonal gammopathy of undetermined significance (MGUS) (6/9), but not in reactive plasma cells. The frequency of FOXP2 protein expression in CD138(+) plasma cells was significantly higher in MGUS (P = 0.0005; mean 46.4%) and MM patients (P < or = 0.0001; mean 57.3%) than in reactive marrows (mean 2.5%). FOXP2 (>10% nuclear positivity) was detectable in 90.2% of MM (55/61) and 90.9% of MGUS (10/11) patients, showing more frequent expression than CD56 and labelling 75% of CD56-negative MM (9/12). FOXP2 represents the first transcription factor whose expression consistently differentiates normal and abnormal plasma cells and FOXP2 target genes are implicated in MM pathogenesis. PMID:20096010

Campbell, Andrew J; Lyne, Linden; Brown, Philip J; Launchbury, Rosalind J; Bignone, Paola; Chi, Jianxiang; Roncador, Giovanna; Lawrie, Charles H; Gatter, Kevin C; Kusec, Rajko; Banham, Alison H

2010-04-01

203

Differential Regulation of ?7 Nicotinic Receptor Gene (CHRNA7) Expression in Schizophrenic Smokers  

PubMed Central

The ?7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the ?7* receptor, as measured by [125I]?-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the ?7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor.

Mexal, Sharon; Berger, Ralph; Logel, Judy; Ross, Randal G.; Freedman, Robert

2009-01-01

204

Mining gene expression databases for association rules  

Microsoft Academic Search

Motivation: Global gene expression profiling, both at the transcript level and at the protein level, can be a valuable tool in the understanding of genes, biological networks, and cellular states. As larger and larger gene expression data sets become available, data mining techniques can be applied to identify patterns of interest in the data. As- sociation rules, used widely in

Chad Creighton; Samir Hanash

2003-01-01

205

Allele-specific gene expression uncovered  

Microsoft Academic Search

Genetic variation in populations can result in variation in levels of gene expression but the extent to which this occurs has been unclear. In this article, recent studies of allele-specific expression among autosomal non-imprinted genes are reviewed. These new data provide evidence that differential expression is relatively common and that allelic differences are heritable and can be highly context specific.

Julian C. Knight

2004-01-01

206

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

207

Gene expression profiles in liver cancer  

US Patent & Trademark Office Database

The present invention identifies the global changes in gene expression associated with liver cancer by examining gene expression in tissue from normal liver, metastatic malignant liver and hepatocellular carcinoma. The present invention also identifies expression profiles which serve as useful diagnostic markers as well as markers that can be used to monitor disease states, disease progression, drug toxicity, drug efficacy and drug metabolism.

2005-12-13

208

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

209

Gene Expression Omnibus: NCBI gene expression and hybridization array data repository  

Microsoft Academic Search

The Gene Expression Omnibus (GEO) project was initiated in response to the growing demand for a public repository for high-throughput gene expression data. GEO provides a flexible and open design that facilitates submission, storage and retrieval of heterogeneous data sets from high-throughput gene expression and genomic hybridization experiments. GEO is not intended to replace in house gene expres- sion databases

Ron Edgar; Michael Domrachev; Alex E. Lash

2002-01-01

210

BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours  

PubMed Central

BORIS (for brother of the regulator of imprinted sites), a paralogue of the transcription factor, CTCF, is a novel member of the cancer-testis antigen family. The aims of the present study were as follows: (1) to investigate BORIS expression in breast cells and tumours using immunohistochemical staining, western and real-time RT–PCR analyses and (2) assess potential correlation between BORIS levels in tumours with clinical/pathological parameters. BORIS was detected in all 18 inspected breast cell lines, but not in a primary normal breast cell culture. In 70.7% (41 of 58 cases) BORIS was observed in breast tumours. High levels of BORIS correlated with high levels of progesterone receptor (PR) and oestrogen receptor (ER). The link between BORIS and PR/ER was further confirmed by the ability of BORIS to activate the promoters of the PR and ER genes in the reporter assays. Detection of BORIS in a high proportion of breast cancer patients implies potential practical applications of BORIS as a molecular biomarker of breast cancer. This may be important for diagnosis of the condition and for the therapeutic use of BORIS. The ability of BORIS to activate promoters of the RP and ER genes points towards possible involvement of BORIS in the establishment, progression and maintenance of breast tumours.

D'Arcy, V; Pore, N; Docquier, F; Abdullaev, Z K; Chernukhin, I; Kita, G-X; Rai, S; Smart, M; Farrar, D; Pack, S; Lobanenkov, V; Klenova, E

2008-01-01

211

High prevalence of immunoglobulin light chain gene aberrations as revealed by FISH in multiple myeloma and MGUS.  

PubMed

Multiple myeloma (MM) is a malignant B-cell neoplasm characterized by an uncontrolled proliferation of aberrant plasma cells in the bone marrow. Chromosome aberrations in MM are complex and represent a hallmark of the disease, involving many chromosomes that are altered both numerically and structurally. Nearly half of the cases are nonhyperdiploid and show IGH translocations with the following partner genes: CCND1, FGFR3 and MMSET, MAF, MAFB, and CCND3. The remaining 50% are grouped into a hyperdiploid group that is characterized by multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. In this study, we analyzed the immunoglobulin light chain kappa (IGK, 2p12) and lambda (IGL, 22q11) loci in 150 cases, mostly with MM but in a few cases monoclonal gammopathy of undetermined significance (MGUS), without IGH translocations. We identified aberrations in 27% (= 40 patients) including rearrangements (12%), gains (12%), and deletions (4.6%). In 6 of 18 patients with IGK or/and IGL rearrangements, we detected a MYC rearrangement which suggests that MYC is the translocation partner in the majority of these cases. © 2014 Wiley Periodicals, Inc. PMID:24729354

Türkmen, Seval; Binder, Anastasia; Gerlach, Antje; Niehage, Sylke; Theodora Melissari, Maria; Inandiklioglu, Nihal; Dörken, Bernd; Burmeister, Thomas

2014-08-01

212

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

213

Aberrant splicing and altered spatial expression patterns in fruitless mutants of Drosophila melanogaster.  

PubMed Central

The fruitless (fru) gene functions in Drosophila males to establish the potential for male sexual behaviors. fru encodes a complex set of sex-specific and sex-nonspecific mRNAs through the use of multiple promoters and alternative pre-mRNA processing. The male-specific transcripts produced from the distal (P1) fru promoter are believed to be responsible for its role in specifying sexual behavior and are only expressed in a small fraction of central nervous system (CNS) cells. To understand the molecular etiology of fruitless mutant phenotypes, we compared wild-type and mutant transcription patterns. These experiments revealed that the fru(2), fru(3), fru(4), and fru(sat) mutations, which are due to P-element inserts, alter the pattern of sex-specific and sex-nonspecific fru RNAs. These changes arise in part from the P-element insertions containing splice acceptor sites that create alternative processing pathways. In situ hybridization revealed no alterations in the locations of cells expressing the P1-fru-promoter-derived transcripts in fru(2), fru(3), fru(4), and fru(sat) pharate adults. For the fru(1) mutant (which is due to an inversion breakpoint near the P1 promoter), Northern analyses revealed no significant changes in fru transcript patterns. However, in situ hybridization revealed anomalies in the level and distribution of P1-derived transcripts: in fru(1) males, fewer P1-expressing neurons are found in regions of the dorsal lateral protocerebrum and abdominal ganglion compared to wild-type males. In other regions of the CNS, expression of these transcripts appears normal in fru(1) males. The loss of fruitless expression in these regions likely accounts for the striking courtship abnormalities exhibited by fru(1) males. Thus, we suggest that the mutant phenotypes in fru(2), fru(3), fru(4), and fru(sat) animals are due to a failure to appropriately splice P1 transcripts, whereas the mutant phenotype of fru(1) animals is due to the reduction or absence of P1 transcripts within specific regions of the CNS.

Goodwin, S F; Taylor, B J; Villella, A; Foss, M; Ryner, L C; Baker, B S; Hall, J C

2000-01-01

214

Genetics of human gene expression.  

PubMed

A steadily growing number of studies have identified and characterized expression quantitative trait loci (eQTLs) in human cell-lines, primary cells, and tissues. This class of variation has been shown to play a role in complex traits, including disease. Here, we discuss how eQTLs have the potential to accelerate discovery of disease genes and functional mechanisms underlying complex traits. We discuss how context-specificity of eQTLs is being characterized at an unprecedented scale and breadth, and how this both informs on the intricacy of human genome function, and has important ramifications for elucidating function of genetic variants of interest, particularly for those contributing to disease. PMID:24238872

Stranger, Barbara E; Raj, Towfique

2013-12-01

215

From circadian clock gene expression to pathologies  

Microsoft Academic Search

In most organisms, circadian rhythms are generated by a molecular clockwork involving so-called clock genes. These circadian clock genes participate in regulatory feedback loops, in which proteins regulate their own expression. The outcome is that ribonucleic acids (RNAs) and proteins produced from many of these genes oscillate with a circadian rhythm. Here, we describe the regulation of clock genes and

Elaine Waddington Lamont; Francine O. James; Diane B. Boivin; Nicolas Cermakian

2007-01-01

216

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) [Davis, CA; Bachkirova, Elena (Davis, CA) [Davis, CA; Rey, Michael (Davis, CA) [Davis, CA

2008-06-01

217

Activation of zygotic gene expression in mammals  

Microsoft Academic Search

Preimplantation development in the mouse involves expression of about 11,000 genes, only a few hundred of which appear during the transition from maternal to zygotic gene expression. Transcription begins in most, if not all, mammals during the late 1-cell stage (phase I), but expression of most zygotic genes is delayed until the 2-cell to the 16-cell stages, depending on the

Melvin L. DePamphilis; Kotaro J. Kaneko; Alex Vassilev

2002-01-01

218

Identification of additional genes that influence baculovirus late gene expression.  

PubMed

We were unable to confirm transient late gene expression using constructs of 18 genes that had been reported to support Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) late gene expression when transfected into Spodoptera frugiperda cells [Lu, A., and Miller, L. K. (1995). J. Virol. 69, 975-982]. Three genes (orf66, orf68, and orf41) were included, all or in part, in the constructs used in that study, but they had not been independently tested. Therefore we investigated these and neighboring orfs for their influence on late gene expression. We found that orf41 was required for late gene expression and that sequences within orf45 appeared to be required for the expression of orf41. Although orf66 and orf68 did not appear to affect late gene expression, orf69 stimulated expression. orf69 was found to have high homology to recent entries in GenBank from a variety of organisms. In addition, it was found that orf121, which was shown to be involved in early gene expression, and the viral homolog of pcna did not influence late gene expression. PMID:10049816

Li, L; Harwood, S H; Rohrmann, G F

1999-03-01

219

Protein expression analysis of chronic lymphocytic leukemia defines the effect of genetic aberrations and uncovers a correlation of CDK4, P27 and P53 with hierarchical risk  

PubMed Central

Background Chronic lymphocytic leukemia has a variable clinical course. Genomic aberrations identify prognostic subgroups, pointing towards distinct underlying biological mechanisms that are poorly understood. In particular it remains unclear whether the prognostic subgroups of chronic lymphocytic leukemia are characterized by different levels of leukemogenic proteins. Design and Methods Expression of 23 proteins involved in apoptosis, proliferation, DNA damage, and signaling or whose genes map to chromosomal regions known to be critical in chronic lymphocytic leukemia was quantified in 185 cytogenetically well characterized cases of chronic lymphocytic leukemia using immunoblotting. Cases were categorized hierarchically into deletion(17p), deletion(11q), trisomy 12, deletion(13q) as sole abnormality or normal karyotype. Statistical analysis was performed for expression differences between these subgroups. In addition, the expression levels of CDK4, P27 and P53 were quantified over the clinical course and compared to levels in immunopurified B cells from healthy individuals. Results In subgroups with a good prognosis, differential expression was mainly seen for proteins that regulate apoptosis. In contrast, in cytogenetic subgroups with a worse prognosis, differential expression was mostly detected for proteins that control DNA damage and proliferation. Expression levels of CDK4, P27 and P53 were higher compared to those in B cells from healthy individuals and significantly correlated with increasing hierarchical risk. In addition, no significant longitudinal changes of expression levels of CDK4, P27 and P53 could be detected in chronic lymphocytic leukemia patients. Conclusions Differences in expression levels of apoptosis- and proliferation-controlling proteins define distinct prognostic subgroups of chronic lymphocytic leukemia and uncover a correlation of levels of CDK4, P27 and P53 proteins with higher hierarchical risk.

Winkler, Dirk; Schneider, Christof; Zucknick, Manuela; Bogelein, Daniela; Schulze, Kerstin; Zenz, Thorsten; Mohr, Julia; Philippen, Angela; Huber, Henriette; Buhler, Andreas; Habermann, Annett; Benner, Axel; Dohner, Hartmut; Stilgenbauer, Stephan; Mertens, Daniel

2010-01-01

220

Amplification of kinetic oscillations in gene expression  

NASA Astrophysics Data System (ADS)

Because of the feedbacks between the DNA transcription and mRNA translation, the gene expression in cells may exhibit bistability and oscillations. The deterministic and stochastic calculations presented illustrate how the bistable kinetics of expression of one gene in a cell can be influenced by the kinetic oscillations in the expression of another gene. Due to stability of the states of the bistable kinetics of gene 1 and the relatively small difference between the maximum and minimum protein amounts during the oscillations of gene 2, the induced oscillations of gene 1 are found to typically be related either to the low-or high-reactive state of this gene. The quality of the induced oscillations may be appreciably better than that of the inducing oscillations. This means that gene 1 can serve as an amplifier of the kinetic oscillations of gene 2.

Zhdanov, V. P.

2008-10-01

221

Differential expression of genes characterizing myofibre phenotype.  

PubMed

Skeletal muscle is composed of metabolically heterogeneous myofibres that exhibit high plasticity at both the morphological and transcriptional levels. The objective of this study was to employ microarray analysis to elucidate the differential gene expression between the tonic-'red' anterior latissimus dorsi (ALD) muscle, the phasic-'white' posterior latissimus dorsi (PLD) and 'mixed'-phenotype biceps femoris (BF) in 1-week-and 19-week-old male turkeys. A total of 170 differentially expressed genes were identified in the muscle samples analysed (P < 0.05). Gene GO analysis software was utilized to identify top gene networks and metabolic pathways involving differentially expressed genes. Quantitative real-time PCR for selected genes (BAT2D, CLU, EGFR and LEPROT) was utilized to validate the microarray data. The largest differences were observed between ALD and PLD muscles, in which 32 genes were over-expressed and 82 genes were under-expressed in ALD1-PLD1 comparison, and 70 genes were over-expressed and 70 under-expressed in ALD19-PLD19 comparison. The largest number of genes over-expressed in ALD muscles, as compared to other muscles, code for extracellular matrix proteins such as dystroglycan and collagen. The gene analysis revealed that phenotypically 'red' BF muscle has high expression of glycolytic genes usually associated with the 'white' muscle phenotype. Muscle-specific differences were observed in expression levels of genes coding for proteins involved in mRNA processing and translation regulation, proteosomal degradation, apoptosis and insulin resistance. The current findings may have large implications in muscle-type-related disorders and improvement of muscle quality in agricultural species. PMID:22486501

Nierobisz, L S; Sporer, K R B; Strasburg, G M; Reed, K M; Velleman, S G; Ashwell, C M; Felts, J V; Mozdziak, P E

2012-06-01

222

Abnormal miR-148b Expression Promotes Aberrant Glycosylation of IgA1 in IgA Nephropathy  

PubMed Central

Aberrant O-glycosylation in the hinge region of IgA1 characterizes IgA nephropathy. The mechanisms underlying this abnormal glycosylation are not well understood, but reduced expression of the enzyme core 1, ?1,3-galactosyltransferase 1 (C1GALT1) may contribute. In this study, high-throughput microRNA (miRNA) profiling identified 37 miRNAs differentially expressed in PBMCs of patients with IgA nephropathy compared with healthy persons. Among them, we observed upregulation of miR-148b, which potentially targets C1GALT1. Patients with IgA nephropathy exhibited lower C1GALT1 expression, which negatively correlated with miR-148b expression. Transfection of PBMCs from healthy persons with a miR-148b mimic reduced endogenous C1GALT1 mRNA levels threefold. Conversely, loss of miR-148b function in PBMCs of patients with IgA nephropathy increased C1GALT1 mRNA and protein levels to those observed in healthy persons. Moreover, we found that upregulation of miR-148b directly correlated with levels of galactose-deficient IgA1. In vitro, we used an IgA1-producing cell line to confirm that miR-148b modulates IgA1 O-glycosylation and the levels of secreted galactose-deficient IgA1. Taken together, these data suggest a role for miRNAs in the pathogenesis of IgA nephropathy. Abnormal expression of miR-148b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA nephropathy.

Serino, Grazia; Sallustio, Fabio; Cox, Sharon N.; Pesce, Francesco

2012-01-01

223

Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus  

PubMed Central

Prostaglandins (PGs) are lipid molecules that profoundly affect cellular processes including inflammation and immune response. Pathways contributing to PG output are highly regulated in antigen-presenting cells such as macrophages and monocytes, which produce large quantities of these molecules upon activation. In this report, we demonstrate aberrant constitutive expression of the normally inducible cyclooxygenase PG synthase 2 (PGS2/ COX-2) in nonactivated monocytes of humans with insulin-dependent diabetes mellitus (IDDM) and those with islet autoantibodies at increased risk of developing this disease. Constitutive PGS2 appears to characterize a high risk for diabetes as it correlates with and predicts a low first-phase insulin response in autoantibody-positive subjects. Abnormal PGS2 expression in at-risk subjects affected immune response in vitro, as the presence of a specific PGS2 inhibitor, NS398, significantly increased IL-2 receptor ?-chain (CD25) expression on phytohemagglutinin-stimulated T cells. The effect of PGS2 on CD25 expression was most profound in subjects expressing both DR04 and DQ?0302 high-risk alleles, suggesting that this cyclooxygenase interacts with diabetes-associated MHC class II antigens to limit T-cell activation. These results indicate that constitutive PGS2 expression in monocytes defines an antigen-presenting cell defect affecting immune response, and that this expression is a novel cell-associated risk marker for IDDM. J. Clin. Invest. 104:515-523 (1999).

Litherland, S.A.; Xie, X.T.; Hutson, A.D.; Wasserfall, C.; Whittaker, D.S.; She, J.-X.; Hofig, A.; Dennis, M.A.; Fuller, K.; Cook, R.; Schatz, D.; Moldawer, L.L.; Clare-Salzler, M.J.

1999-01-01

224

Genomic aberrations in hepatocellular carcinoma related to osteopontin expression detected by array-CGH  

Microsoft Academic Search

Purpose  We have demonstrated that overexpression of osteopontin (OPN) could contribute to metastasis in hepatocellular carcinoma (HCC),\\u000a and that OPN-positive cancer cells are often localized in the periphery of cancer nodules adjacent to stromal cells. This\\u000a study was to identify the difference of intratumor genomic aberrations between OPN-positive and OPN-negative HCC cells.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Immunohistochemical staining for OPN was performed in both archival

Jin-Cai Wu; Bing-Sheng Sun; Ning Ren; Qing-Hai Ye; Lun-Xiu Qin

2010-01-01

225

Expression analysis of stem cell-related genes reveal OCT4 as a predictor of poor clinical outcome in medulloblastoma  

Microsoft Academic Search

Aberrant expression of stem cell-related genes in tumors may confer more primitive and aggressive traits affecting clinical\\u000a outcome. Here, we investigated expression and prognostic value of the neural stem cell marker CD133, as well as of the pluripotency genes LIN28 and OCT4 in 37 samples of pediatric medulloblastoma, the most common and challenging type of embryonal tumor. While most medulloblastoma

Carolina Oliveira Rodini; Daniela Emi Suzuki; Najsla Saba-Silva; Andréa Cappellano; Jorge Estefano Santana de Souza; Sérgio Cavalheiro; Silvia Regina Caminada Toledo; Oswaldo Keith Okamoto

226

Expression Profile of the REG Gene Family in Colorectal Carcinoma  

PubMed Central

Regenerating (REG) gene family belongs to the calcium-dependent lectin gene superfamily and encodes small multifunctional secretory proteins, which might be involved in cell proliferation, differentiation, and carcinogenesis. To clarify REG expression profile in colorectal carcinoma (CRC), the authors examined the expression of REG I?, I?, III, HIP/PAP, and REG IV by immunohistochemistry on tissue microarray. The expression of REG I?, III, and HIP/PAP was more frequently observed in the CRCs than adjacent non-neoplastic mucosa (p < 0.001), whereas it was the converse for REG I? and IV (p < 0.001). The expression of REG I?, I?, III, and HIP/PAP was negatively correlated with the depth of invasion of CRCs (p < 0.05). The REG I? and HIP/PAP were less expressed in CRCs with than without venous invasion (p < 0.05). The positive rates of REG I? and HIP/PAP were significantly higher in CRCs without than with lymph node metastasis (p < 0.05). Mucinous carcinoma more frequently expressed REG IV protein than well- and moderately differentiated ones (p < 0.05). There was a positive relationship between REG I?, I?, III, and HIP/PAP expression (p < 0.05). Survival analysis indicated the REG I? or HIP/PAP expression was positively linked to favorable prognosis of carcinoma patients (p < 0.05). This study indicated that aberrant REG expression might be closely linked to the pathogenesis, invasion, or lymph node metastasis of CRCs. REG I? and HIP/PAP could be considered reliable markers of favorable prognosis of CRC patients.

Zheng, Hua-chuan; Sugawara, Akira; Okamoto, Hiroshi; Takasawa, Shin; Takahashi, Hiroyuki; Masuda, Shinji; Takano, Yasuo

2011-01-01

227

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

228

Aberrant Promoter Methylation Profile of Niemann-Pick Type C1 Gene in Cardiovascular Disease  

PubMed Central

Background: The protein of Niemann-pick type C1 (NPC1) gene promotes the egress of cholesterol from late endosomes and lysosomes to other cellular compartments and contributes to a process known as reverse cholesterol transport. This study aimed to examine whether promoter methylation of NPC1 is associated with risk of cardiovascular disease (CVD). Methods: Fifty CVD patients and 50 healthy subjects as the control group were recruited in this study. Promoter methylation of NPC1 gene was defined using a nested-methylation specific polymerase chain reaction method. Statistical analyses were done using the chi-square, t-test or ANOVA tests. Results: Our study showed that the frequency of semi-methylated promoter (methylated/unmethylated status) was significantly higher in CVD patients than that in controls (OR = 6.521, 95% CI = 2.211-19.215, P = 0.008). However, a completely methylated promoter (methylated/methylated status) was not detected in any subjects in either of the two groups tested. Additionally, the analysis of clinical data according to the methylation status of NPC1 gene demonstrated that serum levels of total cholesterol, total triglycerides, high low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) are influenced by NPC1 methylation, so that subjects with a completely unmethylated promoter (Unmethylated/unmethylated status) held lower levels of total triglycerides, total cholesterol, LDL-C and higher levels of HDL-C. Conclusion: Our findings propose that the NPC1 promoter methylation is a probable mechanism that can result in reduced/impaired NPC1 expression/activity and may thus contribute to progression of CVD.

Afzali, Masoumeh; Nakhaee, Alireza; Tabatabaei, Seyed Payman; Tirgar-Fakheri, Kourosh; Hashemi, Mohammad

2013-01-01

229

Impaired NK Cell Development in an IFN Transgenic Mouse: Aberrantly Expressed IFN Enhances Hematopoietic Stem Cell Apoptosis and Affects NK Cell Differentiation1  

Microsoft Academic Search

Aberrant expression of IFN- has been demonstrated to cause a wide variety of alterations in cell function and development. Previously we reported that constitutive expression of IFN- in bone marrow (BM) and thymus results in a total absence of B cells and a substantial decrease in the number of hematopoietic progenitor cells. In this study, we demonstrate a severe deficiency

Osamu Shimozato; John R. Ortaldo; Kristin L. Komschlies; Howard A. Young

230

Deregulated expression of circadian clock and clock-controlled cell cycle genes in chronic lymphocytic leukemia.  

PubMed

Circadian rhythms are endogenous and self-sustained oscillations of multiple biological processes with approximately 24-h rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends from core clock genes to various clock-controlled genes that include various cell cycle genes. Aberrant expression of circadian clock genes, therefore, may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) at mRNA level and determination of serum melatonin levels in peripheral blood samples of 37 CLL (chronic lymphocytic leukemia) patients and equal number of age- and sex-matched healthy controls in order to indicate association between deregulated circadian clock and manifestation of CLL. Results showed significantly down-regulated expression of Bmal1, Per1, Per2 and Wee1 and significantly up-regulated expression of Myc and Cyclin D1 (P < 0.0001) in CLL patients as compared to healthy controls. When expression of these genes was compared between shift-workers and non-shift-workers within the CLL group, the expression was found more aberrant in shift-workers as compared to non-shift-workers. However, this difference was found statistically significant for Myc and Cyclin D1 only (P < 0.05). Serum melatonin levels were found significantly low (P < 0.0001) in CLL subjects as compared to healthy controls whereas melatonin levels were found still lower in shift-workers as compared to non-shift-workers within CLL group (P < 0.01). Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are involved in cell proliferation and apoptosis and hence may result in manifestation of CLL. Moreover, shift-work and low melatonin levels may also contribute in etiology of CLL by further perturbing of circadian clock. PMID:24190490

Rana, Sobia; Munawar, Mustafa; Shahid, Adeela; Malik, Meera; Ullah, Hafeez; Fatima, Warda; Mohsin, Shahida; Mahmood, Saqib

2014-01-01

231

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

2012-09-28

232

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

233

Ranking differentially expressed genes from Affymetrix gene expression data: methods with reproducibility, sensitivity, and specificity  

Microsoft Academic Search

BACKGROUND: To identify differentially expressed genes (DEGs) from microarray data, users of the Affymetrix GeneChip system need to select both a preprocessing algorithm to obtain expression-level measurements and a way of ranking genes to obtain the most plausible candidates. We recently recommended suitable combinations of a preprocessing algorithm and gene ranking method that can be used to identify DEGs with

Koji Kadota; Yuji Nakai; Kentaro Shimizu

2009-01-01

234

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.

235

Gene expression drives local adaptation in humans  

PubMed Central

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.

Fraser, Hunter B.

2013-01-01

236

The gene expression signatures of melanoma progression  

PubMed Central

Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma.

Haqq, Christopher; Nosrati, Mehdi; Sudilovsky, Daniel; Crothers, Julia; Khodabakhsh, Daniel; Pulliam, Brian L.; Federman, Scot; Miller, James R.; Allen, Robert E.; Singer, Mark I.; Leong, Stanley P. L.; Ljung, Britt-Marie; Sagebiel, Richard W.; Kashani-Sabet, Mohammed

2005-01-01

237

The gene expression signatures of melanoma progression.  

PubMed

Because of the paucity of available tissue, little information has previously been available regarding the gene expression profiles of primary melanomas. To understand the molecular basis of melanoma progression, we compared the gene expression profiles of a series of nevi, primary melanomas, and melanoma metastases. We found that metastatic melanomas exhibit two dichotomous patterns of gene expression, which unexpectedly reflect gene expression differences already apparent in comparing laser-capture microdissected radial and vertical phases of a large primary melanoma. Unsupervised hierarchical clustering accurately separated nevi and primary melanomas. Multiclass significance analysis of microarrays comparing normal skin, nevi, primary melanomas, and the two types of metastatic melanoma identified 2,602 transcripts that significantly correlated with sample class. These results suggest that melanoma pathogenesis can be understood as a series of distinct molecular events. The gene expression signatures identified here provide the basis for developing new diagnostics and targeting therapies for patients with malignant melanoma. PMID:15833814

Haqq, Christopher; Nosrati, Mehdi; Sudilovsky, Daniel; Crothers, Julia; Khodabakhsh, Daniel; Pulliam, Brian L; Federman, Scot; Miller, James R; Allen, Robert E; Singer, Mark I; Leong, Stanley P L; Ljung, Britt-Marie; Sagebiel, Richard W; Kashani-Sabet, Mohammed

2005-04-26

238

Biological characteristics and gene expression pattern of bone marrow mesenchymal stem cells in patients with psoriasis.  

PubMed

Mesenchymal stem cells (MSCs) have immunoregulatory and proangiogenic effects and are suggested to be involved in the pathological processes of immune-related diseases, including psoriasis. Biological characteristics of bone marrow MSCs (BMSCs) from patients with autoimmune diseases, such as systemic lupus erythematosus or rheumatoid arthritis, but not psoriasis, have been characterized. We compared the gene expression profile and biological characteristics of BMSCs from patients with psoriasis and healthy controls. Although the phenotype, differentiation potential and ability to support CD34(+) cell proliferation were similar to those of normal BMSCs, psoriatic BMSCs showed aberrant proliferative activity, increased apoptosis rate and a characteristic gene expression profile. These aberrations may develop after the abnormal immune response in psoriasis and result in BMSC dysfunction. The functionally deficient BMSCs may then fail to suppress overactive immune cells, thereby contributing to the pathogenesis of psoriasis. PMID:24816596

Hou, Ruixia; Liu, Ruifeng; Niu, Xuping; Chang, Wenjuan; Yan, Xin; Wang, Chunfang; Li, Junqin; An, Peng; Li, Xinhua; Yin, Guohua; Zhang, Kaiming

2014-07-01

239

Rough Overlapping Biclustering of Gene Expression Data  

Microsoft Academic Search

A great number of biclustering algorithms have been proposed for analyzing gene expression data. Many of them assume to find exclusive biclusters whose subsets of genes are co-regulated under subsets of conditions without intersection. This is not consistent with a general understanding of biological processes that many genes participate in multiple different processes. Therefore nonexclusive biclustering algorithms are required. In

Ruizhi Wang; Duoqian Miao; Gang Li; Hongyun Zhang

2007-01-01

240

Sample size for gene expression microarray experiments  

Microsoft Academic Search

Motivation: Microarray experiments often involve hundreds or thou- sands of genes. In a typical experiment, only a fraction of genes are expected to be differentially expressed; in addition, the measured intensities among different genes may be correlated. Depending on the experimental objectives, sample size calculations can be based on one of the three specified measures: sensitivity, true discovery and accuracy

Chen-an Tsai; Sue-jane Wang; Dung-tsa Chen; James J. Chen

2005-01-01

241

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

242

Regulation of KSHV Lytic Gene Expression  

Microsoft Academic Search

The life cycle of KSHV, latency versus lytic replication, is mainly determined at the transcriptional regulation level. A\\u000a viral immediate-early gene product, replication and transcription activator (RTA), has been identified as the molecular switch\\u000a for initiation of the lytic gene expression program from latency. Here we review progress on two key questions: how RTA gene\\u000a expression is controlled by viral

H. Deng; Y. Liang; R. Sun

243

Gene expression profiles for detecting and distinguishing potential endocrine-disrupting compounds in environmental samples.  

PubMed

Industrial and municipal processes may produce and release endocrine-disrupting compounds (EDCs) into the environment, but the exact nature of their effects is difficult to investigate. EDCs typically exert their effect by affecting gene expression aberrantly. To determine if gene expression profiles could be used to detect and distinguish estrogenic EDCs, an estrogen receptor positive human breast cancer cell line (MCF-7) was exposed to known estrogenic compounds, suspected EDCs, and extracts from three effluent samples. A set of specifically estrogen-regulated genes was identified by microarray analysis. Nine estrogen up-regulated genes (IGFBP4, HSPA8, B4GALT1, XBP1, KRT8, GTPBP4, HNRPAB, SLC2A1, and CALM1) and two estrogen down-regulated genes (ID2 and ZNF217) were consistently detectable in response to estrogen and other estrogenic compounds. Gene expression patterns in cells that were exposed to effluent sample extracts were compared to gene expression patterns in cells that were exposed to known endocrines. Using this technique, two of the effluent samples were shown to have estrogenic activity. This approach could easily be extended to screen for other types of receptor-mediated endocrine disruption. For example, cells expressing androgen or aryl hydrocarbon receptors could be used in gene expression profiling assays to detect androgenic effects or for the presence of bioactive aromatic hydrocarbons. Gene expression profiling is emerging as a sensitive and specific method to screen complex samples for endocrine disrupting activity. PMID:15597897

Wang, Dong-Yu; McKague, Bruce; Liss, Steven N; Edwards, Elizabeth A

2004-12-01

244

Aberrant 3? splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization  

PubMed Central

The frequency distribution of mutation-induced aberrant 3? splice sites (3?ss) in exons and introns is more complex than for 5? splice sites, largely owing to sequence constraints upstream of intron/exon boundaries. As a result, prediction of their localization remains a challenging task. Here, nucleotide sequences of previously reported 218 aberrant 3?ss activated by disease-causing mutations in 131 human genes were compared with their authentic counterparts using currently available splice site prediction tools. Each tested algorithm distinguished authentic 3?ss from cryptic sites more effectively than from de novo sites. The best discrimination between aberrant and authentic 3?ss was achieved by the maximum entropy model. Almost one half of aberrant 3?ss was activated by AG-creating mutations and ?95% of the newly created AGs were selected in vivo. The overall nucleotide structure upstream of aberrant 3?ss was characterized by higher purine content than for authentic sites, particularly in position ?3, that may be compensated by more stringent requirements for positive and negative nucleotide signatures centred around position ?11. A newly developed online database of aberrant 3?ss will facilitate identification of splicing mutations in a gene or phenotype of interest and future optimization of splice site prediction tools.

Vorechovsky, Igor

2006-01-01

245

Analysis of Wnt Gene Expression in Prostate Cancer: Mutual Inhibition by WNT11 and the Androgen Receptor  

Microsoft Academic Search

The Wnt signaling pathway is aberrantly activated in many tumor types, including those of the prostate, in which -catenin accumulates in cell nuclei and acts as a transcriptional coregulator for the androgen receptor. Because activating mutations in the -catenin gene are rare in prostate cancer, we have looked for altered expression of other compo- nents of the Wnt signaling pathway

Hanneng Zhu; Michal Mazor; Yoshiaki Kawano; Marjorie M. Walker; Hing Y. Leung; Kelly Armstrong; Jonathan Waxman; Robert M. Kypta

2004-01-01

246

Gene Expression Profiles in Asbestos-exposed Epithelial and Mesothelial Lung Cell Lines  

Microsoft Academic Search

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

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

2007-01-01

247

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

BEGIN:VCARD VERSION:2.1 FN:Bruce Alberts N:Alberts;Bruce REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Dennis Bray N:Bray;Dennis REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Alexander Johnson N:Johnson;Alexander REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Julian Lewis N:Lewis;Julian REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Martin Raff N:Raff;Martin REV:2005-04-16 END:VCARD; BEGIN:VCARD VERSION:2.1 FN:Keith Roberts N:Roberts;Keith REV:2005-04-16 END:VCARD

1998-07-01

248

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

249

Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival  

PubMed Central

Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies. We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-?B, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-?, a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors, and support the involvement of both homotypic and heterotypic mechanisms. This study shows an unforeseen role for the BAFF-system in the biology of precursor B-cell leukemia, and suggests that the target disruption of BAFF signals may constitute a valid strategy for the treatment of this cancer.

Maia, Sara; Pelletier, Marc; Ding, Jixin; Hsu, Yen-Ming; Sallan, Stephen E.; Rao, Sambasiva P.; Nadler, Lee M.; Cardoso, Angelo A.

2011-01-01

250

A comparative gene expression database for invertebrates  

PubMed Central

Background As whole genome and transcriptome sequencing gets cheaper and faster, a great number of 'exotic' animal models are emerging, rapidly adding valuable data to the ever-expanding Evo-Devo field. All these new organisms serve as a fantastic resource for the research community, but the sheer amount of data, some published, some not, makes detailed comparison of gene expression patterns very difficult to summarize - a problem sometimes even noticeable within a single lab. The need to merge existing data with new information in an organized manner that is publicly available to the research community is now more necessary than ever. Description In order to offer a homogenous way of storing and handling gene expression patterns from a variety of organisms, we have developed the first web-based comparative gene expression database for invertebrates that allows species-specific as well as cross-species gene expression comparisons. The database can be queried by gene name, developmental stage and/or expression domains. Conclusions This database provides a unique tool for the Evo-Devo research community that allows the retrieval, analysis and comparison of gene expression patterns within or among species. In addition, this database enables a quick identification of putative syn-expression groups that can be used to initiate, among other things, gene regulatory network (GRN) projects.

2011-01-01

251

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

252

Aberrant Expression of Interleukin-1? and Inflammasome Activation in Human Malignant Gliomas  

PubMed Central

Objective Glioblastoma is the most frequent and malignant form of primary brain tumor with grave prognosis. Mounting evidence supports that chronic inflammation (such as chronic overactivation of IL-1 system) is a crucial event in carcinogenesis and tumor progression. IL-1 also is an important cytokine with species-dependent regulations and roles in CNS cell activation. While much attention is paid to specific anti-tumor immunity, little is known about the role of chronic inflammation/innate immunity in glioma pathogenesis. In this study, we examined whether human astrocytic cells (including malignant gliomas) can produce IL-1 and its role in glioma progression. Methods We used a combination of cell culture, real-time PCR, ELISA, western blot, immunocytochemistry, siRNA and plasmid transfection, micro-RNA analysis, angiogenesis (tube formation) assay, and neurotoxicity assay. Results Glioblastoma cells produced large quantities of IL-1 when activated, resembling macrophages/microglia. The activation signal was provided by IL-1 but not the pathogenic components LPS or poly IC. Glioblastoma cells were highly sensitive to IL-1 stimulation, suggesting its relevance in vivo. In human astrocytes, IL-1? mRNA was not translated to protein. Plasmid transfection also failed to produce IL-1 protein, suggesting active repression. Suppression of microRNAs that can target IL-1?/? did not induce IL-1 protein. Glioblastoma IL-1? processing occurred by the NLRP3 inflammasome, and ATP and nigericin increased IL-1? processing by upregulating NLRP3 expression, similar to macrophages. RNAi of annexin A2, a protein strongly implicated in glioma progression, prevented IL-1 induction, demonstrating its new role in innate immune activation. IL-1 also activated Stat3, a transcription factor crucial in glioma progression. IL-1 activated glioblastoma-conditioned media enhanced angiogenesis and neurotoxicity. Conclusions Our results demonstrate unique, species-dependent immune activation mechanisms involving human astrocytes and astrogliomas. Specifically, the ability to produce IL-1 by glioblastoma cells may confer them a mesenchymal phenotype including increased migratory capacity, unique gene signature and proinflammatory signaling.

Tarassishin, Leonid; Casper, Diana; Lee, Sunhee C.

2014-01-01

253

Noise Minimisation in Gene Expression Switches  

PubMed Central

Gene expression is subject to stochastic variation which leads to fluctuations in the rate of protein production. Recently, a study in yeast at a genomic scale showed that, in some cases, gene expression variability alters phenotypes while, in other cases, these remain unchanged despite fluctuations in the expression of other genes. These studies suggested that noise in gene expression is a physiologically relevant trait and, to prevent harmful stochastic variation in the expression levels of some genes, it can be subject to minimisation. However, the mechanisms for noise minimisation are still unclear. In the present work, we analysed how noise expression depends on the architecture of the cis-regulatory system, in particular on the number of regulatory binding sites. Using analytical calculations and stochastic simulations, we found that the fluctuation level in noise expression decreased with the number of regulatory sites when regulatory transcription factors interacted with only one other bound transcription factor. In contrast, we observed that there was an optimal number of binding sites when transcription factors interacted with many bound transcription factors. This finding suggested a new mechanism for preventing large fluctuations in the expression of genes which are sensitive to the concentration of regulators.

Monteoliva, Diana; McCarthy, Christina B.; Diambra, Luis

2013-01-01

254

Amplification of NOTCH1 and ABL1 gene loci is a frequent aberration in enteropathy-type T-cell lymphoma  

Microsoft Academic Search

We have shown previously that amplification of chromosomal region 9q34 is the most frequent aberration in enteropathy-type T-cell lymphoma (ETL). To determine the minimum amplified 9q34 region and identify possible candidate gene(s), we performed a detailed microsatellite screening and quantitative real-time PCR (QPCR) on 26 ETL cases. Microsatellite analysis revealed allelic imbalance in both ABL1 and NOTCH1 gene loci (microsatellites

Pavlina Cejkova; Andreas Zettl; Anne K. Baumgärtner; Andreas Chott; German Ott; Hans Konrad Müller-Hermelink; Petr Starostik

2005-01-01

255

Gene expression atlas for human embryogenesis  

PubMed Central

Human embryogenesis is believed to involve an integrated set of complex yet coordinated development of different organs and tissues mediated by the changes in the spatiotemporal expression of many genes. Here, we report a genome-wide expression analysis during wk 4–9 of human embryogenesis, a critical period when most organs develop. About half of all human genes are expressed, and 18.6% of the expressed genes were significantly regulated during this important period. We further identified >5000 regulated genes, most of which previously were not known to be associated with animal development. Our study fills an important gap in mammalian developmental studies by identifying functional pathways involved in this critical but previously not studied period. Our study also revealed that the genes involved here are distinct from those during early embryogenesis, which include three groups of maternal genes. Furthermore, we discovered that genes in a given developmental process are regulated coordinately. This led us to develop an easily searchable database of this entire collection of gene expression profiles, allowing for the identification new genes important for a particular developmental process/pathway and deducing the potential function of a novel gene. The validity of the predictions from the database was demonstrated with two examples through spatiotemporal analyses of the two novel genes. Such a database should serve as a highly valuable resource for the molecular analysis of human development and pathogenesis.—Yi, H., Xue, L., Guo, M.-X. Ma, J., Zeng, Y., Wang, W., Cai, J.-Y. Hu, H.-M., Shu, H.-B. Shi, Y.-B., Li, W.-X. Gene expression atlas for human embryogenesis.

Yi, Hong; Xue, Lu; Guo, Ming-Xiong; Ma, Jian; Zeng, Yan; Wang, Wei; Cai, Jin-Yang; Hu, Hai-Ming; Shu, Hong-Bing; Shi, Yun-Bo; Li, Wen-Xin

2010-01-01

256

Altered expression of topoisomerase II? contributes to cross-resistant to etoposide K562/MX2 cell line by aberrant methylation  

PubMed Central

KRN 8602 (MX2) is a novel morpholino anthracycline derivative having the chemical structure 3?-deamino-3?-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. To investigate the mechanisms of resistance to MX2, we established an MX2-resistant phenotype (K562/MX2) of the human myelogeneous leukaemia cell line (K562/P), by continuously exposing a suspension culture to increasing concentrations of MX2. K562/MX2 cells were more resistant to MX2 than the parent cells, and also showed cross-resistance to etoposide and doxorubicin. Topoisomerase (Topo) II? protein levels in K562/MX2 cells were lower of those in K562/P cells on immunoblot analysis and decreased expression of Topo II? mRNA was seen in K562/MX2 cells. Topoisomerase II catalytic activity was also reduced in the nuclear extracts from K562/MX2 cells when compared with K562/P cells. Aberrant methylated CpG of Topo II? gene was observed in K562/MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis. To overcome the drug resistance to MX2 and etoposide, we investigated treatment with 5-Aza-2?-deoxycytidine (5AZ), which is a demethylating agent, in K562/MX2 cells. 5-Aza-2?-deoxycytidine treatment increased Topo II? mRNA expression in K562/MX2 cells, but not in K562/P cells, and increased the cytotoxicity of MX2 and etoposide. Methylated CpG was decreased in K562/MX2 cells after 5AZ treatment. We concluded that the mechanism of drug resistance to MX2 and etoposide in K562/MX2 cells might be the combination of decreased expression of Topo II? gene and increased methylation, and that 5AZ could prove to be a novel treatment for etoposide-resistant cell lines, such as K562/MX2.

Asano, T; Nakamura, K; Fujii, H; Horichi, N; Ohmori, T; Hasegawa, K; Isoe, T; Adachi, M; Otake, N; Fukunaga, Y

2005-01-01

257

A Testicular Antigen Aberrantly Expressed in Human Cancers Detected by Autologous Antibody Screening  

Microsoft Academic Search

Serological analysis of recombinant cDNA expression libraries (SEREX) using tumor mRNA and autologous patient serum provides a powerful approach to identify immunogenic tumor antigens. We have applied this methodology to a case of esophageal squamous cell carcinoma and identified several candidate tumor targets. One of these, NY-ESO-1, showed restricted mRNA expression in normal tissues, with high-level mRNA expression found only

Yao-Tseng Chen; Matthew J. Scanlan; Ugur Sahin; Ozlem Tureci; Ali O. Gure; Solam Tsang; Barbara Williamson; Elisabeth Stocker; Michael Pfreundschuh; Lloyd J. Old

1997-01-01

258

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

259

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

260

Blood gene expression signatures predict exposure levels  

PubMed Central

To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The indicators are particularly important in the case of acetaminophen (APAP) intoxication, the leading cause of liver failure in the U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful indicators of acute exposure levels. To test this hypothesis, we used a blood gene expression data set from rats exposed to APAP to train classifiers in two prediction algorithms and to extract patterns for prediction using a profiling algorithm. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. The expression profiles of the predictor genes from the patterns extracted from the blood exhibited remarkable (97% accuracy) transtissue APAP exposure prediction when liver gene expression data were used as a test set. Analysis of human samples revealed separation of APAP-intoxicated patients from control individuals based on blood expression levels of human orthologs of the rat discriminatory genes. The major biological signal in the discriminating genes was activation of an inflammatory response after exposure to toxic doses of APAP. These results support the hypothesis that gene expression data from peripheral blood cells can provide valuable information about exposure levels, well before liver damage is detected by classical parameters. It also supports the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.

Bushel, P. R.; Heinloth, A. N.; Li, J.; Huang, L.; Chou, J. W.; Boorman, G. A.; Malarkey, D. E.; Houle, C. D.; Ward, S. M.; Wilson, R. E.; Fannin, R. D.; Russo, M. W.; Watkins, P. B.; Tennant, R. W.; Paules, R. S.

2007-01-01

261

Regulation of tobacco acetolactate synthase gene expression.  

PubMed Central

Acetolactate synthase (ALS) catalyzes the first common step in the biosynthesis of isoleucine, leucine, and valine. The previous cloning of two tobacco (Nicotiana tabacum) ALS genes (SurA and SurB) has allowed transcript accumulation from these genes to be monitored. mRNA blot analysis of ALS transcripts showed a message size of 2.2 kb. Quantitation of the levels of ALS messages in tobacco organs indicated that there was 3- to 4-fold variation in the levels of expression of the ALS genes in different organs. This variability correlated with the developmental stage of the samples, with the highest levels of expression found in developing organs. In situ hybridizations of anti-mRNA probes to plant sections established that ALS messages are most prevalent in metabolically active and dividing cells of roots, stems, and floral tissue. Using RNase protection assays, the transcriptional start sites of the ALS genes were determined, and the expression levels of the two tobacco ALS genes were then followed separately. Both tobacco ALS genes are expressed in a coordinated manner in all tobacco organs examined, with the SurB gene being consistently expressed at higher levels than the SurA gene.

Keeler, S J; Sanders, P; Smith, J K; Mazur, B J

1993-01-01

262

Sexual differences of imprinted genes' expression levels.  

PubMed

In mammals, genomic imprinting has evolved as a dosage-controlling mechanism for a subset of genes that play critical roles in their unusual reproduction scheme involving viviparity and placentation. As such, many imprinted genes are highly expressed in sex-specific reproductive organs. In the current study, we sought to test whether imprinted genes are differentially expressed between the two sexes. According to the results, the expression levels of the following genes differ between the two sexes of mice: Peg3, Zim1, Igf2, H19 and Zac1. The expression levels of these imprinted genes are usually greater in males than in females. This bias is most obvious in the developing brains of 14.5-dpc embryos, but also detected in the brains of postnatal-stage mice. However, this sexual bias is not obvious in 10.5-dpc embryos, a developmental stage before the sexual differentiation. Thus, the sexual bias observed in the imprinted genes is most likely attributable by gonadal hormones rather than by sex chromosome complement. Overall, the results indicate that several imprinted genes are sexually different in terms of their expression levels, and further suggest that the transcriptional regulation of these imprinted genes may be influenced by unknown mechanisms associated with sexual differentiation. PMID:24125951

Faisal, Mohammad; Kim, Hana; Kim, Joomyeong

2014-01-01

263

Correlative gene expression and DNA methylation profiling in lung development nominate new biomarkers in lung cancer.  

PubMed

Although transcriptional control is key for proper lung development, little is known about the possible accompanying epigenetic modifications. Here, we have used gene expression profiling to identify 99 genes that are upregulated in fetal lung and 354 genes that are upregulated in adult lung. From the differentially expressed genes, we analyzed the accompanying 5'-UTR methylation profiles of 43 genes. Out of these, nine genes (COL11A1, MEOX2, SERPINE2, SOX9, FBN2, MDK, COL1A1, LAPTM5 and MARCO) displayed an inverse correlation of their 5'-UTR methylation and the cognate gene expression, suggesting that these genes are at least partially regulated by DNA methylation. Using the differential gene expression/DNA methylation profiles as a guidepost, we identified four genes (MEOX2, MDK, LAPTM5, FGFR3) aberrantly methylated in lung cancer. MEOX2 was uniformly higher methylated in all lung cancer samples (n=15), while the methylation of the other three genes was correlated with either the differentiation state of the tumor (MDK, LAPTM5) or the tumor type itself (FGFR3). PMID:18203646

Cortese, Rene; Hartmann, Oliver; Berlin, Kurt; Eckhardt, Florian

2008-01-01

264

Gene expression variation between mouse inbred strains  

PubMed Central

Background In this study, we investigated the effect of genetic background on expression profiles. We analysed the transcriptome of mouse hindlimb muscle of five frequently used mouse inbred strains using spotted oligonucleotide microarrays. Results Through ANOVA analysis with a false discovery rate of 10%, we show that 1.4% of the analysed genes is significantly differentially expressed between these mouse strains. Differential expression of several of these genes has been confirmed by quantitative RT-PCR. The number of genes affected by genetic background is approximately ten-fold lower than the number of differentially expressed genes caused by a dystrophic genetic defect. Conclusions We conclude that evaluation of the effect of background on gene expression profiles in the tissue under study is an effective and sensible approach when comparing expression patterns in animal models with heterogeneous genetic backgrounds. Genes affected by the genetic background can be excluded in subsequent analyses of the disease-related changes in expression profiles. This is often a more effective strategy than backcrossing and inbreeding to obtain isogenic backgrounds.

Turk, Rolf; 't Hoen, Peter AC; Sterrenburg, Ellen; de Menezes, Renee X; de Meijer, Emile J; Boer, Judith M; van Ommen, Gert-Jan B; den Dunnen, Johan T

2004-01-01

265

[The effect of polymorphism of genes of xenobiotics detoxication on the frequencies of spontaneous and induced chromosome aberrations in human lymphocytes].  

PubMed

Here presented the data on the frequencies of chromosome aberrations in lymphocytes of peripheral blood of 97 volunteers depending on genotypes by genes of xenobiotics detoxication before and after gamma-irradiation with dose of 1 Gy in vitro. The frequencies of aberrations were estimated by analyzing not less than 500-1000 metaphases per person. The data of cytogenetic analysis were compared with the results of PCR-genotyping of loci GSTM1, GSTT1, GSTP1, CYP1A1, CYP2D6, NAT2, and MTHFR. The significant differences by the frequencies of aberrations between "single-locus" genotypes were not found except for GSTM1 locus, for which the enhanced frequency of spontaneous aberrations of chromosome type in "positive" genotypes compared to "zero" ones, i.e., homozygotes by deletion (p = 0.04) was observed. The minimum frequency of spontaneous aberrations of chromosome type was recorded for carriers of double homozygotes by deletion of GSTM1-GSTT1: 0.0006 +/- 0.0003 against 0.0027 +/- 0.0003 for the rest of genotypes (p = 0.016 by the Mann-Witney test). The frequency of gamma-induced chromosome aberrations was correlated with the total amount of minor alleles in loci GSTP1, NAT2, and MTHFR (r = 0.25 at p = 0.0065). PMID:19947517

Sal'nikova, L E; Akaeva, E A; Elisova, T V; Kuznetsova, G I; Kuz'mina, N S; Vesnina, I N; Lapteva, N Sh; Chumachenko, A G; Romanchuk, V A; Rubanovich, A V

2009-01-01

266

Aberrant expression of laminin gamma 2 chain and its prognostic significance in intrahepatic cholangiocarcinoma according to growth morphology.  

PubMed

Laminin gamma 2 chain is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. We report altered expression and characteristic localization of this chain in a series of 105 cases of intrahepatic cholangiocarcinomas examined immunohistochemically. All tumors were grossly classified into the following three types: intraductal growth type (n=9), periductal infiltrating type (n=8) and mass-forming type (n=88). The tumors exhibited three distinct staining types: basement membrane staining, cytoplasmic staining and stromal staining. The basement membranous staining of laminin gamma 2 chain was more frequent in biliary dysplasia, intraductal growth and periductal infiltrating type than in mass-forming type. The cytoplasmic staining of carcinoma cells was observed especially at the cancer-stromal interface or at the invasive front of tumors. Stromal staining of laminin gamma 2 chain was essentially localized in the stroma around cancer cells at the invasive area, and the expression was significantly correlated with tumor aggressive factors and a poor prognosis in patients with intrahepatic cholangiocarcinoma. We conclude that laminin gamma 2 chain exhibits aberrant expression in a stepwise manner through different aggressive stages of tumor progression. PMID:15105812

Aishima, Shinichi; Matsuura, Shuji; Terashi, Takahiro; Taguchi, Kenichi; Shimada, Mitsuo; Maehara, Yoshihiko; Tsuneyoshi, Masazumi

2004-08-01

267

Dynamic modeling of gene expression data  

NASA Technical Reports Server (NTRS)

We describe the time evolution of gene expression levels by using a time translational matrix to predict future expression levels of genes based on their expression levels at some initial time. We deduce the time translational matrix for previously published DNA microarray gene expression data sets by modeling them within a linear framework by using the characteristic modes obtained by singular value decomposition. The resulting time translation matrix provides a measure of the relationships among the modes and governs their time evolution. We show that a truncated matrix linking just a few modes is a good approximation of the full time translation matrix. This finding suggests that the number of essential connections among the genes is small.

Holter, N. S.; Maritan, A.; Cieplak, M.; Fedoroff, N. V.; Banavar, J. R.

2001-01-01

268

Changes in gene expression following EMF exposure  

SciTech Connect

Experiments were designed to examine the effects of electromagnetic field (EMF) exposure on specific gene expression, an effect that can be deleterious, beneficial, or neutral, depending on the long-term consequences; however, the proof of a reproducible, quantitative biological effect (such as change in gene expression) will lead to latter experiments aimed at determining the relative contribution of these changes to cellular consequences. Past work by ourselves and by others has shown that measures of gene expression are extremely sensitive indicators of the cellular and biological effects of ionizing radiation, with transcriptional changes being detected by exposure of cells to doses of {gamma}-rays as low as 0.01 cGy that have no pronounced cellular consequences. On the basis of this work, the authors hypothesized that measures of gene expression will be equally sensitive to EMF effects on cells.

Woloschak, G.E.; Paunesku, T.; Chang-Liu, C.M. [Argonne National Lab., IL (United States). Center for Mechanistic Biology and Biotechnology; Loberg, L.; Gauger, J.; McCormick, D. [IIT Research Inst., Chicago, IL (United States)

1997-10-01

269

From gene expression to gene regulatory networks in Arabidopsis thaliana  

PubMed Central

Background The elucidation of networks from a compendium of gene expression data is one of the goals of systems biology and can be a valuable source of new hypotheses for experimental researchers. For Arabidopsis, there exist several thousand microarrays which form a valuable resource from which to learn. Results A novel Bayesian network-based algorithm to infer gene regulatory networks from gene expression data is introduced and applied to learn parts of the transcriptomic network in Arabidopsis thaliana from a large number (thousands) of separate microarray experiments. Starting from an initial set of genes of interest, a network is grown by iterative addition to the model of the gene, from another defined set of genes, which gives the 'best' learned network structure. The gene set for iterative growth can be as large as the entire genome. A number of networks are inferred and analysed; these show (i) an agreement with the current literature on the circadian clock network, (ii) the ability to model other networks, and (iii) that the learned network hypotheses can suggest new roles for poorly characterized genes, through addition of relevant genes from an unconstrained list of over 15,000 possible genes. To demonstrate the latter point, the method is used to suggest that particular GATA transcription factors are regulators of photosynthetic genes. Additionally, the performance in recovering a known network from different amounts of synthetically generated data is evaluated. Conclusion Our results show that plausible regulatory networks can be learned from such gene expression data alone. This work demonstrates that network hypotheses can be generated from existing gene expression data for use by experimental biologists.

Needham, Chris J; Manfield, Iain W; Bulpitt, Andrew J; Gilmartin, Philip M; Westhead, David R

2009-01-01

270

Mining Gene Expression Data of Multiple Sclerosis  

PubMed Central

Objectives Microarray produces a large amount of gene expression data, containing various biological implications. The challenge is to detect a panel of discriminative genes associated with disease. This study proposed a robust classification model for gene selection using gene expression data, and performed an analysis to identify disease-related genes using multiple sclerosis as an example. Materials and methods Gene expression profiles based on the transcriptome of peripheral blood mononuclear cells from a total of 44 samples from 26 multiple sclerosis patients and 18 individuals with other neurological diseases (control) were analyzed. Feature selection algorithms including Support Vector Machine based on Recursive Feature Elimination, Receiver Operating Characteristic Curve, and Boruta algorithms were jointly performed to select candidate genes associating with multiple sclerosis. Multiple classification models categorized samples into two different groups based on the identified genes. Models’ performance was evaluated using cross-validation methods, and an optimal classifier for gene selection was determined. Results An overlapping feature set was identified consisting of 8 genes that were differentially expressed between the two phenotype groups. The genes were significantly associated with the pathways of apoptosis and cytokine-cytokine receptor interaction. TNFSF10 was significantly associated with multiple sclerosis. A Support Vector Machine model was established based on the featured genes and gave a practical accuracy of ?86%. This binary classification model also outperformed the other models in terms of Sensitivity, Specificity and F1 score. Conclusions The combined analytical framework integrating feature ranking algorithms and Support Vector Machine model could be used for selecting genes for other diseases.

Zhu, Zhenli; Huang, Zhengliang; Li, Ke

2014-01-01

271

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

272

Localized Gene Expression in Pseudomonas aeruginosa Biofilms  

Microsoft Academic Search

Gene expression in biofilms is dependent on bacterial responses to the local environmental conditions. Most techniques for studying bacterial gene expression in biofilms characterize average values across the entire population. Here, we describe the use of laser capture microdissection microscopy (LCMM) combined with multiplex quantitative real-time reverse transcriptase PCR (qRT-PCR) to isolate and quantify RNA tran- scripts from small groups

Ailyn P. Lenz; Kerry S. Williamson; Betsey Pitts; Philip S. Stewart; Michael J. Franklin

2008-01-01

273

Gene expression of interleukin-1? during hemodialysis  

Microsoft Academic Search

Gene expression of interleukin-1? during hemodialysis. It is still controversial whether the hemodialysis (HD) procedure is an inflammatory process in vivo. Therefore, we studied the gene expression of interleukin-1? (IL-1?) as a marker of inflammation in peripheral blood mononuclear cells (PBMC) of patients during HD by Northern blotting and polymerase chain reaction. Compared to PBMC separated pre-HD (1.0 densitometric units),

Ralf Schindler; Silvia Linnenweber; Matthias Schulze; Martin Oppermann; Charles A Dinarello; Karl-Martin Koch

1993-01-01

274

Differential gene expression of cultured human osteoblasts.  

PubMed

Human cells with osteogenic capacity were studied for differential gene expression. In the first part of the study we compared gene expression of marrow stroma cells (MSC) in comparison to matured osteoblasts cultured from trabecular bone (TBC) that were analyzed by RT-PCR for series of messages. High expression was detected for PTH-r, TGFb1 and biglycan in TBC compared to MSC's. The messages for c-MYC, IL-6, IL-11, M-CSF, osteonectin, and osteocalcin were expressed at the same level in the two populations of cells. In the second part of the study, we analyzed gene expression within the MSC derived from 25 donors (2.5-49 years old) with respect to donors' age and gender. Increased message levels for M-CSF and biglycan were measured in correlation with age of the donors. Gender differences did not affect the expression of cytokines studied (IL-6, IL-11, MCSF, TGFb1). We investigated the effect of Dexamethasone treatment on MSC and monitored an increased expression of IL-11, M-CSF, biglycan, and osteocalcin messages. This study employs primary cell systems (MSC and TBC) to illustrate differential gene expression by osteoblastic cells. The expression was correlated with maturation status of the cells with respect to differences between donors. PMID:11746498

Shur, I; Lokiec, F; Bleiberg, I; Benayahu, D

2001-01-01

275

PRAME gene expression profile in medulloblastoma.  

PubMed

Medulloblastoma is the most common malignant tumors of central nervous system in the childhood. The treatment is severe, harmful and, thus, has a dismal prognosis. As PRAME is present in various cancers, including meduloblastoma, and has limited expression in normal tissues, this antigen can be an ideal vaccine target for tumor immunotherapy. In order to find a potential molecular target, we investigated PRAME expression in medulloblastoma fragments and we compare the results with the clinical features of each patient. Analysis of gene expression was performed by real-time quantitative PCR from 37 tumor samples. The Mann-Whitney test was used to analysis the relationship between gene expression and clinical characteristics. Kaplan-Meier curves were used to evaluate survival. PRAME was overexpressed in 84% samples. But no statistical association was found between clinical features and PRAME overexpression. Despite that PRAME gene could be a strong candidate for immunotherapy since it is highly expressed in medulloblastomas. PMID:21359415

Vulcani-Freitas, Tânia Maria; Saba-Silva, Nasjla; Cappellano, Andréa; Cavalheiro, Sérgio; Toledo, Sílvia Regina Caminada de

2011-02-01

276

Aberrant expression of let-7a miRNA in the blood of non-small cell lung cancer patients.  

PubMed

Abnormal expression of let-7a microRNA (miRNA) in non-small cell lung cancer (NSCLC) cells and tissue has been previously reported. Our objective was to investigate whether let-7a miRNA is aberrantly expressed in the blood of NSCLC patients. Using real-time PCR (RT-PCR), we analyzed let-7a miRNA in archived whole blood from 65 participants, 35 of whom had NSCLC and 30 of whom did not. Using RT-PCR, we also investigated the expression of let-7a miRNA in NSCLC cell lines (A549 and HCC 1588), a normal human lung fibroblast cell line (WI-38) and in 40 human NSCLC tissues. The 2(-ddCt) of let-7a miRNA in the blood of normal subjects and those with NSCLC was 3242.49±355.28 and 747.85±177.74, respectively. The relative expression of let-7a miRNA in the A549 and HCC 1588 cancer cell lines was approximately 0.3 and 0.35, respectively, compared to WI-38 cells. The 2(-ddCt) of let-7a miRNA in the normal human lung tissues and human NSCLC tissues was 42.30±3.98 and 27.73±3.86, respectively. Let-7a miRNAs were under-expressed in the blood of NSCLC patients, as well as NSCLC cells and NSCLC tissues, compared to normal controls. The possibility of using let-7a miRNA as a serologic marker for lung cancer warrants further study. PMID:21468581

Jeong, Hye Cheol; Kim, Eun Kyung; Lee, Ji Hyun; Lee, Ji Min; Yoo, Han Na; Kim, Jin Kyeoung

2011-01-01

277

Homeobox genes expressed during echinoderm arm regeneration.  

PubMed

Regeneration in echinoderms has proved to be more amenable to study in the laboratory than the more classical vertebrate models, since the smaller genome size and the absence of multiple orthologs for different genes in echinoderms simplify the analysis of gene function during regeneration. In order to understand the role of homeobox-containing genes during arm regeneration in echinoderms, we isolated the complement of genes belonging to the Hox class that are expressed during this process in two major echinoderm groups: asteroids (Echinaster sepositus and Asterias rubens) and ophiuroids (Amphiura filiformis), both of which show an extraordinary capacity for regeneration. By exploiting the sequence conservation of the homeobox, putative orthologs of several Hox genes belonging to the anterior, medial, and posterior groups were isolated. We also report the isolation of a few Hox-like genes expressed in the same systems. PMID:24309817

Ben Khadra, Yousra; Said, Khaled; Thorndyke, Michael; Martinez, Pedro

2014-04-01

278

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

279

Regulation of gene expression in plant mitochondria  

Microsoft Academic Search

Many genes in plant mitochondria have been analyzed in the past 15 years and regulatory processes controlling gene expression can now be investigated. In vitro systems capable of initiating transcription faithfully at promoter sites have been developed for both monocot and dicot plants and will allow the identification of the interacting nucleic acid elements and proteins which specify and guide

Stefan Binder; Anita Marchfelder; Axel Brennicke

1996-01-01

280

In Vivo Imaging of mdrla Gene Expression.  

National Technical Information Service (NTIS)

The authors' experience studying the MDR1 gene prompted them to initiate work on a novel animal model to study MDR1/mdr1 gene expression under a variety of normal and breast cancer-related physiological conditions. With the advent of new bioimaging techno...

T. W. Synold

2005-01-01

281

Gene expression analysis using single molecule detection  

PubMed Central

Recent developments of single molecule detection techniques and in particular the introduction of fluorescence correlation spectroscopy (FCS) led to a number of important applications in biological research. We present a unique approach for the gene expression analysis using dual-color cross-correlation. The expression assay is based on gene-specific hybridization of two dye-labeled DNA probes to a selected target gene. The counting of the dual-labeled molecules within the solution allows the quantification of the expressed gene copies in absolute numbers. As detection and analysis by FCS can be performed at the level of single molecules, there is no need for any type of amplification. We describe the gene expression assay and present data demonstrating the capacity of this novel technology. In order to prove the gene specificity, we performed experiments with gene-depleted total cDNA. The biological application was demonstrated by quantifying selected high, medium and low abundant genes in cDNA prepared from HL-60 cells.

Korn, Kerstin; Gardellin, Paola; Liao, Bohao; Amacker, Mario; Bergstrom, ?sa; Bjorkman, Henrik; Camacho, Agnes; Dorhofer, Sabine; Dorre, Klaus; Enstrom, Johanna; Ericson, Thomas; Favez, Tatiana; Gosch, Michael; Honegger, Adrian; Jaccoud, Sandra; Lapczyna, Markus; Litborn, Erik; Thyberg, Per; Winter, Holger; Rigler, Rudolf

2003-01-01

282

Custom Design of a GeXP Multiplexed Assay Used to Assess Expression Profiles of Inflammatory Gene Targets in Normal Colon, Polyp, and Tumor Tissue  

PubMed Central

Colon cancers are characterized by aberrant gene expression signatures associated with disease initiation and progression. Identification of aberrant gene expression associated with colon carcinogenesis has increased significantly with application of gene array technologies. Downstream processing of these data has been hindered by the lack of robust multiplexed gene quantitative technologies facilitating study of the identified multiple gene targets. The GenomeLab Genetic Analysis System presents a novel technology platform for quantitative multiplexed gene expression analysis. This report describes the custom design of a GeXP multiplexed assay used to assess expression profiles of 14 inflammatory gene targets in normal, polyp, and tumor tissue. Characteristic normal, polyp, and tumor tissue gene expression profiles were obtained. Statistical analysis confirmed comparable relative quantitation of gene expression using the GeXP, macroarray, and single-plex real-time polymerase chain reaction assays. GeXP assays may be usefully applied in clinical and regulatory studies of multiple gene targets. This system permits custom-design options for relative quantification of multiple gene target expression, simultaneously in a single reaction, using nanogram quantities of total RNA template. The system provides an approach to advance the study of multiple targets identified from gene array analysis with potential for characterizing gene expression signatures in clinical diagnostics.

Drew, Janice E.; Mayer, Claus-Dieter; Farquharson, Andrew J.; Young, Pauline; Barrera, Lawrence N.

2011-01-01

283

Epidermal Growth Factor Receptor Regulates Aberrant Expression of Insulin-Like Growth Factor-Binding Protein 3  

Microsoft Academic Search

Epidermal growth factor receptor (EGFR) is frequently overexpressed in esophageal carcinoma and its precursor lesions. To gain insights into how EGFR overexpression affects cellular functions in primary human esophageal cells, we performed gene expression profiling and identified insulin-like growth factor-binding protein (IGFBP)-3 as the most up- regulated gene. IGFBP-3 regulates cell proliferation through both insulin- like growth factor-dependent and independent

Munenori Takaoka; Hideki Harada; Claudia D. Andl; Kenji Oyama; Yoshio Naomoto; Kelly L. Dempsey; Andres J. Klein-Szanto; Wafik S. El-Deiry; Adda Grimberg; Hiroshi Nakagawa

2004-01-01

284

Aberrant DNA methylation of drug metabolism and transport genes in nodular goiter.  

PubMed

The genes encoding drug-metabolizing enzymes and transporters play an important role in maintaining the normal life processes of human body. Their disorder or defect will lead to the occurrence and development of various diseases. Currently, most of studies have focused on genetic variations in these genes, however, in the present study, we analyzed promoter methylation of 11 drug metabolism and transport genes in a cohort of nodular goiter and normal thyroid tissues using methylation-specific PCR (MSP). Our data first revealed a distinct methylation profiling in drug metabolism and transport genes between nodular goiter and normal thyroid tissues, particularly ABCB4, CYP1B1 and CYP24A1 and SLC1A2. Given these genes contribute to the development and progression of various diseases, such as multidrug resistance and tumorigenesis, these epigenetic events may thus play a critical role in the pathogenesis of nodular goiter. PMID:21988780

Zhang, Lihong; Shi, Jing; Xu, Li; Shi, Bingyin; Hou, Peng; Ji, Meiju

2011-01-01

285

Integrated Analysis of Gene Expression and Gene Copy Number for Gene Shaving Based on ICA Approach  

Microsoft Academic Search

Microarray gene expression and array CGH (aCGH) are two genomic approaches, which are widely used for biomedical discovery. While microarray gene expression analysis provides functional information, the aCGH analysis provides structural variations of genome using gene copy number analysis. The integration of this complementary information is challenging. We proposed a method, named as “gene shaving”, to identify subsets of the

Yu-Ping Wang

2011-01-01

286

Aberrantly Over-Expressed TRPM8 Channels in Pancreatic Adenocarcinoma: Correlation with Tumor Size/Stage and Requirement for Cancer Cells Invasion  

PubMed Central

The transient receptor potential melastatin-subfamily member 8 (TRPM8) channels control Ca2+ homeostasis. Recent studies indicate that TRPM8 channels are aberrantly expressed and required for cellular proliferation in pancreatic adenocarcinoma. However, the functional significance of TRPM8 in pancreatic tissues is mostly unknown. The objectives of this study are to examine the expression of TRPM8 in various histopathological types of pancreatic tissues, determine its clinical significance in pancreatic adenocarcinoma, and investigate its functional role in cancer cells invasion. We present evidence that, in normal pancreatic tissues, anti-TRPM8 immunoreactivity is detected in the centroacinar cells and the islet endocrine cells. In pre-malignant pancreatic tissues and malignant neoplasms, TRPM8 is aberrantly expressed to variable extents. In the majority of pancreatic adenocarcinoma, TRPM8 is expressed at moderate or high levels, and anti-TRPM8 immunoreactivity positively correlates with the primary tumor size and stage. In the pancreatic adenocarcinoma cell lines that express relatively high levels of TRPM8, short hairpin RNA-mediated interference of TRPM8 expression impaired their ability of invasion. These data suggest that aberrantly expressed TRPM8 channels play contributory roles in pancreatic tumor growth and metastasis, and support exploration of TRPM8 as a biomarker and target of pancreatic adenocarcinoma.

Yee, Nelson S.; Li, Qin; Kazi, Abid A.; Yang, Zhaohai; Berg, Arthur; Yee, Rosemary K.

2014-01-01

287

New criteria for selecting differentially expressed genes  

Microsoft Academic Search

Two new criteria for identifying differentially expressed genes, the average difference score (ADS) and the mean difference score (MDS), are formulated. The performance of ADS and MDS were compared to that of several commonly used criteria, including Welch t-statistic (WTS), Fisher correlation score (FCS), Wilcoxon rank sum (WRS) and independently consistent expression (ICE) on simulated and real biological datasets. We

Lit-Hsin Loo; Samuel Roberts; Leonid Hrebien; Moshe Kam

2007-01-01

288

Control of gene expression in trypanosomes.  

PubMed Central

Trypanosomes are protozoan agents of major parasitic diseases such as Chagas' disease in South America and sleeping sickness of humans and nagana disease of cattle in Africa. They are transmitted to mammalian hosts by specific insect vectors. Their life cycle consists of a succession of differentiation and growth phases requiring regulated gene expression to adapt to the changing extracellular environment. Typical of such stage-specific expression is that of the major surface antigens of Trypanosoma brucei, procyclin in the procyclic (insect) form and the variant surface glycoprotein (VSG) in the bloodstream (mammalian) form. In trypanosomes, the regulation of gene expression is effected mainly at posttranscriptional levels, since primary transcription of most of the genes occurs in long polycistronic units and is constitutive. The transcripts are processed by transsplicing and polyadenylation under the influence of intergenic polypyrimidine tracts. These events show some developmental regulation. Untranslated sequences of the mRNAs seem to play a prominent role in the stage-specific control of individual gene expression, through a modulation of mRNA abundance. The VSG and procyclin transcription units exhibit particular features that are probably related to the need for a high level of expression. The promoters and RNA polymerase driving the expression of these units resemble those of the ribosomal genes. Their mutually exclusive expression is ensured by controls operating at several levels, including RNA elongation. Antigenic variation in the bloodstream is achieved through DNA rearrangements or alternative activation of the telomeric VSG gene expression sites. Recent discoveries, such as the existence of a novel nucleotide in telomeric DNA and the generation of point mutations in VSG genes, have shed new light on the mechanisms and consequences of antigenic variation.

Vanhamme, L; Pays, E

1995-01-01

289

Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells  

Microsoft Academic Search

Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are associated with aberrant gene\\u000a expression in breast cancer development. However, the precise molecular mechanisms underlying the crosstalk between KDMs and\\u000a HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment\\u000a of human breast cancer cells with inhibitors targeting the

Yi Huang; Shauna N. Vasilatos; Lamia Boric; Patrick G. Shaw; Nancy E. Davidson

290

Diagnostic tests using gene expression ratios  

US Patent & Trademark Office Database

The invention provides methods for diagnosing biological states or conditions based on ratios of gene expression data from cell or tissue samples, such as cancer cell or tissue samples. The invention also provides sets of genes that are expressed differentially in normal and cancer lung cells and tissues. These sets of genes can be used to discriminate between normal and malignant cells or tissues, and between classes of malignant cells or tissues. Accordingly, diagnostic assays for classification of tumors, prediction of tumor outcome, selecting and monitoring treatment regimens and monitoring tumor progression/regression also are provided.

2013-05-28

291

Deletion in the 3' pol sequence correlates with aberration of RNA expression in certain replication-defective avian sarcoma viruses.  

PubMed Central

The RNA expression of a series of replication-defective recovered avian sarcoma viruses (rASVs) were studied. Abnormal-sized viral RNAs, both larger and smaller than the genome, were observed in the nonproducer cells infected with rASVs containing env and pol deletions. Each nonproducer clone contained a single provirus integrated at a unique site and expressed a unique RNA pattern. Upon rescuing of the sarcoma virus with a helper virus and subsequent cloning, the RNA pattern of individual nonproducer clones again displayed variation according to the integration sites. This was not seen in nondefective rASV or in rASVs containing only an env deletion. The aberrant RNA expression did not result from the lack of reverse transcriptase activity per se, since neither nonconditional nor temperature-sensitive mutants of RSV expressed abnormal viral RNAs in the absence of a functional reverse transcriptase. The abnormal RNA patterns could not be corrected in trans by helper virus functions. The unusual-sized RNAs in env- pol- rASV-infected cells are not due to splicing to alternative acceptor sites for src mRNA because there are no extra viral sequences between the 5' leader and the src sequences; instead, they are due to the presence of extra sequences, most likely of cellular origin, at the 3' ends of the viral RNAs. Based upon the extent of deletions in the viral genomes, the data suggest that deletion in the 3' pol region of those rASVs results in a cis effect on the transcription and processing of the 3' ends of viral RNAs. The unusual-sized viral RNAs are most likely due to read-through transcription from the right-hand terminus of provirus into downstream cellular sequences, followed by cleavage and polyadenylation at multiple sites of the 3' region of the RNA transcripts. The extent of read-through transcription appears to depend on the chromosomal location of the provirus. Images

Wang, L H

1985-01-01

292

Aberrant E-cadherin and ?-catenin expression in malignant mesothelioma and its diagnostic and biological relevance  

Microsoft Academic Search

Cadherins and their associated cytoplasmic proteins, catenins, are critical to the maintenance of normal tissue integrity and the suppression of cancer invasion. The cadherin profile in malignant mesothelioma (MM) is not well defined and the role of the cadherin–catenin system in the pathogenesis of MM remains to be determined. By means of Western blot analysis and immunohistochemistry the expression of

Sara Orecchia; Francesca Schillaci; Michela Salvio; Roberta Libener; Pier-Giacomo Betta

2004-01-01

293

Reference Gene Screening for Analyzing Gene Expression Across Goat Tissue  

PubMed Central

Real-time quantitative PCR (qRT-PCR) is one of the important methods for investigating the changes in mRNA expression levels in cells and tissues. Selection of the proper reference genes is very important when calibrating the results of real-time quantitative PCR. Studies on the selection of reference genes in goat tissues are limited, despite the economic importance of their meat and dairy products. We used real-time quantitative PCR to detect the expression levels of eight reference gene candidates (18S, TBP, HMBS, YWHAZ, ACTB, HPRT1, GAPDH and EEF1A2) in ten tissues types sourced from Boer goats. The optimal reference gene combination was selected according to the results determined by geNorm, NormFinder and Bestkeeper software packages. The analyses showed that tissue is an important variability factor in genes expression stability. When all tissues were considered, 18S, TBP and HMBS is the optimal reference combination for calibrating quantitative PCR analysis of gene expression from goat tissues. Dividing data set by tissues, ACTB was the most stable in stomach, small intestine and ovary, 18S in heart and spleen, HMBS in uterus and lung, TBP in liver, HPRT1 in kidney and GAPDH in muscle. Overall, this study provided valuable information about the goat reference genes that can be used in order to perform a proper normalisation when relative quantification by qRT-PCR studies is undertaken.

Zhang, Yu; Zhang, Xiao-Dong; Liu, Xing; Li, Yun-Sheng; Ding, Jian-Ping; Zhang, Xiao-Rong; Zhang, Yun-Hai

2013-01-01

294

Modulation of imprinted gene expression following superovulation.  

PubMed

Although assisted reproductive technologies increase the risk of low birth weight and genomic imprinting disorders, the precise underlying causes remain unclear. Using a mouse model, we previously showed that superovulation alters the expression of imprinted genes in the placenta at 9.5days (E9.5) of gestation. Here, we investigate whether effects of superovulation on genomic imprinting persisted at later stages of development and assess the surviving fetuses for growth and morphological abnormalities. Superovulation, followed by embryo transfer at E3.5, as compared to spontaneous ovulation (controls), resulted in embryos of normal size and weight at 14.5 and 18.5days of gestation. The normal monoallelic expression of the imprinted genes H19, Snrpn and Kcnq1ot1 was unaffected in either the placentae or the embryos from the superovulated females at E14.5 or E18.5. However, for the paternally expressed imprinted gene Igf2, superovulation generated placentae with reduced production of the mature protein at E9.5 and significantly more variable mRNA levels at E14.5. We propose that superovulation results in the ovulation of abnormal oocytes with altered expression of imprinted genes, but that the coregulated genes of the imprinted gene network result in modulated expression. PMID:24631781

Fortier, Amanda L; McGraw, Serge; Lopes, Flavia L; Niles, Kirsten M; Landry, Mylène; Trasler, Jacquetta M

2014-05-01

295

Extracellular Phosphate Alters Cementoblast Gene Expression  

PubMed Central

Genetic data from humans and mice reveal that the formation of cementum is sensitive to intra- and extracellular phosphate/pyrophosphate distribution. The intracellular molecular pathways whereby altered levels of extracellular phosphate concentration may affect cementum formation have not been elucidated. To initiate inquiry, we have studied the temporal effects of extracellular phosphate on global patterns of gene expression in a line of immortalized mouse cementoblasts. Total RNA from cultured cementoblasts treated with 5 mM inorganic phosphate over a designated time period, from 1–48 hrs, was analyzed for global patterns of gene expression by means of DNA microarrays representing the complete mouse genome. Analyses of significant hybridization signals indicated that 5 mM extracellular phosphate alters the expression of genes comprising several gene ontology (GO) groups, including transcription factor activity and Wnt signaling.

Rutherford, R.B.; Foster, B.L.; Bammler, T.; Beyer, R.P.; Sato, S.; Somerman, M.J.

2008-01-01

296

Differential gene expression during multistage carcinogenesis  

SciTech Connect

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(a)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. The authors 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. (Univ. of Arizona Medical School, Tucson (United States)); Krieg, P. (German Cancer Research Center, Heidelberg (West Germany))

1991-06-01

297

Microarray analysis of gene expression in parthenotes and in vitro-derived goat embryos.  

PubMed

The present work was carried out to investigate the global gene expression profile to search differentially expressed candidate transcripts between parthenogenetic and in vitro-fertilized (IVF) caprine morula. For this study, total RNA was isolated from diploid parthenogenetic and IVF embryos, and complementary DNA was synthesized. Microarray and relative real-time polymerase chain reaction analysis were performed to check global gene expression profile and validation, respectively. According to the microarray analysis, the total number of upregulated (UR) and downregulated (DR) genes was 613 and 220, respectively in diploid parthenogenetic morula as compared with IVF morula. The number of genes showing about two-, two- to five-, five- to 10-, 10- to 20-, and above 20-fold UR and DR genes was 147, 229, 122, 59, and 56 and 94, 73, 18, 13, and 22, respectively. Five UR genes validated (PTEN, PHF3, CTNNB1, SELK, and NPDC1) and all of them were significantly higher in parthenotes, which was in accordance with microarray results, whereas the expression of DR (AURKC and KLF15) genes were downregulated in parthenotes as observed in microarray results but the difference was not significant (P < 0.05). In conclusion, our findings demonstrate differential expression of a large number of genes in parthenotes compared with IVF embryos, which may be the reason for aberrant parthenogenetic embryo development in caprine species. PMID:24507961

Singh, Renu; Kumar, Kuldeep; Mahapatra, P S; Kumar, Manish; Agarwal, Pranjali; Bhure, S K; Malakar, Dhruba; Bhanja, S K; Bag, Sadhan

2014-04-01

298

Characterization of TMPRSS2ETS Gene Aberrations in Androgen-Independent Metastatic Prostate Cancer  

Microsoft Academic Search

Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively

Rohit Mehra; Scott A. Tomlins; Jianjun Yu; Xuhong Cao; Lei Wang; Anjana Menon; Kenneth J. Pienta

2008-01-01

299

Frequent b-Catenin Gene Mutations and Accumulations of the Protein in the Putative Preneoplastic Lesions Lacking Macroscopic Aberrant Crypt Foci Appearance, in Rat Colon Carcinogenesis1  

Microsoft Academic Search

Activating mutations in the b-catenin gene is thought to be responsible for the excessive b-catenin signaling involved in the majority of carcino- gen-induced colonic carcinomas. To determine whether b-catenin signal- ing is involved in the initial stage of colon carcinogenesis, mutational analysis of the gene and immunohistochemistry for b-catenin protein were performed in the early appearing lesions, including aberrant crypt

Yasuhiro Yamada; Naoki Yoshimi; Yoshinobu Hirose; Kunihiro Kawabata; Kengo Matsunaga; Masahito Shimizu; Akira Hara; Hideki Mori

2000-01-01

300

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

301

Weighted set enrichment of gene expression data  

PubMed Central

Background Sets of genes that are known to be associated with each other can be used to interpret microarray data. This gene set approach to microarray data analysis can illustrate patterns of gene expression which may be more informative than analyzing the expression of individual genes. Various statistical approaches exist for the analysis of gene sets. There are three main classes of these methods: over-representation analysis, functional class scoring, and pathway topology based methods. Methods We propose weighted hypergeometric and weighted chi-squared methods in order to assign a rank to the degree to which each gene participates in the enrichment. Each gene is assigned a weight determined by the absolute value of its log fold change, which is then raised to a certain power. The power value can be adjusted as needed. Datasets from the Gene Expression Omnibus are used to test the method. The significantly enriched pathways are validated through searching the literature in order to determine their relevance to the dataset. Results Although these methods detect fewer significantly enriched pathways, they can potentially produce more relevant results. Furthermore, we compare the results of different enrichment methods on a set of microarray studies all containing data from various rodent neuropathic pain models. Discussion Our method is able to produce more consistent results than other methods when evaluated on similar datasets. It can also potentially detect relevant pathways that are not identified by the standard methods. However, the lack of biological ground truth makes validating the method difficult.

2013-01-01

302

Cilia gene expression patterns in cancer.  

PubMed

Non-motile cilia are thought to be important determinants of the progression of many types of cancers. Our goal was to identify patterns of cilia gene dysregulation in eight cancer types (glioblastoma multiforme, colon adenocarcinoma, breast adenocarcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, rectal adenocarcinoma, and ovarian cancer) profiled by The Cancer Genome Atlas. Among these types, 2.5-19.8% of cilia-associated genes were significantly differentially expressed (versus 5.5-32.4% dysregulation across all genes). In four cancer types (breast adenocarcinoma, colon adenocarcinoma, glioblastoma multiforme, and ovarian cancer), cilia genes were on average down-regulated (median fold change from -1.53--0.3), in the other four types, cilia genes were up-regulated (fold change=0.86-3.5). Pairwise comparisons between cancer types revealed varying degrees of similarity in the differentially expressed cilia genes, ranging from 7.1% (ovarian cancer and lung squamous cell carcinoma) to 65.8% (ovarian cancer and rectal adenocarcinoma). Hierarchical clustering and principal components analysis of gene expression identified glioblastoma multiforme, colon adenocarcinoma, breast adenocarcinoma; and kidney renal clear cell carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, rectal adenocarcinoma, and ovarian cancer as sub-classes with similar dysregulation patterns. Our study suggests that genes involved in cilia biosynthesis and function are frequently dysregulated in cancer, and may be useful for identifying and classifying cancer types. PMID:24633316

Shpak, Max; Goldberg, Marcus M; Cowperthwaite, Matthew C

2014-01-01

303

Structure, evolution and expression of insulin genes  

SciTech Connect

Since the initial discovery of insulin by Banting and Best in 1922 enoromous progress has been made in understanding the role of this hormone in the control of diabetes and in regulating glucose homeostasis in vertebrates. However, until very recently, little was known abut the structure of the insulin genes or the control of insulin gene expression in the normal and pathological state. We have been studying the structure of the rat and human genes encoding preproinsulin and the chromosomal location of the human gene. In addition, we have reintroduced the isolated insulin genes into mammalian cells growning in culture in order to study the molecular events associated with insulin expression. A summary of our recent findings is reported here.

Cordell, B.; Lebo, R.V.; Yu, L.C.; Lau, Y.F.; Carrano, A.V.; Goodman, H.M.

1980-01-01

304

Three gene expression vector sets for concurrently expressing multiple genes in Saccharomyces cerevisiae.  

PubMed

Yeast has the potential to be used in bulk-scale fermentative production of fuels and chemicals due to its tolerance for low pH and robustness for autolysis. However, expression of multiple external genes in one host yeast strain is considerably labor-intensive due to the lack of polycistronic transcription. To promote the metabolic engineering of yeast, we generated systematic and convenient genetic engineering tools to express multiple genes in Saccharomyces cerevisiae. We constructed a series of multi-copy and integration vector sets for concurrently expressing two or three genes in S. cerevisiae by embedding three classical promoters. The comparative expression capabilities of the constructed vectors were monitored with green fluorescent protein, and the concurrent expression of genes was monitored with three different fluorescent proteins. Our multiple gene expression tool will be helpful to the advanced construction of genetically engineered yeast strains in a variety of research fields other than metabolic engineering. PMID:24447461

Ishii, Jun; Kondo, Takashi; Makino, Harumi; Ogura, Akira; Matsuda, Fumio; Kondo, Akihiko

2014-05-01

305

Aberrant expression of glutathione peroxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis  

Microsoft Academic Search

Objective:To determine the expression of glutathione peroxidase (GPx) in the eutopic and ectopic endometria during the menstrual cycle in endometriosis and adenomyosis.Design:Immunohistochemical identification of GPx in endometrial tissues identified using the polyclonal antibody.Setting:Department of obstetrics and gynecology in a university hospital.Patient(s):One hundred fourteen women divided into three groups: 33 patients with endometriosis, 34 patients with adenomyosis, and 47 fertile control

Hirotaka Ota; Shinichi Igarashi; Naoko Kato; Toshinobu Tanaka

2000-01-01

306

Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia  

PubMed Central

Acute myeloid leukemia (AML) continues to be extremely difficult to treat successfully, and the unacceptably low overall survival rates mandate that we assess new potential therapies to ameliorate poor clinical response to conventional therapy. Abnormal tyrosine kinase activation in AML has been associated with poor prognosis and provides strategic targets for novel therapy development. We found that Mer receptor tyrosine kinase was over-expressed in a majority of pediatric (29/36, 80%) and adult (10/10, 100%) primary AML patient blasts at the time of diagnosis, and 100% of patient samples at the time of relapse. Mer was also found to be expressed in 12 of 14 AML cell lines (86%). In contrast, normal bone marrow myeloid precursors expressed little to no Mer. Following AML cell line stimulation with Gas6, a Mer ligand, we observed activation of prosurvival and proliferative signaling pathways, including phosphorylation of ERK1/2, p38, MSK1, CREB, ATF1, AKT and STAT6. To assess the phenotypic role of Mer in AML, two independent short-hairpin RNA (shRNA) constructs were used to decrease Mer expression in the AML cell lines Nomo-1 and Kasumi-1. Reduction of Mer protein levels significantly increased rates of myeloblast apoptosis two to threefold in response to serum starvation. Furthermore, myeloblasts with knocked-down Mer demonstrated decreased colony formation by 67–87%, relative to control cell lines (P<0.01). NOD-SCID-gamma mice transplanted with Nomo-1 myeloblasts with reduced levels of Mer had a significant prolongation in survival compared with mice transplanted with the parental or control cell lines (median survival 17 days in parental and control cell lines, versus 32–36 days in Mer knockdown cell lines, P<0.0001). These data suggest a role for Mer in acute myeloid leukemogenesis and indicate that targeted inhibition of Mer may be an effective therapeutic strategy in pediatric and adult AML.

Lee-Sherick, A B; Eisenman, K M; Sather, S; McGranahan, A; Armistead, P M; McGary, C S; Hunsucker, S A; Schlegel, J; Martinson, H; Cannon, C; Keating, A K; Earp, H S; Liang, X; DeRyckere, D; Graham, D K

2013-01-01

307

Aberrant expression and localization of connexin43 and connexin30 in a rat glioma cell line.  

PubMed

Gap junctions are cellular structures which permit direct exchanges of small molecules from cytoplasm to cytoplasm in most of the cells of metazoan organisms. For four decades, it has been observed that the inhibition of this type of intercellular communication is often associated with tumorigenesis. The assumption that loss of homeostasis which characterizes tumor growth could be a consequence of a lack of gap junctional intercellular communication (GJIC) has been reinforced by strategies able to reinduce both GJIC and normalization of the phenotype. So far, no molecular data may explain clearly how gap junctions can regulate cell proliferation. It has been argued that the gap-junction tumor suppressive effect may depend specifically on the connexin type which is expressed. For instance, the transfection of connexin30 (Cx30), a gap junction protein, has been previously associated with a slower growth of rat glioma cells (9L cells). Here, we show that these cells do communicate less compared to the Cx43-expressing parental cells even if the Cx30-transfected cells do express more Cx43. This result was related to the cytoplasmic distribution of Cx43 and a nuclear localization of both the Cx30 and a 20-kDa fragment corresponding to a Cx43 signal. According to these data, it seems that cell growth regulation may depend more on the behavior of connexins than the simple establishment of GJIC. PMID:18058800

Mennecier, Grégory; Derangeon, Mickaël; Coronas, Valérie; Hervé, Jean-Claude; Mesnil, Marc

2008-05-01

308

Lessons from a decade of integrating cancer copy number alterations with gene expression profiles  

PubMed Central

Over the last decade, multiple functional genomic datasets studying chromosomal aberrations and their downstream effects on gene expression have accumulated for several cancer types. A vast majority of them are in the form of paired gene expression profiles and somatic copy number alterations (CNA) information on the same patients identified using microarray platforms. In response, many algorithms and software packages are available for integrating these paired data. Surprisingly, there has been no serious attempt to review the currently available methodologies or the novel insights brought using them. In this work, we discuss the quantitative relationships observed between CNA and gene expression in multiple cancer types and biological milestones achieved using the available methodologies. We discuss the conceptual evolution of both, the step-wise and the joint data integration methodologies over the last decade. We conclude by providing suggestions for building efficient data integration methodologies and asking further biological questions.

Huang, Norman; Li, Cheng

2012-01-01

309

Lessons from a decade of integrating cancer copy number alterations with gene expression profiles.  

PubMed

Over the last decade, multiple functional genomic datasets studying chromosomal aberrations and their downstream effects on gene expression have accumulated for several cancer types. A vast majority of them are in the form of paired gene expression profiles and somatic copy number alterations (CNA) information on the same patients identified using microarray platforms. In response, many algorithms and software packages are available for integrating these paired data. Surprisingly, there has been no serious attempt to review the currently available methodologies or the novel insights brought using them. In this work, we discuss the quantitative relationships observed between CNA and gene expression in multiple cancer types and biological milestones achieved using the available methodologies. We discuss the conceptual evolution of both, the step-wise and the joint data integration methodologies over the last decade. We conclude by providing suggestions for building efficient data integration methodologies and asking further biological questions. PMID:21949216

Huang, Norman; Shah, Parantu K; Li, Cheng

2012-05-01

310

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

311

Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation.  

PubMed

Aberrant gluconeogenic gene expression is associated with diabetes, glycogen storage disease, and liver cancer. However, little is known how these genes are regulated at the chromatin level. In this study, we investigated in HepG2 cells whether histone demethylation is a potential mechanism. We found that knockdown or pharmacological inhibition of histone demethylase LSD1 causes remarkable transcription activation of two gluconeogenic genes, FBP1 and G6Pase, and consequently leads to increased de novo glucose synthesis and decreased intracellular glycogen content. Mechanistically, LSD1 occupies the promoters of FBP1 and G6Pase, and modulates their H3K4 dimethylation levels. Thus, our work identifies an epigenetic pathway directly governing gluconeogenic gene expression, which might have important implications in metabolic physiology and diseases. PMID:23755305

Pan, Dongning; Mao, Chunxiao; Wang, Yong-Xu

2013-01-01

312

Adenoviral Targeting of Gene Expression to Tumors  

PubMed Central

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 to 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, SR?) varied widely in their tumor selectivity, but hypoxia-responsive promoters (carbonic anhydrase 9, PAI-1, SOD2, and several chimeric constructs) demonstrated 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.

Hogg, Richard T.; Garcia, Joseph A.; Gerard, Robert D.

2010-01-01

313

Diagnostic Utility of Gene Expression Profiles  

PubMed Central

Two crucial problems arise from a microarray experiment in which the primary objective is to locate differentially expressed genes for the diagnosis of diseases such as cancer and Alzheimer’s. The first problem is the detection of a subset of genes which provides an optimum discriminatory power between diseased and normal subjects, and the second problem is the statistical estimation of discriminatory power from the optimum subset of genes between two groups of subjects. We develop a new method to select an optimum subset of discriminatory genes by searching over possible linear combinations of gene expression profiles and locating the one which provides the maximum discriminatory power between two sources of RNA as measured by the area under the receiver operating characteristic (ROC) curve. We further provide an estimate to the optimum discriminatory power between the diseased and the healthy subjects over the selected subsets of genes. The proposed stepwise approach takes in account of the gene-to-gene correlations in the estimation of discriminating power as well as the associated variability and allows the number of genes to be selected based on the increment of the discriminating power. Finally, the proposed methodology is applied to a benchmark microarray experiment and compared to the results obtained through existing approaches in the literature.

Xiong, Chengjie; Yan, Yan; Gao, Feng

2013-01-01

314

Aberrant hypermethylation of ID4 gene promoter region increases risk of lymph node metastasis in T1 breast cancer  

Microsoft Academic Search

ID4 gene is a member of the inhibitor of DNA-binding (ID) family, which inhibits DNA binding of basic helix–loop–helix transcription factors. Certain human primary breast cancers reportedly have low or no expression of ID4 protein, but its role in carcinogenesis and cancer progression is unknown. To determine its possible role, we examined epigenetic inactivation of ID4 gene by promoter hypermethylation

Naoyuki Umetani; Takuji Mori; Kazuo Koyanagi; Masaru Shinozaki; Joseph Kim; Armando E Giuliano; Dave S B Hoon; DSB Hoon

2005-01-01

315

Evidence that aberrant expression of tissue transglutaminase promotes stem cell characteristics in mammary epithelial cells.  

PubMed

Cancer stem cells (CSCs) or tumor initiating cells (TICs) make up only a small fraction of total tumor cell population, but recent evidence suggests that they are responsible for tumor initiation and the maintenance of tumor growth. Whether CSCs/TICs originate from normal stem cells or result from the dedifferentiation of terminally differentiated cells remains unknown. Here we provide evidence that sustained expression of the proinflammatory protein tissue transglutaminase (TG2) confers stem cell like properties in non-transformed and transformed mammary epithelial cells. Sustained expression of TG2 was associated with increase in CD44(high)/CD24(low/-) subpopulation, increased ability of cells to form mammospheres, and acquisition of self-renewal ability. Mammospheres derived from TG2-transfected mammary epithelial cells (MCF10A) differentiated into complex secondary structures when grown in Matrigel cultures. Cells in these secondary structures differentiated into Muc1-positive (luminal marker) and integrin ?6-positive (basal marker) cells in response to prolactin treatment. Highly aggressive MDA-231 and drug-resistant MCF-7/RT breast cancer cells, which express high basal levels of TG2, shared many traits with TG2-transfected MCF10A stem cells but unlike MCF10A-derived stem cells they failed to form the secondary structures and to differentiate into Muc1-positive luminal cells when grown in Matrigel culture. Downregulation of TG2 attenuated stem cell properties in both non-transformed and transformed mammary epithelial cells. Taken together, these results suggested a new function for TG2 and revealed a novel mechanism responsible for promoting the stem cell characteristics in adult mammary epithelial cells. PMID:21687668

Kumar, Anupam; Gao, Hui; Xu, Jia; Reuben, James; Yu, Dihua; Mehta, Kapil

2011-01-01

316

The Filamentous Fungal Gene Expression Database (FFGED)  

PubMed Central

Filamentous fungal gene expression assays provide essential information for understanding systemic cellular regulation. To aid research on fungal gene expression, we constructed a novel, comprehensive, free database, the Filamentous Fungal Gene Expression Database (FFGED), available at http://bioinfo.townsend.yale.edu. FFGED features user-friendly management of gene expression data, which are assorted into experimental metadata, experimental design, raw data, normalized details, and analysis results. Data may be submitted in the process of an experiment, and any user can submit multiple experiments, thus classifying the FFGED as an “active experiment” database. Most importantly, FFGED functions as a collective and collaborative platform, by connecting each experiment with similar related experiments made public by other users, maximizing data sharing among different users, and correlating diverse gene expression levels under multiple experimental designs within different experiments. A clear and efficient web interface is provided with enhancement by AJAX (Asynchronous JavaScript and XML) and through a collection of tools to effectively facilitate data submission, sharing, retrieval and visualization.

Zhang, Zhang; Townsend, Jeffrey P.

2010-01-01

317

Measurement of bacterial gene expression in vivo.  

PubMed Central

The complexities of bacterial gene expression during mammalian infection cannot be addressed by in vitro experiments. We know that the infected host represents a complex and dynamic environment, which is modified during the infection process, presenting a variety of stimuli to which the pathogen must respond if it is to be successful. This response involves hundreds of ivi (in vivo-induced) genes which have recently been identified in animal and cell culture models using a variety of technologies including in vivo expression technology, differential fluorescence induction, subtractive hybridization and differential display. Proteomic analysis is beginning to be used to identify IVI proteins, and has benefited from the availability of genome sequences for increasing numbers of bacterial pathogens. The patterns of bacterial gene expression during infection remain to be investigated. Are ivi genes expressed in an organ-specific or cell-type-specific fashion? New approaches are required to answer these questions. The uses of the immunologically based in vivo antigen technology system, in situ PCR and DNA microarray analysis are considered. This review considers existing methods for examining bacterial gene expression in vivo, and describes emerging approaches that should further our understanding in the future.

Hautefort, I; Hinton, J C

2000-01-01

318

Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer.  

PubMed

Abnormal intracellular signaling contributes to carcinogenesis and may represent novel therapeutic targets. mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is associated with aggressive prostate cancer. In this study, we examined the role of extracellular signal-regulated kinase (ERK5, an MAPK and specific substrate for MEK5) in prostate cancer. ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer when compared to benign prostatic hyperplasia (P<0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (P<0.0001), bony metastases (P=0.0044) and locally advanced disease at diagnosis (P=0.0023), with a weak association with shorter disease-specific survival (P=0.036). A subgroup of patients showed strong nuclear ERK5 localization, which correlated with poor disease-specific survival and, on multivariant analysis, was an independent prognostic factor (P<0.0001). Analysis of ERK5 expression in matched tumor pairs (before and after hormone relapse, n=26) revealed ERK5 nuclear expression was significantly associated with hormone-insensitive disease (P=0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following in vitro and in vivo evidence to support the above expression data: (1) cotransfection of ERK5wt and MEK5D constructs in PC3 cells results in predominant ERK5 nuclear localization, similar to that observed in aggressive clinical disease; (2) ERK5-overexpressing PC3 cells have enhanced proliferative, migrative and invasive capabilities in vitro (P<0.0001), and were dramatically more efficient in forming tumors, with a shorter mean time for tumors to reach a critical volume of 1000 mm(3), in vivo (P<0.0001); (3) the MEK1 inhibitor, PD184352, blocking ERK1/2 activation at low dose, did not suppress proliferation but did significantly decrease proliferation at a higher dose required to inhibit ERK5 activation. Taken together, our results establish the potential importance of ERK5 in aggressive prostate cancer. PMID:18071319

McCracken, S R C; Ramsay, A; Heer, R; Mathers, M E; Jenkins, B L; Edwards, J; Robson, C N; Marquez, R; Cohen, P; Leung, H Y

2008-05-01

319

Expression of myriapod pair rule gene orthologs  

PubMed Central

Background Segmentation is a hallmark of the arthropods; most knowledge about the molecular basis of arthropod segmentation comes from work on the fly Drosophila melanogaster. In this species a hierarchic cascade of segmentation genes subdivides the blastoderm stepwise into single segment wide regions. However, segmentation in the fly is a derived feature since all segments form virtually simultaneously. Conversely, in the vast majority of arthropods the posterior segments form one at a time from a posterior pre-segmental zone. The pair rule genes (PRGs) comprise an important level of the Drosophila segmentation gene cascade and are indeed the first genes that are expressed in typical transverse stripes in the early embryo. Information on expression and function of PRGs outside the insects, however, is scarce. Results Here we present the expression of the pair rule gene orthologs in the pill millipede Glomeris marginata (Myriapoda: Diplopoda). We find evidence that these genes are involved in segmentation and that components of the hierarchic interaction of the gene network as found in insects may be conserved. We further provide evidence that segments are formed in a single-segment periodicity rather than in pairs of two like in another myriapod, the centipede Strigamia maritima. Finally we show that decoupling of dorsal and ventral segmentation in Glomeris appears already at the level of the PRGs. Conclusions Although the pair rule gene network is partially conserved among insects and myriapods, some aspects of PRG interaction are, as suggested by expression pattern analysis, convergent, even within the Myriapoda. Conserved expression patterns of PRGs in insects and myriapods, however, may represent ancestral features involved in segmenting the arthropod ancestor.

2011-01-01

320

Dimerizer-mediated regulation of gene expression.  

PubMed

Several systems have been developed that allow transcription of a target gene to be chemically controlled, usually by an allosteric modulator of transcription factor activity. An alternative is to use chemical inducers of dimerization, or "dimerizers," to reconstitute active transcription factors from inactive fusion proteins. The most widely used system employs the natural product rapamycin, or a biologically inert analog, as the dimerizing drug. A key feature of this system is the tightness of regulation, with basal expression usually undetectable and induced expression levels comparable to constitutive promoters. In our experiments, the use of the minimal interleukin-2 (IL-2) promoter is an important determinant of this; substitution of a minimal simian virus 40 (SV40) or cytomegalovirus (CMV) promoter results in significantly higher levels of basal expression. The key factor dictating the successful use of the system is achieving high expression levels of the activation domain fusion protein. In the context of clinical gene therapies, the system has the advantage of being built exclusively from human proteins, potentially minimizing immunogenicity in the clinical setting. The dimerizer system has been successfully incorporated into diverse vector backgrounds and has been used to achieve long-term regulated gene expression in vitro and in vivo. This article provides guidance in designing constructs and experiments to achieve dimerizer-regulated expression of a target gene both in vitro and in vivo. PMID:22753597

Rivera, Victor M; Berk, Lori; Clackson, Tim

2012-07-01

321

Alternative-splicing-mediated gene expression  

NASA Astrophysics Data System (ADS)

Alternative splicing (AS) is a fundamental process during gene expression and has been found to be ubiquitous in eukaryotes. However, how AS impacts gene expression levels both quantitatively and qualitatively remains to be fully explored. Here, we analyze two common models of gene expression, each incorporating a simple splice mechanism that a pre-mRNA is spliced into two mature mRNA isoforms in a probabilistic manner. In the constitutive expression case, we show that the steady-state molecular numbers of two mature mRNA isoforms follow mutually independent Poisson distributions. In the bursting expression case, we demonstrate that the tail decay of the steady-state distribution for both mature mRNA isoforms that in general are not mutually independent can be characterized by the product of mean burst size and splicing probability. In both cases, we find that AS can efficiently modulate both the variability (measured by variance) and the noise level of the total mature mRNA, and in particular, the latter is always lower than the noise level of the pre-mRNA, implying that AS always reduces the noise. These results altogether reveal that AS is a mechanism of efficiently controlling the gene expression noise.

Wang, Qianliang; Zhou, Tianshou

2014-01-01

322

Model-Based Clustering with Genes Expression Dynamics for Time-Course Gene Expression Data  

Microsoft Academic Search

Microarray technologies are emerging as a promising tool for genomic studies. A huge body of time-course gene expression data has been and will continuously be produced by microarray experiments. Such gene expression data contains important information and has been proven useful in medical diagnosis, treatment, and drug design. The challenge now is how to analyze such data to obtain the

Fang-xiang Wu; Wen-jun Zhang; Anthony J. Kusalik

2004-01-01

323

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

324

Global expression analysis of CESA and CSL genes in Arabidopsis  

Microsoft Academic Search

We have used Affymetrix gene chips to measure the expression of 10 CESA and 29 CSL genes of Arabidopsis in different developmental stages or organs. These measurements reveal that many of the genes exhibit different levels of expression in the various organs. While several CESA genes are highly expressed in all the tissues examined, very few CSL genes approach such

Thorsten Hamann; Erin Osborne; Heather L. Youngs; Julie Misson; Laurent Nussaume; Chris Somerville

2004-01-01

325

Premature lethality, hyperactivity, and aberrant phosphorylation in transgenic mice expressing a constitutively active form of Fyn  

PubMed Central

The kinase Fyn, the microtubule-associated protein tau and the peptide amyloid-? (A?) constitute a toxic triad in Alzheimer's disease (AD). Tau's subcellular localization is mainly regulated by phosphorylation whereas Fyn's localization is dictated by palmitoylation targeting it to the plasma membrane in a reversible manner. We have previously shown that tau is required for Fyn to be targeted to the dendritic spine. We had also shown that a truncated form of tau (?tau) that accumulates in the cell soma is capable of trapping Fyn and preventing it from entering the spine. Here we determined that palmitoylation is required for Fyn's membrane and spine localization. We further evaluated the functional consequences of neuronal over-expression of the constitutively active Y531F mutant form of Fyn (FynCA) in transgenic mice. We found that the FynCA transgenic mice displayed a reduced weight, a massively reduced lifespan and a high level of hyperactivity. The lifespan of the FynCA mice was only slightly extended by crossing them with ?tau transgenic mice, possibly reflecting differences in expression patterns of the transgenes and high levels of transgenic FynCA compared to endogenous Fyn. Analysis of synaptosomes revealed that FynCA accumulated at high levels in the spine, resulting in increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472. Tau was strongly phosphorylated at the AT8 epitope S202/T205 as shown by Western blot and immunohistochemistry indicating that an increased tyrosine kinase activity of Fyn has down-stream consequences for serine/threonine-directed phosphorylation.

Xia, Di; Gotz, Jurgen

2014-01-01

326

Evolutionary Approach for Relative Gene Expression Algorithms  

PubMed Central

A Relative Expression Analysis (RXA) uses ordering relationships in a small collection of genes and is successfully applied to classiffication using microarray data. As checking all possible subsets of genes is computationally infeasible, the RXA algorithms require feature selection and multiple restrictive assumptions. Our main contribution is a specialized evolutionary algorithm (EA) for top-scoring pairs called EvoTSP which allows finding more advanced gene relations. We managed to unify the major variants of relative expression algorithms through EA and introduce weights to the top-scoring pairs. Experimental validation of EvoTSP on public available microarray datasets showed that the proposed solution significantly outperforms in terms of accuracy other relative expression algorithms and allows exploring much larger solution space.

Czajkowski, Marcin

2014-01-01

327

Polyandry and sex-specific gene expression  

PubMed Central

Polyandry is widespread in nature, and has important evolutionary consequences for the evolution of sexual dimorphism and sexual conflict. Although many of the phenotypic consequences of polyandry have been elucidated, our understanding of the impacts of polyandry and mating systems on the genome is in its infancy. Polyandry can intensify selection on sexual characters and generate more intense sexual conflict. This has consequences for sequence evolution, but also for sex-biased gene expression, which acts as a link between mating systems, sex-specific selection and the evolution of sexual dimorphism. We discuss this and the remarkable confluence of sexual-conflict theory and patterns of gene expression, while also making predictions about transcription patterns, mating systems and sexual conflict. Gene expression is a key link in the genotype–phenotype chain, and although in its early stages, understanding the sexual selection–transcription relationship will provide significant insights into this critical association.

Mank, Judith E.; Wedell, Nina; Hosken, David J.

2013-01-01

328

Gene expression profiles in irradiated cancer cells  

SciTech Connect

Knowledge of the molecular and genetic mechanisms underlying cellular response to radiation may provide new avenues to develop innovative predictive tests of radiosensitivity of tumours and normal tissues and to improve individual therapy. Nowadays very few studies describe molecular changes induced by hadrontherapy treatments, therefore this field has to be explored and clarified. High-throughput methodologies, such as DNA microarray, allow us to analyse mRNA expression of thousands of genes simultaneously in order to discover new genes and pathways as targets of response to hadrontherapy. Our aim is to elucidate the molecular networks involved in the sensitivity/resistance of cancer cell lines subjected to hadrontherapy treatments with a genomewide approach by using cDNA microarray technology to identify gene expression profiles and candidate genes responsible of differential cellular responses.

Minafra, L.; Bravatà, V.; Russo, G.; Ripamonti, M.; Gilardi, M. C. [IBFM CNR - LATO, Cefalù, Segrate (Italy)] [IBFM CNR - LATO, Cefalù, Segrate (Italy)

2013-07-26

329

Gene expression profiles in irradiated cancer cells  

NASA Astrophysics Data System (ADS)

Knowledge of the molecular and genetic mechanisms underlying cellular response to radiation may provide new avenues to develop innovative predictive tests of radiosensitivity of tumours and normal tissues and to improve individual therapy. Nowadays very few studies describe molecular changes induced by hadrontherapy treatments, therefore this field has to be explored and clarified. High-throughput methodologies, such as DNA microarray, allow us to analyse mRNA expression of thousands of genes simultaneously in order to discover new genes and pathways as targets of response to hadrontherapy. Our aim is to elucidate the molecular networks involved in the sensitivity/resistance of cancer cell lines subjected to hadrontherapy treatments with a genomewide approach by using cDNA microarray technology to identify gene expression profiles and candidate genes responsible of differential cellular responses.

Minafra, L.; Bravatà, V.; Russo, G.; Ripamonti, M.; Gilardi, M. C.

2013-07-01

330

Induction of Aberrant Vascular Growth, But Not of Normal Angiogenesis, by Cell-Based Expression of Different Doses of Human and Mouse VEGF Is Species-Dependent  

PubMed Central

Abstract Therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery is an attractive approach to treat ischemia. VEGF remains localized around each producing cell in vivo, and overexpression of mouse VEGF164 (mVEGF164) induces normal or aberrant angiogenesis, depending strictly on its dose in the microenvironment in vivo. However, the dose-dependent effects of the clinically relevant factor, human VEGF165 (hVEGF165), are unknown. Here we exploited a highly controlled gene delivery platform, based on clonal populations of transduced myoblasts overexpressing specific VEGF levels, to rigorously compare the in vivo dose-dependent effects of hVEGF165 and mVEGF164 in skeletal muscle of severe combined immune deficient (SCID) mice. While low levels of both factors efficiently induced similar amounts of normal angiogenesis, only high levels of mVEGF164 caused widespread angioma-like structures, whereas equivalent or even higher levels of hVEGF165 induced exclusively normal and mature capillaries. Expression levels were confirmed both in vitro and in vivo by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). However, in vitro experiments showed that hVEGF165 was significantly more effective in activating VEGF receptor signaling in human endothelial cells than mVEGF164, while the opposite was true in murine endothelial cells. In conclusion, we found that, even though hVEGF is similarly efficient to the syngenic mVEGF in inducing angiogenesis at lower doses in a widely adopted and convenient mouse preclinical model, species-dependent differences in the relative activation of the respective receptors may specifically mask the toxic effects of high doses of the human factor.

Mujagic, Edin; Gianni-Barrera, Roberto; Trani, Marianna; Patel, Abdulsamie; Gurke, Lorenz; Heberer, Michael

2013-01-01

331

Downregulation of DBC1 expression in acute lymphoblastic leukaemia is mediated by aberrant methylation of its promoter.  

PubMed

The DBC1 gene is a potential tumour suppressor gene that is commonly hypermethylated in epithelial cancers. We studied the role of promoter hypermethylation in the regulation of DBC1 in acute lymphoblastic leukaemia (ALL) cell lines and 170 ALL patients at diagnosis. Abnormal methylation of DBC1 was observed in all ALL cell lines and in 17% of ALL patients. Moreover, DBC1 methylation was associated with decreased DBC1 expression, while treatment of ALL cells with 5-Aza-2'-deoxycytidine resulted in demethylation of the promoter and upregulation of DBC1 expression. Fluorescence in situ hybridisation identified the deletion of one allele of DBC1 in some ALL cell lines, which indicated that the lack of DBC1 expression was due to deletion of one allele and methylation of the other. In conclusion, these results demonstrate, for the first time, that the expression of DBC1 is downregulated in a percentage of patients with ALL due to the hypermethylation of its promoter and/or gene deletion. PMID:16846474

San José-Enériz, Edurne; Agirre, Xabier; Román-Gómez, José; Cordeu, Lucia; Garate, Leire; Jiménez-Velasco, Antonio; Vázquez, Iria; Calasanz, María José; Heiniger, Anabel; Torres, Antonio; Prósper, Felipe

2006-07-01

332

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

2013-10-01

333

Transforming genes and chromosome aberrations in therapy-related leukemia and myelodysplastic syndrome  

Microsoft Academic Search

Summary The presence of activated transforming genes was investigated in four patients with therapy-related leukemia and in three with therapy-related myelodysplastic syndrome. DNA of bone marrow cells from six of the patients exhibited transforming activity in the tumorigenicity assay. Five of the six patients who were positive in the tumorigenicity assay contained activated N-ras oncogenes, and three contained activated K-ras

K. Inokuchi; N. Amuro; M. Futaki; K. Dan; T. Shinohara; S. Kuriya; T. Okazaki; T. Nomura

1991-01-01

334

Gene Expression Profiling with DNA Microarrays  

Microsoft Academic Search

DNA microarrays are small solid supports on the surface of which DNA probes for thousands of genes have been orderly arrayed.\\u000a Hybridization of labeled RNA from tissues or tumors allows evaluation of the relative amount of any specific mRNA present\\u000a in the samples, depicting its gene expression profile. During development and progression of breast cancers, specific genetic\\u000a programs are activated,

Michele Bortoli; Nicoletta Biglia

335

Human ARX gene: genomic characterization and expression  

Microsoft Academic Search

Arx is a homeobox-containing gene with a high degree of sequence similarity between mouse and zebrafish. Arx is expressed in the forebrain and floor plate of the developing central nervous systems of these vertebrates and in the presumptive cortex of fetal mice. Our goal was to identify genes in Xp22.1–p21.3 involved in human neuronal development. Our in silico search for

R Ohira; Y.-H Zhang; W Guo; K Dipple; S. L Shih; J Doerr; B.-L Huang; L. J Fu; A Abu-Khalil; D Geschwind; E. R. B McCabe

2002-01-01

336

Aberrant Regulation of HDAC2 Mediates Proliferation of Hepatocellular Carcinoma Cells by Deregulating Expression of G1/S Cell Cycle Proteins  

PubMed Central

Histone deacetylase 2 (HDAC2) is crucial for embryonic development, affects cytokine signaling relevant for immune responses and is often significantly overexpressed in solid tumors; but little is known about its role in human hepatocellular carcinoma (HCC). In this study, we showed that targeted-disruption of HDAC2 resulted in reduction of both tumor cell growth and de novo DNA synthesis in Hep3B cells. We then demonstrated that HDAC2 regulated cell cycle and that disruption of HDAC2 caused G1/S arrest in cell cycle. In G1/S transition, targeted-disruption of HDAC2 selectively induced the expression of p16INK4A and p21WAF1/Cip1, and simultaneously suppressed the expression of cyclin D1, CDK4 and CDK2. Consequently, HDAC2 inhibition led to the down-regulation of E2F/DP1 target genes through a reduction in phosphorylation status of pRb protein. In addition, sustained suppression of HDAC2 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Further, we found that HDAC2 suppresses p21WAF1/Cip1 transcriptional activity via Sp1-binding site enriched proximal region of p21WAF1/Cip1 promoter. In conclusion, we suggest that the aberrant regulation of HDAC2 may play a pivotal role in the development of HCC through its regulation of cell cycle components at the transcription level providing HDAC2 as a relevant target in liver cancer therapy.

Noh, Ji Heon; Jung, Kwang Hwa; Kim, Jeong Kyu; Eun, Jung Woo; Bae, Hyun Jin; Xie, Hong Jian; Chang, Young Gyoon; Kim, Min Gyu; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

2011-01-01

337

Clustering of High Throughput Gene Expression Data  

PubMed Central

High throughput biological data need to be processed, analyzed, and interpreted to address problems in life sciences. Bioinformatics, computational biology, and systems biology deal with biological problems using computational methods. Clustering is one of the methods used to gain insight into biological processes, particularly at the genomics level. Clearly, clustering can be used in many areas of biological data analysis. However, this paper presents a review of the current clustering algorithms designed especially for analyzing gene expression data. It is also intended to introduce one of the main problems in bioinformatics - clustering gene expression data - to the operations research community.

Pirim, Harun; Eksioglu, Burak; Perkins, Andy; Yuceer, Cetin

2012-01-01

338

Light-regulated gene expression in yeast.  

PubMed

An important basic requirement of synthetic genetic networks is the option of external control of gene expression. Although several chemically inducible systems are available, all of these suffer from the common problem: the chemical inducers are difficult to remove so that to terminate the response. We have described a regulatory expression system for yeast, which employs light as inducer. This light switch translates light-controlled protein-protein interactions into the transcription of selected genes in a dose-dependent and reversible manner. PMID:22083743

Kozma-Bognar, Laszlo; Hajdu, Anita; Nagy, Ferenc

2012-01-01

339

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

340

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

2012-01-01

341

Genetics of chronic lymphocytic leukemia: genomic aberrations and VH gene mutation status in pathogenesis and clinical course  

Microsoft Academic Search

The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. While conventional cytogenetic analyses only detected chromosome aberrations in 40–50% of cases, new molecular cytogenetic methods, such as fluorescence in situ hybridization (FISH), have greatly enhanced our ability to detect chromosomal abnormalities in CLL. Today, genomic aberrations are detected in over 80% of

S Stilgenbauer; L Bullinger; P Lichter; H Döhner

2002-01-01

342

Intracellular Gene Expression Profile of Listeria monocytogenes †  

PubMed Central

Listeria monocytogenes is a gram-positive, food-borne microorganism responsible for invasive infections with a high overall mortality. L. monocytogenes is among the very few microorganisms that can induce uptake into the host cell and subsequently enter the host cell cytosol by breaching the vacuolar membrane. We infected the murine macrophage cell line P388D1 with L. monocytogenes strain EGD-e and examined the gene expression profile of L. monocytogenes inside the vacuolar and cytosolic environments of the host cell by using whole-genome microarray and mutant analyses. We found that ?17% of the total genome was mobilized to enable adaptation for intracellular growth. Intracellularly expressed genes showed responses typical of glucose limitation within bacteria, with a decrease in the amount of mRNA encoding enzymes in the central metabolism and a temporal induction of genes involved in alternative-carbon-source utilization pathways and their regulation. Adaptive intracellular gene expression involved genes that are associated with virulence, the general stress response, cell division, and changes in cell wall structure and included many genes with unknown functions. A total of 41 genes were species specific, being absent from the genome of the nonpathogenic Listeria innocua CLIP 11262 strain. We also detected 25 genes that were strain specific, i.e., absent from the genome of the previously sequenced L. monocytogenes F2365 serotype 4b strain, suggesting heterogeneity in the gene pool required for intracellular survival of L. monocytogenes in host cells. Overall, our study provides crucial insights into the strategy of intracellular survival and measures taken by L. monocytogenes to escape the host cell responses.

Chatterjee, Som Subhra; Hossain, Hamid; Otten, Sonja; Kuenne, Carsten; Kuchmina, Katja; Machata, Silke; Domann, Eugen; Chakraborty, Trinad; Hain, Torsten

2006-01-01

343

Imprinted genes and regulation of gene expression by epigenetic inheritance.  

PubMed

Six new imprinted genes have recently been identified by association with established imprinted regions, in systematic screens or by serendipity. This brings the total to seventeen imprinted genes, which display a wide variety of functions. Some imprinted genes have been shown to be both physically and mechanistically linked within domains that are under the control of an imprinting centre. Others may apparently undergo imprinting independently. Methylation is clearly required for maintenance of mono-allelic expression while chromatin structure and non-coding RNAs may also play a role. PMID:8743885

John, R M; Surani, M A

1996-06-01

344

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

345

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

346

Regulation of 14-3-3sigma expression in human thyroid carcinoma is epigenetically regulated by aberrant cytosine methylation.  

PubMed

Increased 14-3-3sigma expression has been observed by immunohistochemistry in papillary and anaplastic tumors, but not follicular thyroid cancers. 14-3-3sigma mRNA expression and methylation status was examined in tumor cell lines and primary thyroid tissues using real-time RT-PCR, bisulfite sequencing and methylation-specific PCR. Most of the 27 CpG's in the gene's CpG island were methylated in normal thyroid, TPC-1, NPA, FTC-238 and 2-7, which did not express 14-3-3sigma. In contrast, they were unmethylated in KAK-1 and anaplastic lines KAT4 and DRO-90. 14-3-3sigma expression was not increased in thyroid carcinomas, the majority of which had a methylated CpG island. In addition, 5-aza-dC treatment increased 14-3-3sigma expression in the FTC-238 and NPA cell lines, which had low baseline expression. We conclude 14-3-3sigma expression in thyroid carcinomas is regulated by CpG island hypermethylation. PMID:18440129

Lal, Geeta; Padmanabha, Lakshmi; Provenzano, Matthew; Fitzgerald, Matthew; Weydert, Jamie; Domann, Frederick E

2008-08-18

347

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

348

Aberrant methylation of gene associated CpG sites occurs in borderline personality disorder.  

PubMed

Borderline personality disorder (BPD) is a complex psychiatric disease with an increased impact in the last years. While the diagnosis and therapy are well established, little is known on the pathogenesis of borderline personality disorder. Previously, a significant increase in DNA methylation of relevant neuropsychiatric genes in BPD patients has been reported. In our study we performed genome wide methylation analysis and revealed specific CpG sites that exhibited increased methylation in 24 female BPD patients compared to 11 female healthy controls. Bead chip technology and quantitative bisulfite pyrosequencing showed a significantly increased methylation at CpG sites of APBA2 (1.1 fold) and APBA3 (1.1 fold), KCNQ1 (1.5 fold), MCF2 (1.1 fold) and NINJ2 (1.2 fold) in BPD patients. For the CpG sites of GATA4 and HLCS an increase in DNA methylation was observed, but was only significant in the bead chip assay. Moreover genome wide methylation levels of blood samples of BPD patients and control samples are similar. In summary, our results show a significant 1.26 fold average increase in methylation at the analyzed gene associated CpG sites in the blood of BPD patients compared to controls samples (p<0.001). This data may provide new insights into epigenetic mechanisms underlying the pathogenesis of BPD. PMID:24367640

Teschler, Stefanie; Bartkuhn, Marek; Künzel, Natascha; Schmidt, Christian; Kiehl, Steffen; Dammann, Gerhard; Dammann, Reinhard

2013-01-01

349

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

350

Downregulation of retinoic acid receptor-?2 expression is linked to aberrant methylation in esophageal squamous cell carcinoma cell lines  

Microsoft Academic Search

AIM: To study the role of hypermethylation in the loss of retinoic acid receptor ?2 (RAR?2) in esophageal squamous cell carcinoma (ESCC). METHODS: The role of hypermethylation in RAR?2 gene silencing in 6 ESCC cell lines was determined by methylation- specific PCR (MSP), and its methylation status was compared with RAR?2 mRNA expression by RT-PCR. The MSP results were confirmed

Zhong-Min Liu; Fang Ding; Ming-Zhou Guo; Li-Yong Zhang; Min Wu; Zhi-Hua Liu

2004-01-01

351

Annotation of gene function in citrus using gene expression information and co-expression networks  

PubMed Central

Background The genus Citrus encompasses major cultivated plants such as sweet orange, mandarin, lemon and grapefruit, among the world’s most economically important fruit crops. With increasing volumes of transcriptomics data available for these species, Gene Co-expression Network (GCN) analysis is a viable option for predicting gene function at a genome-wide scale. GCN analysis is based on a “guilt-by-association” principle whereby genes encoding proteins involved in similar and/or related biological processes may exhibit similar expression patterns across diverse sets of experimental conditions. While bioinformatics resources such as GCN analysis are widely available for efficient gene function prediction in model plant species including Arabidopsis, soybean and rice, in citrus these tools are not yet developed. Results We have constructed a comprehensive GCN for citrus inferred from 297 publicly available Affymetrix Genechip Citrus Genome microarray datasets, providing gene co-expression relationships at a genome-wide scale (33,000 transcripts). The comprehensive citrus GCN consists of a global GCN (condition-independent) and four condition-dependent GCNs that survey the sweet orange species only, all citrus fruit tissues, all citrus leaf tissues, or stress-exposed plants. All of these GCNs are clustered using genome-wide, gene-centric (guide) and graph clustering algorithms for flexibility of gene function prediction. For each putative cluster, gene ontology (GO) enrichment and gene expression specificity analyses were performed to enhance gene function, expression and regulation pattern prediction. The guide-gene approach was used to infer novel roles of genes involved in disease susceptibility and vitamin C metabolism, and graph-clustering approaches were used to investigate isoprenoid/phenylpropanoid metabolism in citrus peel, and citric acid catabolism via the GABA shunt in citrus fruit. Conclusions Integration of citrus gene co-expression networks, functional enrichment analysis and gene expression information provide opportunities to infer gene function in citrus. We present a publicly accessible tool, Network Inference for Citrus Co-Expression (NICCE, http://citrus.adelaide.edu.au/nicce/home.aspx), for the gene co-expression analysis in citrus.

2014-01-01

352

Aberrant methylation accounts for cell adhesion-related gene silencing during 3-methylcholanthrene and diethylnitrosamine induced multistep rat lung carcinogenesis associated with overexpression of DNA methyltransferases 1 and 3a  

SciTech Connect

To evaluate the significance of alterations in cell adhesion-related genes methylation during lung multistep carcinogenesis induced by the genotoxic carcinogens 3-methylcholanthrene (MCA) and diethylnitrosamine (DEN), tissue samples microdissected from MCA/DEN-induced rat lung carcinogenesis model were subjected to methylation-specific PCR to evaluate the DNA methylation status of CADM1, TIMP3, E-cadherin and N-cadherin. Immunohistochemistry was used to determine protein expression of CADM1, TIMP3, N-cadherin and the DNA methyltransferases (DNMTs) 1, 3a and 3b. E-cadherin hypermethylation was not detected in any tissue. CADM1, TIMP3 and N-cadherin hypermethylation was correlated with the loss of their protein expression during the progression of pathologic lesions. The prevalence of DNA methylation of at least one gene and the average number of methylated genes increased with the histological progression. DNMT1 and DNMT3a protein expression increased progressively during the stages of lung carcinogenesis, whereas DNMT3b overexpression was only found in several samples. Furthermore, DNMT1 protein expression levels were correlated with CADM1 methylation, and DNMT3a protein expression levels were correlated with CADM1, TIMP3 and N-cadherin methylation. The average number of methylated genes during carcinogenesis was significantly correlated with DNMT1 and DNMT3a protein expression levels. Moreover, mRNA expression of CADM1 significantly increased after treatment with DNMT inhibitor 5-aza-2'-deoxycytidine in CADM1-methylated primary tumor cell lines. Our findings suggest that an accumulation of hypermethylation accounts for cell adhesion-related gene silencing is associated with dynamic changes in the progression of MCA/DEN-induced rat lung carcinogenesis. We suggest that DNMT1 and DNMT3a protein overexpression may be responsible for this aberrant DNA methylation.

Liu Wenbin; Cui Zhihong; Ao Lin; Zhou Ziyuan; Zhou Yanhong; Yuan Xiaoyan; Xiang Yunlong; Liu Jinyi, E-mail: jinyiliutmmu@163.com; Cao Jia, E-mail: caojia1962@126.com

2011-02-15

353

GBA server: EST-based digital gene expression profiling  

PubMed Central

Expressed Sequence Tag-based gene expression profiling can be used to discover functionally associated genes on a large scale. Currently available web servers and tools focus on finding differentially expressed genes in different samples or tissues rather than finding co-expressed genes. To fill this gap, we have developed a web server that implements the GBA (Guilt-by-Association) co-expression algorithm, which has been successfully used in finding disease-related genes. We have also annotated UniGene clusters with links to several important databases such as GO, KEGG, OMIM, Gene, IPI and HomoloGene. The GBA server can be accessed and downloaded at .

Wu, Xin; Walker, Michael G.; Luo, Jingchu; Wei, Liping

2005-01-01

354

Gene Expression Commons: an open platform for absolute gene expression profiling.  

PubMed

Gene expression profiling using microarrays has been limited to comparisons of gene expression between small numbers of samples within individual experiments. However, the unknown and variable sensitivities of each probeset have rendered the absolute expression of any given gene nearly impossible to estimate. We have overcome this limitation by using a very large number (>10,000) of varied microarray data as a common reference, so that statistical attributes of each probeset, such as the dynamic range and threshold between low and high expression, can be reliably discovered through meta-analysis. This strategy is implemented in a web-based platform named "Gene Expression Commons" (https://gexc.stanford.edu/) which contains data of 39 distinct highly purified mouse hematopoietic stem/progenitor/differentiated cell populations covering almost the entire hematopoietic system. Since the Gene Expression Commons is designed as an open platform, investigators can explore the expression level of any gene, search by expression patterns of interest, submit their own microarray data, and design their own working models representing biological relationship among samples. PMID:22815738

Seita, Jun; Sahoo, Debashis; Rossi, Derrick J; Bhattacharya, Deepta; Serwold, Thomas; Inlay, Matthew A; Ehrlich, Lauren I R; Fathman, John W; Dill, David L; Weissman, Irving L

2012-01-01

355

E-cadherin gene re-expression in chronic lymphocytic leukemia cells by HDAC inhibitors  

PubMed Central

Background The tumor suppressor gene E-cadherin gene is frequently silenced in chronic lymphocytic leukemia (CLL) cells and results in wnt-pathway activation. We analyzed the role of histone epigenetic modifications in E-cadherin gene silencing. Methods CLL specimens were treated with histone deacetylase inhibitor (HDACi) MS-275 and analyzed for E-cadherin expression with western blot and RT-PCR analysis. The downstream effects of HDACi treated leukemic cells were studied by analyzing the effect on wnt-pathway signaling. HDACi induced alterations in E-cadherin splicing were investigated by transcript specific real time PCR analysis. Results Treatment of CLL specimens with histone deacetylase inhibitors (HDACi) treatment resulted in an increase of the E-cadherin RNA transcript (5 to 119 fold increase, n=10) in eight out of ten CLL specimens indicating that this gene is down regulated by histone hypoacetylation in a majority of CLL specimens. The E-cadherin re-expression in CLL specimens was noted by western blot analysis as well. Besides epigenetic silencing another mechanism of E-cadherin inactivation is aberrant exon 11 splicing resulting in an alternatively spliced transcript that lacks exon 11 and is degraded by the non-sense mediated decay (NMD) pathway. Our chromatin immunoprecipitation experiments show that HDACi increased the acetylation of histones H3 and H4 in the E-cadherin promoter region. This also affected the E-cadherin exon 11 splicing pattern as HDACi treated CLL specimens preferentially expressed the correctly spliced transcript and not the exon 11 skipped aberrant transcript. The re-expressed E- cadherin binds to ?-catenin with inhibition of the active wnt-beta-catenin pathway in these cells. This resulted in a down regulation of two wnt target genes, LEF and cyclinD1 and the wnt pathway reporter. Conclusion The E-cadherin gene is epigenetically modified and hypoacetylated in CLL leukemic cells. Treatment of CLL specimens with HDACi MS-275 activates transcription from this silent gene with expression of more correctly spliced E-cadherin transcripts as compared to the aberrant exon11 skipped transcripts that in turn inhibits the wnt signaling pathway. The data highlights the role of epigenetic modifications in altering gene splicing patterns.

2013-01-01

356

Epigenetic aberrant methylation of tumor suppressor genes in small cell lung cancer  

PubMed Central

Small cell lung cancer (SCLC), a special type of lung cancer, is reputed to carry a poor prognosis. The morbidity of SCLC is increasing in China and other countries. A variety of DNA alterations associated with non-small cell lung cancer (NSCLC) have been described. However, genetic and epigenetic changes of SCLC are not well established. Few studies have demonstrated that epigenetic silencing of key tumor suppressor genes (TSGs) is pivotal to initiation and development of SCLC. Recently, promoter methylation of many TSGs have been identified in SCLC. These novel TSGs are potential tumor biomarkers for early diagnosis and prognostic prediction. Moreover, epigenetic promoter methylation of TSGs could be a target of intervention with a wide prospect of clinical application. This review summarizes recent studies on promoter methylation of TSGs in SCLC and aims to provide better understanding of the promoter methylation in tumorigenesis and progression of SCLC.

Wang, Shuai

2013-01-01

357

Genes Differentially Expressed in Titanium Implant Healing  

Microsoft Academic Search

Bone generation occurs around titanium implants; however, its underlying mechanisms are unknown. We hypothesized that molecular determinants distinct from those undertaking normal bone healing regulate osseointegration. Using differential display-polymerase chain-reaction in the male rat model, we isolated 3 genes that are differentially expressed in bone healing with implants, but not in osteotomy healing. A homology search indicated that these 3

T. Ogawa; I. Nishimura

2006-01-01

358

Gene expression and the thiol redox state  

Microsoft Academic Search

The intracellular redox status is a tightly regulated parameter which provides the cell with an optimal ability to counteract the highly oxidizing extracellular environment. Intracellular redox homeostasis is regulated by thiol-containing molecules, such as glutathione and thioredoxin. Essential cellular functions, such as gene expression, are influenced by the balance between pro- and antioxidant conditions. The mechanism by which the transcription

André-Patrick Arrigo

1999-01-01

359

Multiple Stochastic Point Processes in Gene Expression  

NASA Astrophysics Data System (ADS)

We generalize the idea of multiple-stochasticity in chemical reaction systems to gene expression. Using Chemical Langevin Equation approach we investigate how this multiple-stochasticity can influence the overall molecular number fluctuations. We show that the main sources of this multiple-stochasticity in gene expression could be the randomness in transcription and translation initiation times which in turn originates from the underlying bio-macromolecular recognition processes such as the site-specific DNA-protein interactions and therefore can be internally regulated by the supra-molecular structural factors such as the condensation/super-coiling of DNA. Our theory predicts that (1) in case of gene expression system, the variances ( ?) introduced by the randomness in transcription and translation initiation-times approximately scales with the degree of condensation ( s) of DNA or mRNA as ? ? s -6. From the theoretical analysis of the Fano factor as well as coefficient of variation associated with the protein number fluctuations we predict that (2) unlike the singly-stochastic case where the Fano factor has been shown to be a monotonous function of translation rate, in case of multiple-stochastic gene expression the Fano factor is a turn over function with a definite minimum. This in turn suggests that the multiple-stochastic processes can also be well tuned to behave like a singly-stochastic point processes by adjusting the rate parameters.

Murugan, Rajamanickam

2008-04-01

360

Trigger finger, tendinosis, and intratendinous gene expression.  

PubMed

The pathogenesis of trigger finger has generally been ascribed to primary changes in the first annular ligament. In contrast, we recently found histological changes in the tendons, similar to the findings in Achilles tendinosis or tendinopathy. We therefore hypothesized that trigger finger tendons would show differences in gene expression in comparison to normal tendons in a pattern similar to what is published for Achilles tendinosis. We performed quantitative real-time polymerase chain reaction on biopsies from finger flexor tendons, 13 trigger fingers and 13 apparently healthy control tendons, to assess the expression of 10 genes which have been described to be differently expressed in tendinosis (collagen type 1a1, collagen 3a1, MMP-2, MMP-3, ADAMTS-5, TIMP-3, aggrecan, biglycan, decorin, and versican). In trigger finger tendons, collagen types 1a1 and 3a1, aggrecan and biglycan were all up-regulated, and MMP-3and TIMP-3 were down-regulated. These changes were statistically significant and have been previously described for Achilles tendinosis. The remaining four genes were not significantly altered. The changes in gene expression support the hypothesis that trigger finger is a form of tendinosis. Because trigger finger is a common condition, often treated surgically, it could provide opportunities for clinical research on tendinosis. PMID:22882155

Lundin, A-C; Aspenberg, P; Eliasson, P

2014-04-01

361

Congenital analbuminemia caused by a novel aberrant splicing in the albumin gene  

PubMed Central

Introduction: Congenital analbuminemia is a rare autosomal recessive disorder manifested by the presence of a very low amount of circulating serum albumin. It is an allelic heterogeneous defect, caused by variety of mutations within the albumin gene in homozygous or compound heterozygous state. Herein we report the clinical and molecular characterization of a new case of congenital analbuminemia diagnosed in a female newborn of consanguineous (first degree cousins) parents from Ankara, Turkey, who presented with a low albumin concentration (< 8 g/L) and severe clinical symptoms. Materials and methods: The albumin gene of the index case was screened by single-strand conformation polymorphism, heteroduplex analysis, and direct DNA sequencing. The effect of the splicing mutation was evaluated by examining the cDNA obtained by reverse transcriptase - polymerase chain reaction (RT-PCR) from the albumin mRNA extracted from proband’s leukocytes. Results: DNA sequencing revealed that the proband is homozygous, and both parents are heterozygous, for a novel G>A transition at position c.1652+1, t