UNIPROT:B0FTZ7 - FACTA Search

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Query: UNIPROT:B0FTZ7 (catenin)
18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of the beta-catenin gene (CTNNB1) have recently been implicated in the initiation of some colon carcinomas and melanomas. In these tumors, beta-catenin abnormally accumulates in the cell nuclei. In an ongoing immunohistochemical study of the cadherin-catenin complex protein expression in ovarian carcinomas, we observed beta-catenin in tumor cell nuclei in some cases; this prompted us to study whether or not this abnormal immunostaining pattern was due to mutation in the beta-catenin gene itself. This study examines beta-catenin immunohistochemical expression in 40 stage I and II ovarian borderline tumors and carcinomas of the most common histological types. Membrane expression was heterogeneous in all 40 cases. However, the cytoplasm and nucleus of five (one borderline tumor and four carcinomas) of the six endometrioid lesions contained beta-catenin expression. PCR and sequencing analyses of a 200-bp fragment of exon 3 of the CTNNB1 gene, encompassing the sequence for glycogen synthetase kinase-3beta phosphorylation, were performed in 11 tumors. Heterozygous substitution mutations at codon 37 in two cases (S37F and S37C) and at codon 41 in one case (T41A) were found in three endometrioid lesions (one borderline tumor and two carcinomas) with abnormal beta-catenin expression. Three endometrioid carcinomas and five tumors of other histological types analyzed showed normal DNA sequences. These results implicate beta-catenin gene mutations in ovarian malignant transformation with a characteristic phenotype: endometrioid ovarian carcinoma.
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PMID:Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. 953 26

beta-Catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor- and lymphoid enhancer factor-regulated gene transcription. The level of beta-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation sites of the beta-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of beta-catenin and constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes, a mechanism occurring in many cancers. Melanoma cell lines may harbor beta-catenin mutations; in vivo, however, cellular accumulation of beta-catenin is rarely caused by CTNNB1 mutations. In our study, 43 primary cutaneous melanoma and 30 metastases were screened for CTNNB1 exon 3 mutations by using a denaturing gradient gel electrophoresis technique and sequencing. beta-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of beta-catenin in these cases. Cellular expression of beta-catenin was evaluated by immunohistochemistry and by reverse polymerase chain reaction (RT-PCR) in 80 and 70 cases, respectively. Immunohistochemistry revealed a significant loss of membranous beta-catenin staining between the primary and metastatic melanomas as well as between radial and vertical growth phase. RT-PCR showed a significant inverse correlation between the amount of RNA and the proportion of cells with membranous expression of beta-catenin (P =.0015); no correlation existed between the amount of RNA and the number of cells with nuclear or cytoplasmic expression of beta-catenin. In conclusion, nuclear expression of beta-catenin is seen in cutaneous melanoma but, in contrast to the case of many other cancers, does not correlate with tumor stage or mutation status. A combination of immunohistochemistry and RT-PCR showed that down-regulation of membranous beta-catenin was associated with an increased amount of beta-catenin RNA in primary or metastatic melanoma. Our results suggest that posttranslational events, rather than CTNNB1 mutations, are responsible for the altered distribution of beta-catenin in cutaneous melanoma.
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PMID:Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations. 1195 Sep 21

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

DKK1 protein belongs to a family of inhibitors of the Wnt/beta1-catenin signaling pathway. Sporadic mutations affecting almost each major player of the Wnt/beta1-catenin pathway have been described in a variety of human carcinomas. DKK1 translation can be induced by p53, thereby linking TP53 and Wnt/beta1-catenin signaling pathways. These findings raise questions in regard to human gliomas, which similar to carcinomas carry a high rate of mutations in TP53. To analyze DKK1 for its role in initiation or progression, we screened a series of 73 brain tumors for structural alterations in the entire coding sequence by single-strand conformation polymorphism and direct sequencing. While several sequence variants were detected, there were no obvious mutations affecting DKK1. Further, we analyzed the prevalence of mRNA from TP53, DKK1 and CTNNB1 and of p53 and beta1-catenin protein in a series of human gliomas with and without mutations in TP53. Transcription and expression of CTNNB1/beta1-catenin and DKK1 proved to be independent of TP53/p53. These data support in vivo function of DKK1, independent of p53, in human gliomas with no major impact on their pathogenesis.
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PMID:Mutation analysis of DKK1 and in vivo evidence of predominant p53-independent DKK1 function in gliomas. 1566 88

Members of the catenin family of proteins are thought to play a major role in the folding and lamination of the cerebral cortex. We have used in situ hybridization to determine the cellular expression patterns of four members of this family, Alpha-E-, Alpha-N-, Beta-, and Gamma-catenins (CTNNA1, CTNNA2, CTNNB1, and JUP respectively) in the adult primate dorsolateral prefrontal cortex (DLPFC) and hippocampus. CTNNA2, CTNNB1, and JUP mRNAs were detected in all layers of the DLPFC and in all neuronal subregions of the hippocampal formation, however CTNNA1 mRNA, coding for an 'epithelial' specific catenin, was not detected in any region of the cortex or hippocampus. CTNNA2, a 'neuronal-specific' catenin, and CTNNB1 mRNAs were abundant in both DLPFC and hippocampus, with a distinct neuronal localization. CTNNA2 mRNA was concentrated in both granular/stellate cells and large pyramidal cell bodies, while CTNNB1 expression was more strongly associated with granular cell bodies throughout the DLPFC, with expression in pyramidal cells confined mainly to cortical Layers III and VI. CTNNA2 and CTNNB1 mRNAs were also abundant in the granule cells of the dentate gyrus and pyramidal cells of Ammon's horn, apparently co-expressed in the same neurons. JUP mRNA was rather diffusely localized in the DLPFC without the distinct laminar patterns seen for CTNNA2 and CTNNB1 but was distinctly localized in the granule cells of the dentate gyrus and pyramidal cells of Ammon's horn. These studies demonstrate a distinct neuronal pattern of gene expression for catenin family members in primate brain structures characterized by high degrees of folding and strong lamination. The high level expression of these transcripts supports the notion of a major role for catenins even in the adult brain. Such an understanding is also important in view of the multiple interactions that catenins have with many other proteins in the adult and ageing brain. This may also have implications for understanding the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, as well as emerging neuronal stem cell therapies.
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PMID:Expression of Catenin family members CTNNA1, CTNNA2, CTNNB1 and JUP in the primate prefrontal cortex and hippocampus. 1585 85

Diagnosis of synchronous endometrioid carcinomas of the uterine corpus and ovary as either separate independent primary or as metastatic tumors requires careful consideration of a number of gross and histological features. Although such assessment is often sufficient, recent evidence has suggested that molecular analysis may facilitate the diagnosis in problematic cases. Furthermore, as independent synchronous tumors limited to the uterus and ovary are generally associated with favorable outcome, determination of genetic alterations associated with this group of neoplasms may indicate molecular markers of less aggressive behavior. We examined 12 cases of synchronous carcinomas of the uterus and ovary, correlating conventional gross and histological parameters with molecular genetic alterations common to single endometrioid carcinomas occurring in these sites. We identified a frequency of molecular alterations in both independent and metastatic tumors, including microsatellite instability (uterine tumors, 50% and 67%, respectively; ovarian tumors, 33% and 67%) and PTEN mutations (uterine tumors, 38% and 100%; ovarian tumors, 33% and 83%) that is higher than that observed in single sporadic tumors. Loss of heterozygosity for chromosome 17p and 10q was also frequently observed. Nuclear immunoreactivities for beta -catenin and CTNNB1 mutations were restricted to independent uterine and ovarian tumors and were absent in all of the metastatic tumors, providing direct evidence for a divergence of molecular oncogenetic mechanisms in the subset of synchronous endometrioid carcinomas. Furthermore, our data show that molecular genetic classification of synchronous independent versus metastatic tumors based on beta -catenin expression/mutation correlates with clinical outcome.
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PMID:Synchronous endometrioid carcinomas of the uterine corpus and ovary: alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis. 1602 66

The WNT/beta-catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/beta-catenin pathway in these tumors have yet to be identified. To compare gene expression profiles of Wilms tumors with and without mutations of CTNNB1, we used 11.5-k cDNA microarrays. Most of the tumors (86%) had received preoperative chemotherapy as mandated by the European SIOP protocol. The comparison between Wilms tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms tumors. Among these, PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. This overexpression may be a negative feedback mechanism in tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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PMID:Target genes of the WNT/beta-catenin pathway in Wilms tumors. 1657 72

WNTs (Wingless-type MMTV integration site family member) are involved in critical developmental and growth processes in animals. These studies investigated WNT pathways in the ovine uterus and conceptus during the periimplantation period of pregnancy. WNT2 and WNT2B mRNAs were detected in endometrial stroma. WNT5A and WNT5B mRNAs were most abundant in the stroma and less so in the luminal epithelium, whereas WNT11 mRNA was detected primarily in the glands. WNT7A mRNA was present in the luminal epithelium on d 10, absent on d 12 and 14, and increased between d 16 and 20. Only WNT2, WNT2B, and WNT4 were detected in conceptus trophectoderm. FZD6/8 (frizzled receptor) and GSK3B (glycogen synthase kinase 3beta) mRNAs were detected primarily in endometrial epithelia and conceptus trophectoderm, whereas the LRP5/6 (low-density lipoprotein receptor-related proteins 5 and 6) coreceptor was present in all endometrial cells and the trophectoderm. DKK1 (Dickkopf), a WNT signaling inhibitor, increased in the endometrium from d 16-20. CTNNB1 [catenin (cadherin associated protein) beta1] and CDH1 (E-cadherin) mRNAs were most abundant in the endometrial epithelia and trophectoderm. LEF1 (lymphoid enhancer-binding factor 1) mRNA was expressed primarily in uterine epithelia, whereas TCF7L2 [(transcription factor 7-like 2 (T-cell specific, HMG-box)] was primarily in the conceptus. CTNNB1 and TCF7L2 proteins were both abundant in the nuclei of trophoblast giant binucleate cells. WNT7A stimulated a TCF/LEF-luciferase reporter activity in ovine trophectoderm cells that was inhibited by dominant-negative TCF and Sfrp2 (secreted FZD-related protein 2). WNT7A increased trophectoderm cell proliferation as well as MSX2 (msh homeobox 2) and MYC (myelocytomatosis oncogene) mRNA levels. Wnt5a increased trophectoderm cell migration in a Rho kinase-dependent manner. These results support the hypotheses that canonical and noncanonical WNT signaling pathways are conserved regulators of conceptus-endometrial interactions in mammals and regulate periimplantation ovine conceptus development.
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PMID:WNTs in the ovine uterus: potential regulation of periimplantation ovine conceptus development. 1743 Oct 4

(1) This study investigated the functional genomics of glucocorticoid and opioid receptor stimulation in cellular adaptations using a cultured neuronal cell model. (2) Human SH-SY5Y neuroblastoma cells grown in hormone-depleted serum were treated for 2-days with the glucocorticoid receptor-II agonist dexamethasone (30 nM); the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate (DAMGO; 1 nM); or dexamethasone (30 nM) plus DAMGO (1 nM). RNA was extracted; purified, reverse transcribed, and labeled cDNA was hybridized to a 10,000-oliogonucleotide-array human gene chip. Gene expression changes that were significantly different between treatment groups and were of interest due to biological function were verified by real-time reverse transcription polymerase chain reaction (RT-PCR). Five relevant genes were identified for which the combination of dexamethasone plus DAMGO, but neither one alone, significantly up-regulated gene expression (ANOVA, P < 0.05). (3) Proteins coded by the identified genes: FRS2 (fibroblast growth factor receptor substrate-2; CTNNB1 (beta1-catenin); PRCP (prolyl-carboxypeptidase); MPHOSPH9 (M-phase phosphoprotein 9); and ZFP95 (zinc finger protein 95) serve important neuronal functions in signal transduction, synapse formation, neuronal growth and development, or transcription regulation. Neither opioid, glucocorticoid nor combined treatments significantly altered the cell growth rate determined by cell counts and protein. (4) We conclude that sustained mu-opioid receptor stimulation accompanied by glucocorticoids can synergistically regulate genes that influence neuronal function. Future studies are warranted to determine if combined influences of glucocorticoid fluctuations and opioid receptor stimulation in vivo can orchestrate exagerated neuroadaptation to reinforcing drugs under chronic mild stress conditions.
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PMID:Glucocorticoids plus opioids up-regulate genes that influence neuronal function. 1755 24

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