期刊
ONCOGENE
卷 23, 期 25, 页码 4444-4453出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1207587
关键词
beta-catenin degradation by p53; Axin; beta-catenin-phosphorylation
beta-Catenin, a structural component of cell-cell adhesions, is also a potent signaling molecule in the Wnt pathway activating target genes together with Lef/Tcf transcription factors. In colorectal and many other types of cancer, beta-catenin is hyperactive owing to mutations in beta-catenin, or in components regulating beta-catenin degradation. Deregulated beta-catenin can cause the activation of p53, a key tumor suppressor mutated in most cancers. Activated p53 can feed back and downregulate beta-catenin. Here we investigated the mechanisms involved in downregulation of beta-catenin by p53. We found that the p53-mediated reduction in beta-catenin involves enhanced phosphorylation of beta-catenin on key NH2-terminal serines and requires CK1 and GSK-3beta activities, both being components of the beta-catenin degradation machinery. Mutations in these NH2-terminal beta-catenin serines blocked the ability of p53 to enhance the turnover of beta-catenin. p53 also induced a shift in the distribution of the scaffold molecule Axin to a Triton X-100-soluble fraction, and led to depletion of beta-catenin from this Triton-soluble fraction. The majority of Axin and phosphorylated beta-catenin, however, colocalized in Triton X-100-insoluble punctate aggregates near the plasma membrane, and kinetics studies indicated that in the presence of p53 the movement of Axin into and out of the Triton X-100-insoluble fraction is accelerated. These results suggest that p53 induces a faster mobilization of Axin into the degradation complex thereby enhancing beta-catenin turnover as part of a protective mechanism against the development of cancer.
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