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)

Alteration of adenomatous polyposis coli (APC) is known to be an early event in neoplasia, causing activation of the beta-catenin / Tcf pathway. Although it is thought that alterations in APC and beta- catenin may complement one another, the contribution of beta-catenin mutations to colorectal carcinogenesis remains unclear. We therefore performed PCR-single strand conformation polymorphism analysis and direct sequencing of exon 3 of beta-catenin gene in adenomas, adenocarcinomas, and aberrant crypt foci (ACF), considered to be putative precursor lesions of colorectal neoplasias, in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) treated F344 rats. beta-Catenin mutations were identified in all of 7 adenomas (100%) and 6 of 12 (50%) adenocarcinomas. All of the mutations were found in codons 32 through 34, the serine encoded by codon 33 being an important phosphorylation site by glycogen synthase kinase-3beta. Regarding ACF, 14 of 46 (30.4%) were found to be mutated, eleven (78%) in codon 34, and the others in codon 45 (frequently altered in human colon cancer), and codons 47 and 56 (which have not been previously reported). The frequency of beta-catenin mutations in adenomas was significantly higher than in ACF (P < 0.001) and adenocarcinomas (P < 0.05). Thus, beta-catenin mutations may have more importance in the genesis of adenomas than ACF or adenocarcinomas in rat colon carcinogens by PhIP.
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PMID:More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-treated rats. 1096 19

Wnt regulates developmental and oncogenic processes through its downstream effector, beta-catenin, and a set of other intracellular regulators that are largely conserved among species. Wnt family genes encode secreted glycoproteins that act as ligands for membrane receptors belonging to the Frizzled family of proteins. Wnt-1 originally was found as a proto-oncogene that was upregulated in tumors caused by the mouse mammary tumor virus. The Drosophila homologue of Wnt-1, wingless, is a segment polarity gene that regulates body patterning of the fly embryo. In Xenopus, the Wnt pathway regulates formation of the ventral-dorsal axis. Although Wnt proteins are expressed widely in mammals, the function of the Wnt signaling pathway in normal adult mammalian tissues is not understood. Downstream components of the Wnt pathway, APC (adenomatous polyposis coli) and beta-catenin, clearly are involved in human cancer. There are also several reports that Wnt ligands are highly expressed in tumors. Wnt stabilizes cytoplasmic beta-catenin and activates beta-catenin/Lef-1 (lymphoid enhancer factor), Tcf (T-cell factor)-dependent gene transcription. This regulation of cytosolic beta-catenin is mediated by glycogen synthase kinase-3 (GSK-3) activity but in neither case is the mechanism known. The mechanism by which Wnt inhibits GSK-3 is unknown. Recent studies have shown that some of the intracellular signaling molecules that mediate the Wnt pathway are in complexes, including Dishevelled (Dsh or Dvl), GSK-3beta, and APC protein. However, little is known about how Wnt or other upstream stimuli regulate these complexes to stabilize beta-catenin. We took a variety of approaches to identify new components of the Wnt pathway. Using an expression-cloning technique, we isolated casein kinase I (CKI)epsilon as a positive regulator of beta-catenin in the Wnt pathway. Overexpression of CKIepsilon mimics Wnt by stabilizing beta-catenin, thereby increasing expression of beta-catenin-dependent genes. Inhibition of endogenous CKIepsilon attenuated gene transcription stimulated by Wnt or by Dsh. CKIepsilon forms a complex with Axin and the other downstream components of the Wnt pathway. CKIepsilon is a positive regulator of the Wnt pathway and a possible functional link between upstream signals and the intracellular Axin signaling complex that regulates beta-catenin. In separate experiments, we have identified a Dishevelled-associated kinase (DAK) that binds to Dsh and regulates its functions. Dsh is required for two different pathways, the Wnt pathway and planar polarity pathway in Drosophila. DAK dramatically enhances the function of Dsh in the Wnt pathway and inhibits its function in the planar polarity pathway. This chapter will discuss these newly identified components of the Wnt pathway.
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PMID:New steps in the Wnt/beta-catenin signal transduction pathway. 1103 39

Beta-catenin plays important roles in both intercellular adhesion and signal transduction. Mutations in the beta-catenin or adenomatous polyposis coli (APC) gene can alter the degradation of beta-catenin and cause aberrant accumulation of beta-catenin result in increased transcription of target genes. The dysregulated APC/beta-catenin pathway has been recently discovered as an important mechanism of tumorigenesis in various cancers, but its role in esophageal adenocarcinomas is not clear. Therefore, we studied the beta-catenin gene mutation, allelic loss of chromosome 5q, and APC gene mutation in esophageal and esophagogastric junction adenocarcinomas. Two (2%) somatic mutations in exon 3 of the beta-catenin gene, encompassing the region for glycogen synthase kinase-3beta phosphorylation, were detected from 109 adenocarcinomas. Chromosomal allelic loss on 5q was frequent in 45.3% (44/97) of tumors. Only one missense mutation in the mutation cluster region of the APC gene was detected from 38 esophageal and esophagogastric junction adenocarcinomas with the 5q allelic loss. Our results based on partial screening mutational analyses indicate that mutations of APC/beta-catenin pathway, unlike in colorectal carcinoma, involve only a small subset of esophageal and esophagogastric junction adenocarcinoma.
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PMID:Mutations in beta-catenin and APC genes are uncommon in esophageal and esophagogastric junction adenocarcinomas. 1104 97

Fundic gland polyps (FGPs) are the most common gastric polyps. FGPs traditionally have been regarded as nondysplastic hamartomatous or hyperplastic lesions, but their pathogenesis remains unclear. We have recently shown that somatic adenomatous polyposis coli (APC) gene alterations are frequently present in FGPs associated with familial adenomatous polyposis (FAP), raising the possibility that mutations of the beta-catenin gene affecting the APC/beta-catenin pathway might be involved in the pathogenesis of sporadic FGPs. We analyzed somatic beta-catenin gene mutations in 57 sporadic FGPs from 40 patients without FAP and in 19 FGPs from 13 FAP patients. Direct DNA sequencing of exon 3 encompassing the glycogen synthase kinase-3beta phosphorylation region for beta-catenin was used with confirmation by HIN:fI restriction endonuclease digestion. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 22 of 57 sporadic FGPs. Activating beta-catenin gene mutations were present in 91% (52 of 57) of sporadic FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the polyps were shown to have the same somatic beta-catenin mutation in 21 of 22 (95%) sporadic FGPs. In contrast, beta-catenin gene mutations were not present in any of the 19 FAP-associated FGPs (P: < 0.000001). The high frequency of beta-catenin mutations in sporadic FGPs indicates that these lesions arise through activating mutations of the beta-catenin gene. Beta-catenin mutations in gastrointestinal tract polyps have previously only been demonstrated in a subset of adenomatous (dysplastic) or neoplastic polyps. Sporadic FGPs are therefore the only lesions of the gastrointestinal tract to demonstrate beta-catenin mutations while lacking dysplastic morphology.
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PMID:Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. 1123 48

Loss of functional adenomatous polyposis coli (APC) protein results in the stabilization of cytosolic beta-catenin and activation of genes that are responsive to Lef/Tcf family transcription factors. We have recently shown that an independent cell adhesion and integrin linked kinase (ILK)-dependent pathway can also activate beta-catenin/LEF mediated gene transcription and downregulate E-cadherin expression. In addition, ILK activity and expression are elevated in adenomatous polyposis and colon carcinomas. To examine the role of this pathway in the background of APC mutations we inhibited ILK activity in APC-/- human colon carcinoma cell lines. In all cases, inhibition of ILK resulted in substantial inhibition of TCF mediated gene transcription and inhibition of transcription and expression of the TCF regulated gene, cyclin D1. Inhibition of ILK resulted in decreased nuclear beta-catenin expression, and in the inhibition of phosphorylation of GSK-3 and stimulation of its activity, leading to accelerated degradation of beta-catenin. In addition, inhibition of ILK suppressed cell growth in culture as well as growth of human colon carcinoma cells in SCID mice. Strikingly, inhibition of ILK also resulted in the transcriptional stimulation of E-cadherin expression and correlated with the inhibition of gene transcription of snail, a repressor of E-cadherin gene expression. Overexpression of ILK caused a stimulation of expression of snail, but snail expression was found not to be regulated by beta-catenin/Tcf. These data demonstrate that ILK can regulate beta-catenin/TCF and snail transcription factors by distinct pathways. We propose that inhibition of ILK may be a useful strategy in the control of progression of colon as well as other carcinomas. Oncogene (2001) 20, 133 - 140.
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PMID:Inhibition of integrin linked kinase (ILK) suppresses beta-catenin-Lef/Tcf-dependent transcription and expression of the E-cadherin repressor, snail, in APC-/- human colon carcinoma cells. 1124 11

Axin, a negative regulator of the Wnt signaling pathway, forms a complex with glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, adenomatous polyposis coli (APC) gene product, and Dvl, and it regulates GSK-3beta-dependent phosphorylation in the complex and the stability of beta-catenin. Using yeast two-hybrid screening, we found that regulatory subunits of protein phosphatase 2A, PR61beta and -gamma, interact with Axin. PR61beta or -gamma formed a complex with Axin in intact cells, and their interaction was direct. The binding site of PR61beta on Axin was different from those of GSK-3beta, beta-catenin, APC, and Dvl. Although PR61beta did not affect the stability of beta-catenin, it inhibited Dvl- and beta-catenin-dependent T cell factor activation in mammalian cells. Moreover, it suppressed beta-catenin-induced axis formation and expression of siamois, a Wnt target gene, in Xenopus embryos, suggesting that PR61beta acts either at the level of beta-catenin or downstream of it. Taken together with the previous observations that PR61 interacts with APC and functions upstream of beta-catenin, these results demonstrate that PR61 regulates the Wnt signaling pathway at various steps.
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PMID:Inhibition of the Wnt signaling pathway by the PR61 subunit of protein phosphatase 2A. 1129 46

We provide evidence that the androgen receptor (AR) can promote nuclear translocation of beta-catenin in LNCaP and PC3 prostate cancer cells. Using AR-expressing cells (LNCaP) and non-AR-expressing cells (PC3) we showed by time course cell fractionation that the AR can shuttle beta-catenin into the nucleus when exposed to exogenous androgen. Cells exposed to the synthetic androgen, R1881, show distinct, punctate, nuclear co-localization of the AR and beta-catenin. We further showed that the AR does not interact with adenomatous polyposis coli or glycogen synthase kinase-3beta and, therefore, conclude that androgen-mediated transport of beta-catenin occurs through a distinct pathway. The minimal necessary components of the AR and beta-catenin required for binding nuclear accumulation of beta-catenin nuclear import appears to be the DNA/ligand binding regions and the Armadillo repeats of beta-catenin. We also employed a novel DNA binding assay to illustrate that beta-catenin has the capacity to bind to the probasin promoter in an AR-dependent manner. The physiological relevance of AR-mediated transport of beta-catenin and binding to an AR promoter appeared to be a substantial increase in AR transcriptional reporter activity. AR-mediated import represents a novel mode of nuclear accumulation of beta-catenin.
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PMID:The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. 1185 48

Sporadic fundic gland polyposis (SFGP) is defined as multiple fundic gland polyps in patients without familial adenomatous polyposis syndrome (FAP). Although little is known about the genetic changes in SFGP, mutations in the Wnt signaling pathway have been recently linked to fundic gland polyps in other settings: sporadic polyps are linked to activating beta-catenin mutations, whereas FAP-associated fundic gland polyps are caused by second somatic hits in the adenomatous polyposis coli gene. The relationship between SFGP, single sporadic fundic gland polyps, and FAP-associated polyps remains unclear, and SFGP remain poorly characterized at the clinical, histological, and molecular levels. A retrospective study was undertaken of eight patients with SFGP who had >/=10 polyps with at least five endoscopic biopsy specimens available for study. One additional patient with attenuated FAP who underwent partial gastrectomy was included as a control. The medical records and biopsy specimens were reviewed. Mutations of the beta-catenin gene were evaluated in each fundic gland as well as in control nonpolypoid tissue by direct sequencing of a mutational hot spot in exon 3 of the beta-catenin gene, which encodes the GSK-3beta phosphorylation sites, and a HinfI endonuclease digestion assay. The four men and four women in the study were an average of 57 years of age at biopsy. All patients were on acid-suppression therapy, 5/8 with proton-pump inhibitors (PPI) and 3/8 with Zantac. Sixty-two polyps were studied, and all were <10 mm, with most between 2 and 7 mm. The polyps were histologically identical to single sporadic fundic gland polyps. No dysplasia was seen. Forty-seven of 62 polyps (76%) had detectable beta-catenin mutations. Mutations were found in all eight of the patients. All were point mutations in codons 32, 33, 34, and 37 and are either phosphorylation sites or immediately adjacent to phosphorylation sites, findings identical to that seen in single sporadic fundic gland polyps. Each polyp had a single mutation, and each patient had more than one unique mutation (median = 4), indicating a multifocal origin for the polyps. No mutations were found in nonpolypoid control tissue and in polyps from the attenuated FAP patient. The patients with SFGP in this series were all between 40 and 70 years of age and had histories of acid-suppressive therapy. The fundic gland polyps were histologically and genetically identical to single sporadic fundic gland polyps and demonstrated frequent somatic activating mutations in exon 3 of the beta-catenin gene.
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PMID:Sporadic fundic gland polyposis: a clinical, histological, and molecular analysis. 1211 9

Cell polarity is a fundamental property of all cells. In higher eukaryotes, the small GTPase Cdc42, acting through a Par6-atypical protein kinase C (aPKC) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division and directed cell migration. However, little is known about what lies downstream of this complex. Here we show, through the use of primary rat astrocytes in a cell migration assay, that Par6-PKCzeta interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta) to promote polarization of the centrosome and to control the direction of cell protrusion. Cdc42-dependent phosphorylation of GSK-3beta occurs specifically at the leading edge of migrating cells, and induces the interaction of adenomatous polyposis coli (Apc) protein with the plus ends of microtubules. The association of Apc with microtubules is essential for cell polarization. We conclude that Cdc42 regulates cell polarity through the spatial regulation of GSK-3beta and Apc. This role for Apc may contribute to its tumour-suppressor activity.
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PMID:Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell polarity. 1261 Jun 28

Glycogen synthase kinase-3 (GSK-3) is an intermediary enzyme in various cellular pathways, and has been implicated in the pathophysiology and treatment of numerous diseases, including Alzheimer's disease, diabetes, and bipolar disorder. There is therefore in developing potent, selective GSK-3 inhibitors for the treatment of these devastating illnesses. A concern, however, is that the Wnt-signaling pathway-of which GSK-3 is an important intermediary molecule-has been implicated in many human cancers. It is thus of considerable importance to determine if GSK-3 inhibitors have tumorigenic potential in systems predisposed to developing tumors by virtue of mutations of the Wnt-signaling pathway. We therefore investigated the effects of a GSK-3 inhibitor, lithium, in a murine model predisposed to the formation of tumors due to activation of the Wnt pathway-the adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mouse. We found that 60 days of lithium treatment did not produce a significant increase in the number of tumors in these genetically predisposed mice. Lithium treatment resulted in a modest overall increase in the tumor size. The APC (min) mouse has previously been shown to be a robust indicator of tumorigenesis, with large increases in tumor number observed in response to a variety of agents; thus, our results suggest that lithium-and perhaps other inhibitors of GSK-3-pose a low risk for the development of cancers of the Wnt pathway. These results are consistent with the available epidemiological evidence that long-term lithium therapy does not increase cancer morbidity or mortality, but rather is associated with reduced overall mortality in bipolar disorder.
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PMID:Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice. 1277 May 14


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