Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the adenomatous polyposis coli (APC) tumour-suppressor gene occur in most human colon cancers. Loss of functional APC protein results in the accumulation of beta-catenin. Mutant forms of beta-catenin have been discovered in colon cancers that retain wild-type APC genes, and also in melanomas, medulloblastomas, prostate cancer and gastric and hepatocellular carcinomas. The accumulation of beta-catenin activates genes that are responsive to transcription factors of the TCF/LEF family, with which beta-catenin interacts. Here we show that beta-catenin activates transcription from the cyclin D1 promoter, and that sequences within the promoter that are related to consensus TCF/LEF-binding sites are necessary for activation. The oncoprotein p21ras further activates transcription of the cyclin D1 gene, through sites within the promoter that bind the transcriptional regulators Ets or CREB. Cells expressing mutant beta-catenin produce high levels of cyclin D1 messenger RNA and protein constitutively. Furthermore, expression of a dominant-negative form of TCF in colon-cancer cells strongly inhibits expression of cyclin D1 without affecting expression of cyclin D2, cyclin E, or cyclin-dependent kinases 2, 4 or 6. This dominant-negative TCF causes cells to arrest in the G1 phase of the cell cycle; this phenotype can be rescued by expression of cyclin D1 under the cytomegalovirus promoter. Abnormal levels of beta-catenin may therefore contribute to neoplastic transformation by causing accumulation of cyclin D1.
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PMID:Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. 1020 72

Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.
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PMID:beta-catenin signaling and cancer. 1058 Sep 87

WNT2 is one of proto-oncogenes with the potential to activate the WNT - beta-catenin - TCF signaling pathway, which is most homologous to WNT2B among members of the human WNT gene family. Here, expression of WNT2 mRNA was comprehensively investigated. WNT2 mRNAs were highly expressed in fetal lung, and weakly expressed in placenta. Among 2.0-, 2.9-, 4.1-, and 6.0-kb WNT2 mRNAs, the 2.0-kb WNT2 mRNA was the major transcript in fetal lung. In 3 cases of prostate cancer and 1 case each of lung cancer and cervical cancer, WNT2 was over-expressed in non-cancerous portion as well as in primary tumor. WNT2 was up-regulated in 14 out of 18 cases of primary colorectal cancer, 4 out of 7 cases of uterus tumor, 2 out of 9 cases of breast cancer, and in 2 out of 14 cases of kidney tumor. Up-regulation of WNT2 was also detected in 4 out of 8 cases of primary gastric cancer by using expression array filter hybridization, and in 10 out of another 10 cases of primary gastric cancer by using cDNA-PCR. Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer might play a key role in carcinogenesis through activation of the WNT - beta-catenin - TCF signaling pathway.
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PMID:Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. 1160 1

SOX transcription factors with high-mobility-group DNA-binding domain (HMG box) play key roles in embryogenesis. Some members of the SOX family are negative regulators of the WNT-beta-catenin-TCF signaling pathway. We have previously cloned and characterized human SOX17, constituting a subfamily with SOX7 and SOX18. Another group mapped SOX7 gene to human chromosome 8p22, and reported almost ubiquitous expression of 5.0-kb SOX7 mRNA in human normal tissues. Here, expression of SOX7 mRNA was investigated by using SOX7 specific probe, which hybridized to 3.8-kb human SOX7 mRNA, but not to 5.0-kb mRNA. SOX7 mRNA was relatively highly expressed in adult lung, trachea, lymph node, placenta, fetal lung, and heart. In adult heart, SOX7 mRNA was more highly expressed in ventricules, inter-ventricular septum and apex than in atriums. SOX7 mRNA was significantly up-regulated in pancreatic cancer cell lines BxPC-3, PSN-1, Hs766T, and in 4 cases out of 8 cases of primary gastric cancer. SOX7 mRNA was relatively highly expressed in a gastric cancer cell line MKN45, esophageal cancer cell lines TE2, TE3, TE4, TE5, TE7, TE8, TE11, TE12, and TE13. On the other hand, SOX7 mRNA was significantly down-regulated in 7 out of 18 cases of primary colorectal tumors, in 4 out of 9 cases of primary breast cancer, in 4 out of 14 cases of primary kidney tumors, and also in some cases of primary lung and prostate cancer. SOX7 gene might be one of cancer-associated genes on human chromosome 8p22.
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PMID:Expression of human SOX7 in normal tissues and tumors. 1189 28

Mutations in the NH(2)-terminal regulatory domain of the beta-catenin gene lead to aberrant stabilization and accumulation of the protein and increased TCF/LEF-dependent transcription. Although these mutations are common in some cancers, they are infrequent in prostate and breast cancer. We have found that metastatic prostate cancer specimens, obtained through a rapid autopsy tissue procurement program, expressed a novel M(r) 75,000 proteolytic fragment of beta-catenin (beta-cat(75)). beta-Cat(75) was also expressed in multiple prostate and breast cancer cell lines and was closely associated with the activity of the calcium-dependent protease, calpain. In a prostate cancer cDNA microarray, m-calpain RNA levels were found to be significantly increased in metastatic disease compared with normal prostate. We showed calpain-dependent generation of beta-cat(75) in cell culture and in vitro. Molecular mapping revealed that calpain cleavage removed the NH(2)-terminal regulatory domain of the beta-catenin protein. Treatment of MCF-7 cells with ionomycin led to increased accumulation of beta-cat(75) in the nucleus and TCF-dependent transcriptional activity. Overexpression of a similar beta-catenin fragment that lacks the NH(2)-terminal 132 amino acids and has transforming potential activated TCF-dependent transcription. Given the low frequency of mutation-induced activation of beta-catenin in prostate and breast cancers, proteolytic cleavage of beta-catenin by calpain may represent a novel mechanism by which the protein is activated during tumorigenesis.
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PMID:Cleavage of beta-catenin by calpain in prostate and mammary tumor cells. 1549 40

Members of the transforming growth factor beta (TGF-beta) and Wnt/wingless superfamilies regulate cell fate during development and tissue maintenance. Here we report that Smad7 interacts with beta-catenin and lymphoid enhancer binding factor 1/T-cell-specific factor (LEF1/TCF), transcriptional regulators in Wnt signaling, in a TGF-beta-dependent manner. Smad7 was found to be required for TGF-beta1-induced accumulation of beta-catenin and LEF1 in human prostate cancer (PC-3U) cells as well as in human keratinocytes (HaCaT cells). Moreover, when the endogenous Smad7 was repressed by specific small interfering RNA, TGF-beta-induced increase of activated p38, Akt phosphorylated on Ser473, glycogen synthase kinase 3beta phosphorylated on Ser9 was prevented, as well as the TGF-beta-induced association between beta-catenin and LEF1. Notably, the observed physical association of Smad7 and beta-catenin was found to be important for TGF-beta-induced apoptosis, since suppression of beta-catenin expression by small interfering RNA decreased the apoptotic response to TGF-beta.
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PMID:Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis. 1568 97

Dysregulation of the WNT/beta-catenin pathway is thought to contribute to prostate cancer progression. Mutations of beta-catenin occurring in 5-7% of advanced prostate cancers may act by stimulating TCF-dependent and/or androgen receptor (AR)-dependent transcription. Using a reporter gene approach we found overexpressed mutated beta-catenin to enhance AR-regulated probasin-promoter activity in the AR-positive prostate cancer cell line 22Rv1, particularly at low androgen levels. In 22Rv1 cells mutated beta-catenin was able to stimulate TCF-dependent transcription but was unable to do so in LNCaP cells where it activates the AR. Since beta-catenin mutations are rare in vivo, we studied further possible routes of WNT-pathway modulation. Higher concentrations of LiCl, a GSK3beta-inhibitor, were required to activate TCF-dependent rather than AR-dependent reporter constructs. In 22Rv1 overexpression of E-cadherin repressed androgen-dependent transcription, but did not inhibit transcription of TCF-dependent reporter genes as in bladder cancer cell lines. Interestingly, Wnt-3a stimulated proliferation selectively in the AR-positive prostate cancer cell lines 22Rv1 and LNCaP, even though TCF-dependent reporter gene transcription was not induced in LNCaP cells. In summary, the data from our study support the idea that activation of WNT/beta-catenin signaling in AR-positive prostate cancer cells may predominantly act through AR-dependent mechanisms rather than classical TCF-dependent mechanisms.
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PMID:Effects of WNT/beta-catenin pathway activation on signaling through T-cell factor and androgen receptor in prostate cancer cell lines. 1575 99

beta-Catenin, a component of the Wnt signaling pathway, is a coactivator of human androgen receptor (hAR) transcriptional activity. Here, we show that Wnt signaling also influences androgen-mediated signaling through its ability to regulate hAR mRNA and protein in prostate cancer (PCa) cells. Three functional LEF-1/TCF binding sites lie within the promoter of the hAR gene as shown by CHIP assays that captured beta-catenin-bound chromatin from Wnt-activated LNCaP cells. Chimeric reporter vectors that use the hAR gene promoter to drive luciferase expression confirmed that these LEF-1/TCF binding elements are able to confer robust upregulation of luciferase expression when stimulated by Wnt-1 or by transfection with beta-catenin and that dominant-negative TCF or mutations within the dominant TCF-binding element abrogated the response. Semi-quantitative and real time RT-PCR assays confirmed that Wnt activation upregulates hAR mRNA in PCa cells. In contrast, hAR protein expression was strongly suppressed by Wnt activation. The reduction of hAR protein is consistent with evidence that Wnt signaling increased phosphorylation of Akt and its downstream target, MDM2 that promotes degradation of hAR protein through a proteasomal pathway. These data indicate that the hAR gene is a direct target of LEF-1/TCF transcriptional regulation in PCa cells but also show that the expression of the hAR protein is suppressed by a degradation pathway regulated by cross-talk of Wnt to Akt that is likely mediated by Wnt-directed degradation of the B regulatory subunit of protein phosphatase, PP2A.
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PMID:Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells. 1647 50

EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4 and EPHB6 are EPH family receptors for Ephrin family ligands. Ephrin/EPH signaling pathway networks with the WNT signaling pathway during embryogenesis, tissue regeneration, and carcinogenesis. TCF/LEF-binding sites within the promoter region of human EPH family members were searched for by using bioinformatics and human intelligence. Because five TCF/LEF-binding sites were identified within the 5'-promoter region of the EPHA7 gene, comparative genomics analyses on EPHA7 orthologs were further performed. EPHA7-MANEA-FHL5 locus at human chromosome 6q16.1 and EPHA10-MANEAL-FHL3 locus at human chromosome 1p34.3 were paralogous regions within the human genome. Human EPHA7 mRNA was expressed in embryonic stem (ES) cells, neural tissues, duodenal cancer and parathyroid tumors, while mouse Epha7 mRNA was expressed in fertilized egg, Rathke's pouche, visual cortex, pituitary gland, other neural tissues, pancreas, lung tumors and mammary tumors. The chimpanzee EPHA7 gene and cow Epha7 gene were identified within NW_107969.1 and AC155055.2 genome sequences, respectively. Five TCF/LEF-binding sites within human EPHA7 promoter were conserved in the chimpanzee EPHA7 promoter, and three TCF/LEF-binding sites in the cow Epha7 promoter, but none in the mouse Epha7 promoter. Primates and cow EPHA7 orthologs were identified as evolutionarily conserved targets of the WNT/beta-catenin signaling pathway. D6S1056 microsatellite marker within EPHA7 gene is deleted in prostate cancer. Deletion and/or promoter CpG hypermethylation could explain the EPHA7 down-regulation in human tumors. EPHA7 is a target of systems medicine, especially in the fields of regenerative medicine and oncology.
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PMID:Comparative integromics on Eph family. 1659 41

AREG (Amphiregulin), BTC (beta-cellulin), EGF, EPGN (Epigen), EREG (Epiregulin), HBEGF, NRG1, NRG2, NRG3, NRG4 and TGFA (TGFalpha) constitute EGF family ligands for ERBB family receptors. Cetuximab (Erbitux), Pertuzumab (Omnitarg) and Trastuzumab (Herceptin) are anti-cancer drugs targeted to EGF family ligands, while Gefitinib (Iressa), Erlotinib (Tarceva) and Lapatinib (GW572016) are anti-cancer drugs targeted to ERBB family receptors. AREG and TGFA are biomarkers for Gefitinib non-responders. The TCF/LEF binding sites within the promoter region of human EGF family members were searched for by using bioinformatics and human intelligence (Humint). Because three TCF/LEF-binding sites were identified within the 5'-promoter region of human AREG gene, comparative genomics analyses on AREG orthologs were further performed. The EPGN-EREG-AREG-BTC cluster at human chromosome 4q13.3 was linked to the PPBP-CXCL segmental duplicons. AREG was the paralog of HBEGF at human chromosome 5q31.2. Chimpanzee AREG gene, consisting of six exons, was located within NW_105918.1 genome sequence. Chimpanzee AREG was a type I transmembrane protein showing 98.0% and 71.4% total amino-acid identity with human AREG and mouse Areg, respectively. Three TCF/LEF-binding sites within human AREG promoter were conserved in chimpanzee AREG promoter, but not in rodent Areg promoters. Primate AREG promoters were significantly divergent from rodent Areg promoters. AREG mRNA was expressed in a variety of human tumors, such as colorectal cancer, liver cancer, gastric cancer, breast cancer, prostate cancer, esophageal cancer and myeloma. Because human AREG was characterized as potent target gene of WNT/beta-catenin signaling pathway, WNT signaling activation could lead to Gefitinib resistance through AREG upregulation. AREG is a target of systems medicine in the field of oncology.
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PMID:Canonical WNT signaling pathway and human AREG. 1668 31


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