p53 mutations as a source of aberrant Beta-catenin accumulation in cancer cells
Author
Çağatay, T.
Advisor
Öztürk, M.
Date
2002Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
β-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 β-catenin are
important in regulated transcriptional activation of TCF/LEF target genes. Normally,
these levels are kept low by proteosomal degradation of â-catenin through Axin1-
and APC-dependent phosphorylation by CKI and GSK-3β. Deregulation of β-catenin
degradation results in its aberrant accumulation, often leading to cancer.
Accordingly, aberrant accumulation of β-catenin is onberved at high frequency in
many cancers. This accumulation correlates with either mutational activation of
CTNNB1 (β-catenin) or mutational inactivation of APC and Axin1 genes in some
tumors. However, there are many tumors that display β-catenin accumulation in the
absence of a mutation in these genes. Thus, there must be additional sources for
aberrant β-catenin accumulation in cancer cells. Here, we provide experimental
evidence that wild-type β-catenin accumulates in hepatocellular carcinoma (HCC)
cells in association with mutational inactivation of p53 gene. We also show that
worldwide p53 and β-catenin mutation rates are inversely correlated in HCC. These
data suggest that inactivation of p53 is an important cause of aberrant accumulation
of β−catenin in cancer cells.