p53 mutation as a source of aberrant β-catenin accumulation in cancer cells

Abstract

b-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 b-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of bcatenin through Axin1-and APC-dependent phosphorylation by CKI and GSK-3b. Deregulation of b-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of b-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (b-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display b-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant bcatenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type b-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and b-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of b-catenin in cancer cells.

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Firstly, p53-induced SIAH expression may participate in the phosphorylation-independent degradation of bcatenin; however, its relevance in HCCs has not been shown until now (Matsuzawa et al, 1998;Liu et al, 2001a;Matsuzawa and Reed, 2001). Secondly, accumulation of b-catenin wt correlates positively with a high exposure of aflatoxin B1 (Devereux et al, 2001) and with mutational inactivation of p53 in HCCs (Cagatay and Ozturk, 2002); however, a direct connection between all three parameters (aflatoxin intoxication, aflatoxin-specific G/T mutation in p53 mut/249 and bcatenin enrichment) has not been shown so far.…”

Mdm2 Snp309 G allele displays high frequency and inverse correlation with somatic P53 mutations in hepatocellular carcinoma

“…Characteristics of these tumors and methods for DNA isolation have been described previously [13,14]. SNP309 (T/G) of MDM2 were genotyped using PCR amplification of the first intron of the MDM2, followed by MspA1I (Promega) digestion as described elsewhere [15].…”

Coiled-coil domain containing 85B suppresses the β-catenin activity in a p53-dependent manner

“…CCDC85B suppresses TCF/LEF-dependent b-catenin activity It has been reported that activated p53 downregulates b-catenin activity (Cagatay and Ozturk, 2002;Prange et al, 2003). These data prompted us to examine whether CCDC85B production by p53 affects the ability of b-catenin to activate the TCF/LEF-regulated promoter in cells.…”

“…It has been reported that aberrant accumulation of b-catenin in cancers often associated with inactivation of p53 (Sadot et al, 2001;Cagatay and Ozturk, 2002). In this regard, p53-inducible gene PTEN (Stambolic et al, 2001) or Siah-1L (Matsuzawa and Reed, 2001;Iwai et al, 2004) reduces cellular levels of b-catenin.…”

“…Phosphorylated b-catenin is a target for proteasomal degradation. On the other hand, it has been reported that mutations in p53 induce aberrant accumulation of b-catenin in various human cancers and human cell lines without dysfunction of GSK3b-mediated degradation system (Cagatay and Ozturk, 2002;Prange et al, 2003;Harris and Levine, 2005). Moreover, mutation rates of p53 and b-catenin gene are inversely correlated in patients with hepatocellular carcinoma (Cagatay and Ozturk, 2002).…”