No exit strategy? No problem: APC inhibits β-catenin inside the nucleus
- Yue Xiong and
- Yojiro Kotake1
- Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
This extract was created in the absence of an abstract.
The tumor suppressor adenomatous polyposis coli, APC, plays a critical role in regulating the growth, proliferation, and differentiation of cells in different tissues, including the colon. Heterozygous germline mutations in the APC gene predispose individuals to the development of colon cancer at a young age, and somatic mutations inactivating both APC alleles are associated with the majority of nonhereditary colon cancers. The best-established function of the APC protein is to negatively regulate the Wnt signaling pathway by antagonizing the function of β-catenin, a dedicated transcriptional coactivator of Wnt target genes in the nucleus. The current model for the regulation of β-catenin by APC rests on the ability of APC to bind with β-catenin in the nucleus and export it out into the cytoplasm for targeted ubiquitination and proteasomal degradation. A report in the previous issue of Genes & Development Sierra et al. (2006) points to a separate mechanism for APC regulation of β-catenin—repressing it on the chromatin.
The Wnt signaling pathway
The Wnt gene family, whose name is derived from the Drosophila segment polarity gene Wingless and the murine proto-oncogene Int-1, encode secreted signaling proteins characterized by a cysteine-rich pattern instead of a discrete functional domain. The family is highly conserved throughout the animal kingdom, with five members in Caenorhabditis elegans, seven in flies, and 19 in mammals. The Wnt signaling pathway controls various cellular and biological processes, ranging from cell adhesion (Harris and Peifer 2005), stem cell self-renewal (Reya and Clevers 2005), and cancer development (Polakis 2000), to the differentiation of multiple cell lineages and development of various tissues (Cadigan and Nusse 1997). The critical importance of the Wnt signaling pathway in diverse processes was evident from early genetic and pathological studies. Loss of Drosophila Wingless gene function caused numerous developmental defects in embryonic and larval pattern formation and synaptic differentiation …
