The Adenomatous polyposis (APC) tumor suppressor protein binds to b-catenin, a protein recently shown to interact with transcription factors of T cell factor (Tcf) and lymphoid enhancer factor (Lef). APC, familial predisposition to colon cancer, is caused by APC mutations. APC encodes a large multidomain protein that binds b -catenin. APC together with serine-threonine glycogen synthase kinase (GSK)-3 b, regulates the levels of free b -catenin. However, in APC mutant colon cells, degradation is disrupted, and levels of free b -catenin rise dramatically.
In colon cancer cell lines, high levels of free b -catenin drive formation of complexes with Tcf-4 or Lef-1, activating gene expression. Nuclei of APC-/- colon carcinoma cells were found to contain a stable b-catenin-Tcf complex that was constitutive active, as measured by transcription of Tcf reporter gene. The genes activated may include those stimulating cell proliferation or inhibiting apoptosis. There are at least two ways to increase levels of free b -catenin. The first is due to the mutation in APC. The second is to mutate b-catenin itself, altering an NH2-terminal domain that down-regulates b-catenin stability in cell lines. These data firmly establish APC as a negative regulator of b-catenin signaling and this regulation can be circumvented by mutations in either APC or b -catenin.
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