Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in APC or in beta-catenin, which are common in colon cancer, lead to constitutive activation of beta-catenin/Tcf-dependent signaling. alpha-Catenin is also found in some colon cancer cell nuclei, and loss of its expression correlates with increased beta-catenin/Tcf transcriptional activity. Moreover, targeted expression of alpha-catenin in the nucleus inhibits beta-catenin/Tcf-dependent transcription. Thus, an understanding of the regulation of alpha-catenin localization could provide insight into the control of beta-catenin signaling. While the beta-catenin/Tcf complex can promote nuclear import of alpha-catenin, the mechanism for its nuclear export is not known. We found that leptomycin B (LMB) inhibited nuclear export of GFP-alpha-catenin in HCT116 colon cancer cells, suggesting that alpha-catenin localization is regulated by CRM-1-dependent nuclear export. We identified two putative nuclear export signals in a domain of alpha-catenin that overlaps with the beta-catenin binding domain. Using a nuclear export assay, we determined that one of these (NES1) is a weak LMB-insensitive NES, whereas the other (NES2) is strong and LMB-sensitive. Mutations in either NES reduced nuclear export of alpha-catenin in HCT116 cells. In addition, mutations in NES1, but not NES2, reduced binding of alpha-catenin to beta-catenin and impaired the ability of alpha-catenin to repress beta-catenin/Tcf-dependent transcription. Therefore, NES1 is required both for repression of beta-catenin signaling and for nuclear export, while NES2 is required only for nuclear export.
 ...
PMID:Nuclear export of alpha-catenin: overlap between nuclear export signal sequences and the beta-catenin binding site. 1505 98

The E-cadherin/catenin complex is a prime mediator of cell-cell adhesion. APC mutations can result in loss of beta-catenin downregulation and an accumulation of beta-catenin in the cell. Beta-CATENIN mutations can have a similar effect. The aim of this study was to investigate the effect of beta-CATENIN and APC mutations on the expression and assembly of the E-cadherin/catenin complex. Five colorectal carcinoma cell lines with different APC and beta-CATENIN gene status were selected and mutations were confirmed. The expression of members of the E-cadherin/catenin complex was studied by immunohistochemistry and Western blotting. Complex assembly was investigated by immunoprecipitation. It is shown that E-cadherin and catenins are expressed in colorectal carcinoma cell lines with the predominant complex assembly being E-cadherin/beta-catenin/alpha-catenin. The subcellular distribution of the proteins is influenced by cell-cell contact, resulting in membranous localization. The expression and assembly of the E-cadherin/catenin complex does not appear to be affected by the presence of APC and or beta-CATENIN mutations.
 ...
PMID:Characterization of the E-cadherin/catenin complex in colorectal carcinoma cell lines. 1515 12

A loss-of-function mutation in the APC gene initiates colorectal carcinogenesis. Although the molecular mechanism of tumor initiation is complex, several modifier genes have been identified using mouse models, including the ApcMin mouse. Among the familial adenomatous polyposis mouse lines carrying a truncation mutation at codon 580 in Apc (Apc580D), one line (line19-Apc(580D/+)) showed a remarkably reduced incidence of intestinal adenomas (<5% compared with other lines). Extensive genetic analysis identified a deletion in the alpha-catenin (Ctnna1) gene as the cause of this suppression. Notably, the suppression only occurred when the Ctnna1 deletion was in cis-configuration with the Apc580D mutation. In all adenomas generated in line19-Apc(580D/+), somatic recombination between the Apc and Ctnna1 loci retained the wild-type Ctnna1 allele. These data strongly indicate that simultaneous inactivation of alpha-catenin and Apc during tumor initiation suppresses adenoma formation in line19-Apc(580D/+), suggesting that alpha-catenin plays an essential role in the initiation of intestinal adenomas. Although accumulating evidence obtained from human colon tumors with invasive or metastatic potential has established a tumor-suppressive role for alpha-catenin in late-stage tumorigenesis, the role of alpha-catenin in the initiation of intestinal tumorigenesis is not well documented, especially compared with that of beta-catenin. A mouse model used in this study focused on the early stage of tumor initiation and clearly indicated an essential role for alpha-catenin. Thus, alpha-catenin has dual roles in intestinal tumorigenesis, a supporting role in tumor initiation, and a suppressive role in tumor progression.
 ...
PMID:Alpha-catenin is essential in intestinal adenoma formation. 1798 30


<< Previous 1 2 3