Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-Catenin gene mutations and microsatellite instability (MI) have been reported in endometrioid ovarian carcinomas. In colon but not endometrial cancer, beta-catenin gene mutations are associated with a replication error phenotype and MI. In this study the authors investigate whether beta-catenin mutations and MI are two independent oncogenic pathways in endometrioid ovarian carcinomas. They also evaluate the usefulness of these molecular markers in determining the primary origin of simultaneous tumors in the ovary and endometrium. This study was performed on 26 patients diagnosed with primary endometrioid ovarian carcinoma, five of whom also had pathologically diagnosed primary synchronous endometrioid endometrial carcinoma. Immunohistochemical and molecular analyses indicated that there were 25 primary ovarian tumors with four primary synchronous endometrial cancers and one ovarian metastasis of a primary endometrial carcinoma. All studies were performed on formalin-fixed, paraffin-embedded tissue samples. The beta-catenin expression pattern (nuclear vs. membranous) was analyzed immunohistochemically. Mutations in exon 3 of the beta-catenin gene were studied by polymerase chain reaction, single-strand conformational polymorphism, and direct sequencing. MI status was established by studying BAT-26 and BAT-25 mononucleotide repeats. In the group with 21 single ovarian tumors, 18 (85%) had beta-catenin nuclear expression, eight (38%) had beta-catenin gene mutations (always associated with beta-catenin nuclear expression), and four (19%) had MI. Only one case (5%) had both beta-catenin gene mutations and MI. The mutations affected one of the serine/threonine residues targeted for phosphorylation by glycogen synthase kinase-3beta or adjacent residues. At codon 32, a GAC-to-TAC (D32Y) change was found; at codon 33, two TCT-to-TGT (S33C) changes were found; at codon 37, three TCT-to-TTT (S37F) changes and one TCT-to-TGT (S37C) change were found; and, lastly, one ACC-to-GCC change at codon 41 (T41A) was detected. Four of the 25 endometrioid ovarian carcinomas (16%) had an associated synchronous endometrial carcinoma. There was a higher percentage of beta-catenin mutations (n = 3, 75%) in synchronous ovarian carcinomas than in single ones, although with a similar percentage of MI (n = 1, 25%). beta-catenin mutations were S37C in two cases and D32G in one. One of the four endometrial carcinomas showed an S33C beta-catenin mutation, and two carcinomas had MI. None of the four tumors had both beta-catenin gene mutation and MI. beta-catenin gene mutations were always associated with a nuclear beta-catenin expression pattern, whereas MI was associated with a membranous pattern. In one patient both the ovarian and the endometrial carcinomas had beta-catenin gene mutations, in another patient both tumors showed MI, whereas in the remaining two patients the ovarian carcinomas showed beta-catenin gene mutations and the endometrial carcinomas showed MI. To summarize, the results of this study suggest that beta-catenin mutations and MI could represent two independent pathways in endometrioid ovarian carcinomas because they occur simultaneously very infrequently (in 5% of these cases). beta-catenin mutations are always associated with a nuclear beta-catenin expression pattern, whereas cases with a replication error -plus phenotype showed no abnormal beta-catenin subcellular localization. The study of the beta-catenin expression pattern, beta-catenin mutations, and MI, together with conventional clinicopathologic findings, could aid in distinguishing between the metastatic or independent origin of simultaneous endometrioid ovarian and endometrial carcinomas. Tumors with identical immunohistochemical and molecular features should therefore be considered to have a common origin.
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PMID:beta-Catenin expression pattern, beta-catenin gene mutations, and microsatellite instability in endometrioid ovarian carcinomas and synchronous endometrial carcinomas. 1138 21

FRAT1 and FRAT2 are cancer-associated genes encoding GSK-3beta-binding proteins. Over-expression of FRAT1 or FRAT2 lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway. We have previously cloned and characterized FRAT2. Here, we found that FRAT1 and FRAT2 genes were clustered in the human chromosome 10q24.1 region. Blast search revealed that FRAT1 and FRAT2 genes, consisting of a single exon, were located together on human genome draft sequences AC006098.1 and AL355490.7, corresponding to the human chromosome 10q24.1 region. FRAT1 and FRAT2 genes were clustered in a tail to tail manner with an interval of about 10.7 kb. The 2.7-kb FRAT1 mRNA was relatively highly expressed in fetal brain, adult spleen, pancreas, HeLa S3 (cervical cancer), and K-562 (chronic myelogenous leukemia). FRAT1 and FRAT2 were co-expressed in 7 gastric cancer cell lines and 10 cases of primary gastric cancer, and were up-regulated together in gastric cancer cell line TMK1 and 2 cases of primary gastric cancer. These results indicated that FRAT1 and FRAT2 genes were up-regulated together in several cases of human gastric cancer. Up-regulation of FRAT1 and FRAT2 in gastric cancer might lead to carcinogenesis through activation of WNT--beta-catenin--TCF signaling pathway.
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PMID:FRAT1 and FRAT2, clustered in human chromosome 10q24.1 region, are up-regulated in gastric cancer. 1144 44

Whereas deep fibromatoses (abdominal, extra-abdominal, mesenteric) display locally aggressive behavior, superficial fibromatoses typically remain small and less likely to recur despite essentially identical morphology. Somatic beta-catenin or APC gene mutations have been reported in < or =74% of sporadic deep fibromatoses and in virtually 100% of Gardner syndrome-associated fibromatoses, whereas genetic events in superficial fibromatoses remain less well characterized. We performed immunohistochemical staining for beta-catenin on 29 superficial fibromatoses (22 palmar, 5 plantar, 1 penile, and 1 infantile digital fibromatosis) and 5 deep fibromatoses. Mutations of beta-catenin and APC genes were analyzed in cases of superficial fibromatoses by direct DNA sequencing of the beta-catenin gene on Exon 3 encompassing the GSK-3 36 phosphorylation region and of the APC gene on the mutation cluster region. Nuclear accumulation of beta-catenin was present in 86% (25/29) of superficial fibromatosis cases ranging from 5 to 100% of nuclei (mean, 13%; median, 10%), though in a minority of nuclei in most examples. Deep fibromatoses had 60 to 100% nuclear staining in all five cases. No somatic mutations of beta-catenin or APC genes were identified in any of the superficial fibromatoses. In contrast to deep fibromatoses, superficial fibromatoses lack beta-catenin and APC gene mutations; the significance of focal nuclear beta-catenin accumulation is unclear. This difference may account inpart for their divergent clinical manifestations despite their morphologic resemblance to deep fibromatoses.
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PMID:Superficial fibromatoses are genetically distinct from deep fibromatoses. 1145 2

Presenilin 1 (PS1) is linked with Alzheimer's disease but exhibits functional roles regulating growth and development. For instance, PS1 binds to beta-catenin and modulates beta-catenin signaling. In the current study, we observed that knockout of PS1 inhibited beta-catenin-mediated transcription by 35%, as shown by a luciferase reporter driven by the hTcf-4 promoter. Overexpressing wild-type PS1 increased beta-catenin-mediated transcription by 37.5%, and overexpressing PS1 with mutations associated with Alzheimer's disease decreased beta-catenin-mediated transcription by 66%. To examine whether regulation of beta-catenin by PS1 requires phosphorylation by glycogen synthase kinase 3beta (GSK 3beta), we examined whether inhibiting GSK 3beta activity overcomes the inhibition of beta-catenin transcription induced by mutant PS1 constructs. Cells expressing wild-type or mutant PS1 were treated with LiCl, which inhibits GSK 3beta, or transfected with beta-catenin constructs that lack the GSK 3beta phosphorylation sites. Neither treatment overcame PS1-mediated inhibition of beta-catenin signaling, suggesting that regulation of beta-catenin by PS1 was not affected by the activity of GSK 3beta. To investigate how PS1 might regulate beta-catenin signaling, we determined whether PS1 interacts with other elements of the beta-catenin signaling cascade, such as the Tcf-4 transcription factor. Coimmunoprecipitation studies showed binding of PS1 and hTcf-4, and examining nuclear isolates indicated that nuclear hTcf-4 was decreased in cells expressing mutant PS1. These data show that PS1 interacts with multiple components of the beta-catenin signaling cascade and suggest that PS1 regulates beta-catenin in a manner independent of GSK 3beta activity.
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PMID:Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion. 1150 26

Abnormal degradation of beta-catenin caused by alteration of the glycogen synthase kinase-3beta (GSK-3beta) consensus motif is an important step for carcinogenesis. We hypothesize that beta- and gamma-catenin may play an important role in the pathogenesis of bladder cancer. We tested this hypothesis through analysis of beta- and gamma-catenin in both murine and human bladder cancers. A murine bladder cancer model was prepared by use of N-butyl-N-(-4-hydroxybutyl)nitrosamine (BBN) in 6-week-old male B6D2F1 mice. After 4, 8, 12, 16, 20, 24, and 28 weeks of BBN treatment, bladder specimens were harvested and analyzed for both protein and gene expression for beta- and gamma-catenin. Mutational analysis of the NH(2)-terminal regulatory domains of beta- and gamma-catenin was performed in each specimen by PCR-single-strand conformational polymorphism (SSCP) analysis. Mutations were further confirmed by direct DNA sequencing with a dye terminator method. Human bladder cancer specimens with normal tissues, dysplasia, carcinoma in situ, and carcinoma of grades, 1, 2, and 3 were also analyzed for beta- and gamma-catenin expression. beta- and gamma-catenin were analyzed for mutations by SSCP and direct DNA sequencing. Intracellular accumulation of beta- and gamma-catenin was observed in 6 of 20 invasive carcinoma specimens. There was no intracellular accumulation of beta- and gamma-catenin in mucosal dysplasia, papillary or nodular dysplasia, and carcinoma in situ specimens. On an SSCP analysis for beta-catenin, abnormal bandshifts were detected in two invasive carcinomas with intracellular beta-catenin accumulation. Further sequencing revealed two mutations [AGT(S) to ATT(I) and TCT(S) to CCT(P)] within the consensus motif for GSK-3beta phosphorylation. On the other hand, SSCP analysis for gamma-catenin followed by sequencing revealed three mutations in two invasive carcinomas with intracellular accumulation of gamma-catenin. These three alterations affected the 3' downstream region outside the GSK-3beta phosphorylation site [ACC(T) to GCC(A), CTC(L) to ATC(I), and CTC(L) to ATG(M)]. In human bladder cancer, beta- and gamma-catenin expression was significantly weaker than in normal bladder. On SSCP analysis one abnormal bandshift was observed in high-grade human bladder cancer with intracellular beta-catenin accumulation. DNA sequencing revealed mutation TCT(S) to TGT(C). In summary, alterations in beta- and gamma-catenin are late events favoring tumor progression in mouse BBN-induced bladder cancer. Changes affecting the GSK-3beta phosphorylation site appear to be associated with activation of beta-catenin, but not with activation of gamma-catenin. In human blabber cancer, beta- and gamma-catenin expression is similar to the expression in the mouse model. The present study demonstrates that beta- and gamma-catenin may play an important role in bladder cancer progression.
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PMID:Alterations of beta- and gamma-catenin in N-butyl-N-(-4-hydroxybutyl)nitrosamine-induced murine bladder cancer. 1158 41

Presenilin 1 (PS1) regulates beta-catenin stability; however, published data regarding the direction of the effect are contradictory. We examined the effects of wild-type and mutant forms of PS1 on the membrane, cytoplasmic, nuclear, and signaling pools of endogenous and exogenous beta-catenin by immunofluorescence microscopy, subcellular fractionation, and in a transcription assay. We found that PS1 destabilizes the cytoplasmic and nuclear pools of beta-catenin when stabilized by Wnt or Dvl but not when stabilized at lower levels of the Wnt pathway. The PS1 mutants examined were less able to reduce the stability of beta-catenin. PS1 also inhibited the transcriptional activity of endogenous beta-catenin, and the PS1 mutants were again less inhibitory at the level of Dvl but showed a different pattern of inhibition toward transcription below Dvl. The transcriptional activity of exogenously expressed wild-type beta-catenin and two mutants, DeltaN89beta-catenin and DeltaSTbeta-catenin, were also inhibited by wild-type and mutant PS1. We conclude that PS1 negatively regulates the stability and transcriptional activity of beta-catenin at different levels in the Wnt pathway, that the effect on transcriptional activity appears to be independent of the GSK-3beta mediated degradation of beta-catenin, and that mutations in PS1 differentially affect the stability and transcriptional activity of beta-catenin.
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PMID:Presenilin 1 independently regulates beta-catenin stability and transcriptional activity. 1160 87

Mutations in human Adenomatous Polyposis Coli (APC) gene are associated with both familial and sporadic colorectal tumors. APC is known to down regulate beta-catenin levels, a transducer of Wnt signaling. The aim of this study is to provide transgenic Drosophila expressing either full-length or truncated forms of human APC (hAPC) protein and methods for using them in functional genomics and drug screening. Consistent with its biochemical properties, targeted expression of either full-length hAPC or its beta-catenin binding domain alone negatively regulated the function of the beta-catenin homologue, Armadillo (Arm) and thereby, inhibited Wnt/Wg signaling during fly development. hAPC inhibited Arm function even in the absence of GSK-3beta activity, although the latter was required to mediate the degradation of Arm. Consistent with this, hAPC suppressed the phenotypes induced by the over-expression of degradation-resistant forms of Arm. Subsequently, using hAPC-induced eye phenotypes as the assay in a suppressor-enhancer screen, we have identified two new loci in Drosophila, which modulate Wnt/Wg signaling. In addition, an anti-colon cancer drug, indomethacin, specifically enhanced hAPC-induced phenotypes.
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PMID:Studies on human colon cancer gene APC by targeted expression in Drosophila. 1168 66

Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK-3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competitive GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and beta-catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK-3 activity towards Tau and beta-catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and beta-catenin.
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PMID:GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity. 1169 57

The nemo-like kinase (Nlk) connects the MAP kinase and Wnt signalling pathways. We have found that invertebrate (Caenorhabditis elegans, Drosophila melanogaster) and mammalian genomes (Mus musculus and Homo sapiens) each contain only a single functional Nlk gene. The mouse genome also harbours a transcriptionally silent processed Nlk pseudogene residing on chromosome 2. Thus, while genes encoding upstream (such as Wnts and frizzelds) and downstream (such as TCF/LEF) components of the Wnt signalling pathway have been extensively diversified during evolution, genes encoding components of the common core of the connecting signalling structure (such as beta-catenin, GSK beta and Nlk) have been maintained in single copies.
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PMID:Only one nemo-like kinase gene homologue in invertebrate and mammalian genomes. 1170 33

MCF-7 breast cancer cells stably overexpressing protein kinase C-alpha (MCF-7-PKC-alpha cells) exhibit reduced cell-cell adhesion and increased tumorigenicity in nude mice. We investigated the possibility that alterations in E-cadherin and catenins contribute to the unique phenotype of MCF-7-PKC-alpha cells. Northern and Western blotting indicated that MCF-7-PKC-alpha cells express abnormally low amounts of plakoglobin mRNA and protein, and undetectable levels of E-cadherin mRNA and protein. In contrast, even though MCF-7-PKC-alpha cells express low levels of beta-catenin mRNA, they express undetectable levels of beta-catenin protein, suggesting that post-transcriptional events further diminish beta-catenin expression in these cells. Pulse-labeling of the cells with [35S]methionine showed that the half-life of beta-catenin is less than 15 min in MCF-7-PKC-alpha cells, compared to over 2 h in MCF-7-Vector cells [MCF-7 cells transfected with pSV2M(2)6 vector only]. Incubation with LiCl to inactivate glycogen synthase kinase-3 (GSK-3) significantly prolonged the half-life of beta-catenin in MCF-7-PKC-alpha cells, suggesting that the GSK-3-dependent degradation of beta-catenin contributes to beta-catenin instability in these cells. Northern and Western blotting indicated that Wnt-1, which also inhibits GSK-3 activity, is expressed by MCF-7-Vector cells, but not by MCF-7-PKC-alpha cells. Transfection of (S37A)beta-catenin, which is resistant to GSK-3-dependent degradation, stimulated TCF/LEF-dependent luciferase expression from the pTOPFLASH reporter plasmid by 753-fold in MCF-7-PKC-alpha cells, and by 268-fold in MCF-7-Vector cells. Inactivation of GSK-3 by LiCl stimulated luciferase expression from the pTOPFLASH reporter plasmid by 12.4-fold in MCF-7-PKC-alpha cells, and by 4.8-fold in MCF-7-Vector cells. These results suggest that degradation of beta-catenin by GSK-3 contributes to beta-catenin instability in MCF-7-PKC-alpha cells, diminishing the ability of -catenin to act as a transcriptional co-activator. Reduced Wnt-1 expression by MCF-7-PKC-alpha cells may promote beta-catenin degradation by enhancing GSK-3 activity. Loss of beta-catenin-dependent cell-cell adhesion and transcription may contribute to the aggressive phenotype of MCF-7-PKC-alpha cells.
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PMID:Reduced expression of Wnt-1 and E-cadherin, and diminished beta-catenin stability in MCF-7 breast cancer cells that overexpress protein kinase C-alpha. 1171 93


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