Parthenolide repressed endometriosis induced surgically in rats: Role of PTEN/PI3Kinase/AKT/GSK-3β/β-catenin signaling in inhibition of epithelial mesenchymal transition
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beta-Catenin and gamma-catenin (plakoglobin), vertebrate homologs of Drosophila armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein or beta-catenin's amino terminus stabilize beta-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Though beta- and gamma-catenin have analogous structures and functions and like binding to APC, evidence that gamma-catenin has an important role in cancer has been lacking. We report here that APC regulates both beta- and gamma-catenin and gamma-catenin functions as an oncogene. In contrast to beta-catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of gamma-catenin had similar transforming activity. gamma-Catenin's transforming activity, like beta-catenin's, was dependent on Tcf/Lef function. However, in contrast to beta-catenin, gamma-catenin strongly activated c-Myc expression and c-Myc function was crucial for gamma-catenin transformation. Our findings suggest APC mutations alter regulation of both beta- and gamma-catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of beta-catenin mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both beta- and gamma-catenin. Furthermore, the data imply beta- and gamma-catenin may have distinct roles in Wnt signaling and cancer via differential effects on downstream target genes.
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Adenomatous polyposis coli
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beta-catenin plays an important role in the Wnt signaling pathway and the E-cadherin-catenin complex plays a critical role in the maintenance of normal tissue architecture. An alteration of any of the components of the E-cadherin-catenin complex is believed to result in the loss of cell-cell adhesion and to contribute to carcinogenesis. In order to evaluate such alterations in the gastric adenoma-carcinoma sequence, the abnormal expression of beta-catenin and E-cadherin and the mutations of beta-catenin exon 3 were studied. In the case of beta-catenin, nuclear immunoreactivity was noted in 17 (11.3%) out of 150 adenomas and 19 (17.1%) out of 111 carcinomas (p = 0.18). Among 51 gastric adenomas, no mutations were detected by direct sequencing analysis. The loss of membranous expression of both beta-catenin and E-cadherin linearly increased with tumor progression, however, beta-catenin loss was more frequent than E-cadherin. Our results show that the nuclear expression and membranous loss of beta-catenin without exon 3 mutation is relatively frequent in gastric adenomas. These suggest that alteration of other genes is primarily responsible for the nuclear translocation of beta-catenin in gastric adenomas.
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The Wnt-1 proto-oncogene induces the accumulation of beta-catenin and plakoglobin, two related proteins that associate with and functionally modulate the cadherin cell adhesion proteins. Here we have investigated the effects of Wnt-1 expression on the tumor suppressor protein APC, which also associates with catenins. Expression of Wnt-1 in two different cell lines greatly increased the stability of APC-catenin complexes. The steady-state levels of both catenins and APC were elevated by Wnt-1, and the half-lives of both beta-catenin and plakoglobin associated with APC were also markedly increased. The stabilization of catenins by Wnt-1 was primarily the result of a selective increase in the amount of uncomplexed, monomeric beta-catenin and plakoglobin, detected both by affinity precipitation and size-exclusion chromatography of cell extracts. Exogenous expression of beta-catenin was possible in cells already responding to Wnt-1 but not in the parental cells, suggesting that Wnt-1 inhibits an essential regulatory mechanism for beta-catenin turnover. APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1. Thus, the Wnt-1 signal transduction pathway leads to the accumulation of monomeric catenins and stabilization of catenin complex formation with both APC and cadherins.
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Pulmonary sclerosing haemangioma (PSH) is an uncommon tumour that is composed of glandular/papillary lining cells and polygonal cells. The biological behaviour of this tumour has been investigated; however, the molecular pathogenesis of PSH remains unknown.To characterise the role of the Wnt/beta-catenin pathway in the genesis of PSH.37 PSH samples were investigated immunohistochemically for detection of the beta-catenin protein and direct sequencing of exon 3 of the beta-catenin gene.Nuclear expression of beta-catenin was found in the lining component of 23 tumours (62%) and in the polygonal component of 11 tumours (30%). The expression of beta-catenin was stronger in the lining component, but weaker in the polygonal component. Interestingly, all the tumours with expression of beta-catenin in the polygonal component also expressed beta-catenin in the lining component. However, mutation of exon 3 of the beta-catenin gene was detected in only one tumour that expressed nuclear beta-catenin in lining and polygonal components.The Wnt/beta-catenin pathway is involved in the genesis of PSH, but mutation of exon 3 of the beta-catenin gene rarely contributes to the activation of the Wnt/beta-catenin pathway in PSH.
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Read the full review for this Faculty Opinions recommended article: Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis.
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Abstract Nuclear β‐catenin affects the developmental process and progression of tumors. However, the precise mechanism for the nuclear export of β‐catenin is not completely understood. We found that β‐catenin can bind directly to CRM1 through its central armadillo (ARM) repeats region, independently of the adenomatous polyposis coli (APC) protein. CRM1 overexpression transports nuclear β‐catenin into the cytoplasm and decreases LEF‐1/β‐catenin‐dependent transcriptional activity, which is also affected by the co‐overexpression of E‐cadherin. CRM1 competed with E‐cadherin and LEF‐1 for binding to β‐catenin. β‐catenin could interact directly with APC through its essential sequences between amino acids 342 and 350. The site‐directed β‐catenin mutant (NES2 − ), which could interact with CRM1, but not with APC, still retained its ability to export from the nucleus and its transactivational activity. This suggests that CRM1 can function as an efficient nuclear exporter for β‐catenin independently of APC. These results strongly suggest that the CRM1‐mediated pathway is involved in the efficient transport of nuclear β‐catenin in the nucleus of cells.
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Nuclear export signal
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E-cadherin is a calcium-dependant cell-cell adhesion molecule that plays a key role in the maintenance of tissue integrity. Its function is mediated by a group of cytoplasmic proteins termed catenins. Loss or dysfunction of E-cadherin has been implicated in the gain of tumour cell invasive potential, a crucial requirement of metastasising tumour cells. This study examined the expression of E-cadherin, alpha-, beta- and gamma-catenin in a series of colorectal cancer patients. Western blotting and immunohistochemical staining demonstrated the frequent loss of E-cadherin and alpha-catenin in 50% and 41% of these samples respectively. Increased levels of beta-catenin were seen in 41% of cases; no significant change in gamma-catenin was observed. We conclude that alterations in the levels of both catenins and E-cadherin within tumour tissue may lead to increased cancer cell invasive potential and thus could play a role in the initiation of the early stages of metastatic spread.
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