Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-Catenin is a multifunctional protein originally identified as a component of the cadherin cell-cell adhesion complex. It also binds the adenomatous polyposis coli (APC) tumour suppressor which controls beta-catenin cellular levels through its degradation. (beta-Catenin and/or APC mutations result in increased cytoplasmic Beta-catenin and nuclear translocation. The aim of the present study was to examine the expression and cellular localisation of alpha and beta-catenin, p120 and E-cadherin in a chemically-induced mouse model of colo-rectal cancer using 1,2-dimethylhydrazine (DMH). Female Balb/C mice were injected subcutaneously with a solution providing 25 mg DMH base/kg body weight for 17 weeks. Animals were killed and tumours identified in the intestine with a dissecting microscope. Formalin-fixed paraffin-embedded sections of normal and dysplastic colonic mucosa were stained by an indirect avidin-biotin immunohistochemical technique using mouse monoclonal antibodies, and membranous, cytoplasmic and nuclear cellular localisation was assessed by light microscopy. Staining distribution scored as follows: 3, > 90 % positive epithelial cells; 2, >50 % positive epithelial cells; 1, <50 % positive epithelial cells. Non-dysplastic colonic epithelial cells revealed beta-catenin expression at the membrane (33/41 scored 3),areas of cytoplasmic expression (24/41 scored 1) and no nuclear staining. Dysplastic colonic epithelium revealed increased membranous and cytoplasmic, beta-catenin immunoreactivity (39/41 and 38/41 both scored 3) with focal nuclear staining (14/41). Expression patterns for ac-catenin, p120, and E-cadherin were similar to beta-catenin with increased membranous and cytoplasmic immunoreactivity in dysplastic mucosa, although no nuclear staining was observed. Increased cytoplasmic expression and nuclear localisation of beta-catenin are consistent with a possible mutation in its gene, and this finding was in keeping with the mutational analysis of exon 3 by single-strand conformational polymorphism. Increased immunoreactivity of the other catenins also suggests further disruption in catenin regulation. In summary, alterations in the beta-catenin expression and cellular localisation in the DMH-induced tumours are similar to those seen inhuman sporadic colorectal tumours. The DMH is therefore a useful model for studying the abnormalities of the E-cadherin-catenin pathway in colorectal carcinogenesis.
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PMID:Abnormalities of the cadherin-catenin complex in chemically-induced colo-rectal carcinogenesis. 1275 72

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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PMID:Expression of beta-catenin and E-cadherin in the adenoma-carcinoma sequence of the stomach. 1292 24

Beta-catenin integrates intracellular WNT signalling and the intercellular E-cadherin-catenin adhesion system. To date, little is known about the role of beta-catenin activation and nuclear accumulation in hepatocarcinogenesis. This study has analysed beta-catenin expression patterns in human dysplastic nodules (DNs), as well as in hepatocellular carcinomas (HCCs) in comparison with proliferation, expression of WNT-1 target genes, E-cadherin, and p53. One hundred and seventy HCCs and 25 DNs were categorized according to established criteria and analysed for the expression pattern of beta-catenin. Analysis of the proliferative activity and expression of E-cadherin, cyclin D1, MMP-7, c-myc, and p53 was performed on a representative subgroup of cases. All DNs lacked nuclear beta-catenin, while 36% of all HCCs were positive, with the number of nuclear stained cells ranging from less than 1% to more than 90%. Increasing nuclear accumulation of beta-catenin correlated with reduced membranous E-cadherin expression and nuclear p53 but not with proliferation. Cyclin D1, MMP-7, and c-myc expression was detected in 54%, 26%, and 65% of HCCs, respectively, but did not correlate with nuclear beta-catenin, proliferation, or grading. Sequence analysis of the beta-catenin gene revealed no detectable mutations in DNs, but mutations in the GSK-3beta binding site were present in 14.3% of the HCCs. In conclusion, this study has demonstrated that nuclear accumulation of beta-catenin is a frequent progression event in human hepatocarcinogenesis which correlates with nuclear p53 accumulation and loss of membranous E-cadherin, but not with the expression pattern of established WNT-1 target genes. It is hypothesized that the role of beta-catenin in human HCC differs significantly from its established function in colon carcinogenesis.
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PMID:Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes. 1451 42

The present study aimed to confirm the hypothesis that the expression and phosphorylation status of the E-cadherin/catenin adhesion complex is related to cervical carcinogenesis and cervical cancer invasion, and to investigate the expression and the tyrosine phosphorylation of focal adhesion kinase (FAK) and its relation with E-cadherin/catenin adhesion complex. The expression of E-cadherin, alpha- and beta-catenin, and FAK were studied by a western blot analysis with 26 cervical carcinomas, nine normal cervices, and five carcinomas in situ of cervix. The tyrosine phosphorylation of alpha- and beta-catenin and FAK were examined by an immunoprecipitation. The expressions of alpha- and beta-catenin and E-cadherin were reduced in cervical carcinoma, and the tyrosine phosphorylation of alpha- and beta-catenin in cervical carcinoma was higher than in normal cervix and carcinoma in situ of cervix. Tyrosine phosphorylation of FAK was elevated in cervical carcinoma although the expression of FAK was not significantly different. Moreover, alpha- and beta-catenin were coimmunoprecipitated with FAK. We conclude that the loss of E-cadherin/catenin proteins and the tyrosine phosphorylation of E-cadherin/catenin are involved in cervical carcinogenesis and cancer invasion. Tyrosine phosphorylation of focal adhesion kinase is also related to the cervical cancer invasion. The E-cadherin/catenin complex and FAK may be related functionally and structurally.
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PMID:The expression and tyrosine phosphorylation of E-cadherin/catenin adhesion complex, and focal adhesion kinase in invasive cervical carcinomas. 1467 48

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of alpha, beta, and gamma-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of beta-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.
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PMID:E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. 1472 63

Although the overview above provides a partial molecular picture of the early stages of stepwise hepatocarcinogenesis. it should be emphasized that tumor and nontumor liver contain multiple changes, and that there is variability in their profile among different patients even within single studies. Variability in the number and types of genetic changes has also been observed geographically, and may be dependent upon the etiology of the tumor (viral, chemical or both). Interestingly, HBxAg inactivates tumor suppressors (such as p53 [by direct binding] and Rb [by stimulating its phosphorylation]) early in carcinogenesis that are mutated later during tumor progression. HBxAg also constitutively activates signal transduction pathways, such as those involving c-jun and ras, and activates oncogenes,such as c-nloc, that are otherwise activated by 3-catenin mutations. These findings suggest common molecular targets in hepatocarcinogenesis, despite different mechanisms of activation or inactivation. These observations need to be exploited in future drug discovery and in the development of new therapeutics. Heterogeneity in the mechanisms of tumor development, evidenced by the differences in the up- and down regulated genes reported in micro array analyses, as well as in the genetic loci that undergo mutation or LOH indifferent reports, has now been well documented. This suggests that there are multiple pathways to HCC, and that there is redundancy in the pathways that regulate cell growth and survival. These findings also reflect that,although hepatocarcinogenesis is multistep, the molecular changes that underpin histopathological changes in tumor development are likely to be different or only partially overlapping in individual tumors. Overall, the consequences of these changes suggest that the pathogenesis of HCC is accompanied by a progressive loss of differentiation, loss of normal cell adhesion, loss of the ECM, and constitutive activation of selected signal transduction pathways that promote cell growth and survival. Although mechanisms are important, attention also has to be paid to the target genes whose altered expression actually mediate the neoplastic phenotype. Other key avenues of work need to be explored. For example, it will be important to try to identify germline mutations in HBV-infected patients that are passed on to their children, resulting in the development of HCC in childhood. Clinical materials will also be important for the validation of new markers with diagnostic or prognostic potential. In this context, there is an urgent need to establish simple and low-cost tests based upon molecular changes that are hallmarks of HCC development. Identification of patients with early HCC will also significantly increase survival through its impact upon treatment. The discovery and validation of HCC markers may permit accurate staging of lesions, determine the proximity of such lesions to malignancy, and determine whether lesions with a particular genetic profile are still capable of remodeling through appropriate therapeutic intervention. The efficient reintroduction of the relevant tumor suppressors, or the inhibition of oncogene expression by siRNA, provide just some of the additional opportunities that will ultimately be useful in patient treatment. Together, these approaches will go far in reducing the very high morbidity and mortality associated with HCC.
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PMID:Early molecular and genetic determinants of primary liver malignancy. 1506 49

Smad4 is a tumour suppressor gene predominantly involved in gastrointestinal carcinogenesis. Loss of Smad4 is considered to be a genetically late step and occurs in up to 30% of metastatic colorectal carcinomas. Smad4, originally characterized as an intracellular transmitter of transforming growth factor-beta (TGF-beta) signals, is a transcriptional co-modulator capable of integrating cellular responses to multiple signalling cascades. Thus, there are many Smad4 target genes and they are presumably strongly context-dependent. It was recently shown that re-expression of Smad4 in Smad4-deficient SW480 human colon carcinoma cells restored epithelioid morphology and induced P-cadherin and E-cadherin transcription. The cadherins are key players in cell-cell adhesion connecting adjacent cells via the cadherin-catenin adhesion complex. Frequent loss of E-cadherin expression in human cancers has been a long-standing observation, but the underlying mechanisms are not yet fully understood. To assess the role of Smad4 in E-cadherin regulation in colorectal carcinogenesis further, the present study has analysed Smad4 and E-cadherin RNA and protein expression in colorectal carcinoma cell lines and in 51 late-stage colorectal carcinomas. In primary tumours, loss of Smad4 expression correlated highly significantly with loss of E-cadherin expression, thus providing further evidence for involvement of the tumour suppressor Smad4 in the control of expression of the tumour and invasion suppressor E-cadherin.
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PMID:Loss of Smad4 correlates with loss of the invasion suppressor E-cadherin in advanced colorectal carcinomas. 1509 68

Preneoplastic or precancerous lesions in the large bowel have attracted much attention, and aberrant crypt foci (ACF) topographically identified in the colonic mucosa have found application as effective endpoint lesions for detection of chemopreventive agents as well as carcinogenic risk assessment of environmental agents. While many ACF are regarded as hyperplastic in nature, lacking the potential lesion to give rise to neoplasia, a subset termed dysplastic ACF, or newly identified "mucin depleted foci (MDF)", and "beta-catenin accumulated crypts (BCAC)" are suggested to be more reliably related to colorectal tumorigenesis in rodents. ACF and MDF can be visualized on the surface of colonic mucosa and BCAC were recently identified by our laboratory in rodents en face in cross sections. In particular, BCAC having a similar pattern of beta-catenin gene mutation to that observed in colonic carcinomas appear to be direct precursors. This review provides a review and discussion of the relevant literature relative to early lesions in colorectal carcinogenesis.
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PMID:Significance and role of early-lesions in experimental colorectal carcinogenesis. 1590 5

Beta-catenin-dependent or canonical Wnt signals are fundamental in animal development and tumor progression. Using Xenopus laevis, we report that the BTB/POZ zinc finger family member Kaiso directly represses canonical Wnt gene targets (Siamois, c-Fos, Cyclin-D1, and c-Myc) in conjunction with TCF/LEF (TCF). Analogous to beta-catenin relief of TCF repressive activity, we show that p120-catenin relieves Kaiso-mediated repression of Siamois. Furthermore, Kaiso and TCF coassociate, and combined Kaiso and TCF derepression results in pronounced Siamois expression and increased beta-catenin coprecipitation with the Siamois promoter. The functional interdependency is underlined by Kaiso suppression of beta-catenin-induced axis duplication and by TCF-3 rescue of Kaiso depletion phenotypes. These studies point to convergence of parallel p120-catenin/Kaiso and beta-catenin/TCF signaling pathways to regulate gene expression in vertebrate development and possibly carcinogenesis.
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PMID:Kaiso/p120-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets. 1593 66

Not only genomic mutations but also abnormal epigenetic methylation can significantly contribute to gene silencing and carcinogenesis. Methylation is particularly often observed in the CpG islands of the promoter regions in the regulatory genes. However, there are considerable differences in the incidence of methylation e.g. in the tumor suppressor genes, so that aberrant methylation of p16(INK4a) is relatively frequently observed in tumors, p27(Kip1) methylation is rare, and the incidence of E-cadherin methylation occurs at an intermediate rate. Although true genomic defects are generally much less common than methylation, parallel tendencies for both are often observed, probably reflecting the different levels of evolutionary advantage for tumor cells from inactivation of different genes. This also suggests that loss of p27 expression could be more a consequence of carcinogenesis, while lost p16 expression is a true oncogenic event. Due to the role of p27 in maintaining cellular quiescence, however, loss of its expression can still be a useful partial indicator of the aggressiveness of cancer. Loss of E-cadherin or its catenin partners of cellular adhesion will result in increasing invasiveness and metastatic potential of neoplastic cells but, because of several alternative routes to the same effect, incidence of lost expression for one component gene like E-cadherin does not need to be very high. Similarly, there must be a relatively high number of genes with modest or low incidence of aberrant silencing by methylation, to reflect multiple alternatives for the multistep process of carcinogenesis. Nevertheless, methylation of different genes also shows characteristic differences between different cancer and tumor types, and the epigenetic methylation patterns therefore have considerable diagnostic and prognostic potential. Realising this potential requires efficient methods for profiling the status of methylation. Such profiling methods have only recently become available and are still under relatively rapid development.
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PMID:Methylation of tumor suppressor genes p16(INK4a), p27(Kip1) and E-cadherin in carcinogenesis. 1597 59


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