Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates the majority of colorectal (CR) cancers. One consequence of this inactivation is constitutive activation of beta-catenin/Tcf-mediated transcription. To further explore the role of the APC/beta-catenin/Tcf pathway in CR tumorigenesis, we searched for mutations in genes implicated in this pathway in CR tumors lacking APC mutations. No mutations of the gamma-catenin (CTNNG1), GSK-3alpha (GSK3A), or GSK-3beta (GSK3B) genes were detected. In contrast, mutations in the NH2-terminal regulatory domain of beta-catenin (CTNNB1) were found in 13 of 27 (48%) CR tumors lacking APC mutations. Mutations in the beta-catenin regulatory domain and APC were observed to be mutually exclusive, consistent with their equivalent effects on beta-catenin stability and Tcf transactivation. In addition, we found that CTNNB1 mutations can occur in the early, adenomatous stage of CR neoplasia, as has been observed previously with APC mutations. These results suggest that CTNNB1 mutations can uniquely substitute for APC mutations in CR tumors and that beta-catenin signaling plays a critical role in CR tumorigenesis.
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PMID:Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. 951 95

Inactivation of the adenomatous polyposis coli (APC) gene has been shown to initiate the majority of colorectal cancer (CRC), including a familial form called familial adenomatous polyposis (FAP). One consequence of the APC mutation is the activation of the beta-catenin (CTNNB1)/T-cell transcription factor (Tcf) pathway. A recent study has shown that about half of the sporadic CRC lacking APC mutation has CTNNB1 mutation, suggesting that CTNNB1 mutation can substitute for APC mutation in the initiation of colorectal tumorigenesis. However, the frequency of CTNNB1 germline mutation in FAP has not been reported. In the present study, we investigated the frequencies of APC and CTNNB1 germline mutations in 26 unrelated FAP families. We used the Protein Truncation Test (PTT) to screen the entire coding region of APC and found germline mutations in twenty families. We then screened for CTNNB1 germline mutations in the rest of the families lacking detectable APC mutations. No missense mutations at GSK-3beta phosphorylation sites or interstitial deletion of exon 3 of CTNNB1 was found. Our results indicate that APC germline mutations are frequent but CTNNB1 germline mutations are rare in FAP patients, suggesting that CTNNB1 mutation cannot substitute for APC mutation in the initiation of FAP. Genes Chromosomes Cancer 25:396-398, 1999.
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PMID:Germline mutations are frequent in the APC gene but absent in the beta-catenin gene in familial adenomatous polyposis patients. 1039 35

Some colorectal tumors with wild-type adenomatous polyposis coli gene have activating mutations in beta-catenin (encoded by CTNNB1) that result in decreased phosphorylation by GSK-3beta and increased signaling through the Tcf/Lef transcription factors. To investigate the relationship between CTNNB1 mutations and underlying pathways of genomic instability, we examined 80 colorectal cancers stratified by the presence or absence of microsatellite instability (MSI). CTNNB1 mutations were identified in 13 (25%) of 53 cancers with high frequency MSI (MSI-H), including 12 point mutations at exon 3 phosphorylation sites (codons 41 and 45) and one deletion of the entire exon 3 degradation box. No CTNNB1 mutations were identified in 27 microsatellite stable or low frequency MSI (MSI-L) colorectal cancers (P < 0.01). In contrast, CTNNB1 mutations were identified in 3 of 9 (33%) MSI-H and 10 of 20 (50%) MSS/MSI-L endometrial carcinomas, suggesting a more generalized involvement in these tumors. Only six (46%) of the endometrial carcinoma CTNNB1 mutations occurred at residues directly phosphorylated by GSK-3beta, and only one of these was at either codon 41 or 45. All point mutations in MSI-H cancers were transitions, whereas 64% of those in MSS/MSI-L cancers were transversions (P < 0.01). The differences in the mutation profiles suggest that there may be molecular fingerprints of CTNNB1 mutations, determined by biological factors related to both tumor type and underlying pathways of genomic instability.
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PMID:Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. 1041 91

Constitutive activation of the Wnt signaling pathway as a result of genetic alterations of APC, AXIN1, and CTNNB1 has been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. To investigate the pathogenetic significance of constitutive activation of the Wnt signaling pathway in human lung carcinogenesis, CTNNB1 alterations in exon 3, a region known to represent a mutation hot spot, were screened in 46 lung cancer cell lines and 47 primary lung cancers. Missense mutations causing substitutions of Ser/Thr residues critical for regulation by GSK-3beta were detected in one (2%) of the cell lines, A427, and two (4%) of the surgical specimens. The three lung cancers with CTNNB1 mutations were adenocarcinomas. To explore the prevalence of constitutive activation of the Wnt signaling pathway in human lung cancer, we assessed 15 lung cancer cell lines representing major histological subtypes of lung cancers for constitutive Tcf transcriptional activity (CTTA). CTTA was observed only in the A427 adenocarcinoma cell line, but not in the remaining 14 cell lines. The data indicate that constitutive activation of the Wnt signaling pathway caused by CTNNB1 mutation is involved in the development and/or progression of a subset of lung carcinoma, preferentially in adenocarcinoma.
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PMID:Constitutive activation of the Wnt signaling pathway by CTNNB1 (beta-catenin) mutations in a subset of human lung adenocarcinoma. 1117 Feb 92

Beta-catenin plays an important role in the Wnt signaling pathway by activating T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-regulated gene transcription. The level of beta-catenin is regulated through GSK-3beta phosphorylation of specific serine and threonine residues, all of which are encoded for in exon 3 of the beta-catenin gene (CTNNB1). Mutations altering the GSK-3beta phosphorylation sites lead to cellular accumulation of beta-catenin and constitutive transcription of Tcf/Lef target genes. Such mutations have previously been found in melanoma cell lines. In our study, primary melanomas and their corresponding metastases were screened for CTNNB1 exon 3 mutations using single-strand conformation polymorphism and nucleotide sequence analysis. One of 31 primary tumors and 1 of 37 metastases, both originating from the same patient, had a TCT to TTT mutation at codon 45, changing serine to phenylalanine. Immunohistochemical analysis revealed membranous localization of beta-catenin in a majority of the samples. The mutated primary tumor and metastasis, however, displayed widespread cytoplasmic and nuclear expression of beta-catenin. An additional 30% of the primary tumors showed focal cytoplasmic and nuclear staining. Thus, beta-catenin exon 3 mutations are rare in primary as well as metastatic melanomas and do not explain the abnormal cytoplasmic and nuclear localization of beta-catenin found in a relatively large fraction of primary melanomas.
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PMID:Cytoplasmic and nuclear accumulation of beta-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma. 1135 4

beta-Catenin, a protein that functions in cadherin-mediated cell-cell adhesion as well as in signal transduction, has received increasing attention in recent years due to its role as an oncogene in various human cancers. The primary sequence of the human beta-catenin gene (CTNNB1) has been known for some time, but that of the rat beta-catenin gene (Ctnnb1) has not heretofore been studied in detail. We report here the primary structure of Ctnnb1 using PCR-based methods and direct sequencing. The size of the complete Ctnnb1 gene was determined to be 9082 bp. We found the rat Ctnnb1 gene to contain 14 exons, ranging in size from 61 to 356 bp, and 13 introns ranging in size from 76 to 2524 bp. The transcription start site appears to be 157 bp upstream of the ATG codon located in exon 1. The resulting transcript is 2650 nucleotides long (encoding a protein of 781 amino acids). We found the 5' UTR to consist of 157 nucleotides and the 3' UTR to be 147 nucleotides long. The region coding for the glycogen synthase kinase-3beta domain of beta-catenin is located in exon 2 of rat Ctnnb1, in contrast to human CTNNB1 in which it is found in exon 3. Based on the newly acquired knowledge of the primary sequence, more than a dozen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced rat liver tumors were screened for the presence or absence of mutations in all 14 exons of rat Ctnnb1. Surprisingly, no mutations were found. The results are discussed in the context of the organ-specificity of IQ-induced mutations in beta-catenin, being highly prevalent in colon tumors, but much less common in liver tumors.
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PMID:Sequencing of the rat beta-catenin gene (Ctnnb1) and mutational analysis of liver tumors induced by 2-amino-3-methylimidazo[4,5-f]quinoline. 1186 32

To clarify the roles of Wnt pathway in medulloblastoma oncogenesis, immunohistochemical staining of beta-catenin and Wnt-1 and genomic analyses of CTNNB1 (beta-catenin) and AXIN1 (axin 1) were examined in 23 sporadic cases. Accumulation of beta-catenin in tumor cells was immunohistochemically proven in 5 cases; 2 cases showed positive immunoreactivity for Wnt-1 and another 2 showed mutation of either CTNNB1 or AXIN1. AXIN1 mutation was in exon 3, corresponding to GSK-3beta binding site and CTNNB1 mutation was in exon 3, corresponding to its phosphorylation site. Disruption of these proteins could result in upregulation of the Wnt signaling and accumulation of beta-catenin, followed by cell proliferation and medulloblastoma oncogenesis.
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PMID:Role of Wnt pathway in medulloblastoma oncogenesis. 1220 99

beta-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of beta-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3beta. Deregulation of beta-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of beta-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (beta-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display beta-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant beta-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type beta-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and beta-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of beta-catenin in cancer cells.
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PMID:P53 mutation as a source of aberrant beta-catenin accumulation in cancer cells. 1243 47

Wnt/beta-catenin signaling plays an important role in normal development. However, its aberrant activation is associated with several cancers. The aim of this study is to examine the Wnt/beta-catenin pathway in patients with advanced pancreatic adenocarcinoma (n = 31). Paraffin sections from tumors (n = 16) and normal pancreata (n = 3) were used to determine the localization of beta-catenin. An additional 15 frozen tumors, adjacent normal pancreata (n = 5), or normal pancreata (n = 4) were utilized for protein isolation. Tumors were also examined for mutations in exon 3 of the CTNNB1 gene. More than 65% of the tumors showed an increase in total beta-catenin, consistent with its enhanced membranous, cytoplasmic, and nuclear localization, but only two showed mutations in CTNNB1. The majority of the remaining tumors demonstrated concurrent increases in Wnt-1 and frizzled-2 (positive regulators) and a decrease in Ser45/Thr41-phospho-beta-catenin. Electrophoretic mobility shift assay demonstrated beta-catenin-T-cell factor binding in tumors only. Adenomatous polyposis coli and axin, which are both negative regulators, remained unchanged. Unexpectedly, total glycogen synthase kinase-3beta protein was elevated in these tumors. Elevated levels of E-cadherin were also observed, although E-cadherin-beta-catenin association in tumors remained unaffected. Thus, Wnt/beta-catenin activation was observed in 65% of pancreatic adenocarcinomas, independently of beta-catenin gene mutations in most tumors.
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PMID:Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. 1675 20

Helicobacter pylori eradication can reverse gastric intestinal metaplasia (IM) in some but not all patients. H. pylori induces high levels of nuclear beta-catenin staining in IM tissues, as well as overexpression of cyclooxygenase-2 (COX-2). This study investigated whether the Wnt/beta-catenin pathway plays a role in IM regression following H. pylori eradication. Sixty-five H. pylori-infected patients with IM who had achieved successful H. pylori eradication provided paired gastric samples before and after eradication to analyse the persistence of IM, and to assess COX-2 and nuclear beta-catenin expression. The host genotypes of single nucleotide polymorphisms (SNPs) of the COX-2, beta-catenin (CTNNB1) and adenomatous polyposis coli (APC) genes were analysed. In addition, expression of beta-catenin, E-cadherin and phosphorylated and unphosphorylated glycogen synthase kinase 3beta (GSK-3beta) in cell lines challenged with H. pylori isolates from patients with and without IM persistence was compared by immunoanalysis. After a mean 33.9-month follow-up after H. pylori eradication, 44 patients (67.7%) with IM persistence had a higher rate of high-level nuclear beta-catenin expression in IM tissue than those without IM persistence (P=0.008). The patients with IM persistence had a higher rate of AA, GG and AA APC SNP genotypes at positions 4479, 5268 and 5465, respectively, than the patients without IM persistence (P=0.022). The H. pylori isolates from the patients with IM regression after H. pylori eradication induced more phospho-GSK-3beta in AGS cells than isolates from patients with IM persistence (P=0.011). It is likely that interactions with H. pylori and the patient's Wnt/beta-catenin genetic predisposition determine the outcome of IM persistence following H. pylori eradication.
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PMID:Host Wnt/beta-catenin pathway triggered by Helicobacter pylori correlates with regression of gastric intestinal metaplasia after H. pylori eradication. 1936 17


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