Survivin-induced Aurora-B kinase activation: A mechanism by which APC mutations contribute to increased mitoses during colon cancer development.

ABSTRACT: APC mutations initiate most colorectal cancers (CRCs), but cellular mechanisms linking this to CRC pathology are unclear. We reported that wild-type APC in the colon down-regulates the anti-apoptotic protein survivin, and APC mutation up-regulates it, explaining why most CRCs display survivin overexpression and apoptosis inhibition. However, it does not explain another hallmark of CRC pathology--increased mitotic figures and cell proliferation. Because survivin activates aurora-B kinase (ABK) in vitro, catalyzing mitosis, we hypothesized that in normal colonic crypts, APC controls ABK activity, while in neoplastic APC-mutant crypts, ABK activity is up-regulated, increasing mitosis. We quantitatively mapped intracryptal distributions of survivin, ABK, and markers of activated downstream signaling and mitosis (INCENP, phospho-histone-H3, phospho-centromere-protein-A). In normal crypts, gradients for these markers, ABK:survivin:INCENP complexes, and ABK activity were highest in the lower crypt (inverse to the APC gradient). In neoplastic crypts that harbor APC mutations, proliferating (Ki-67+) cells and cells expressing survivin, ABK, and phospho-histone-H3 were distributed farther up the crypt. Hence, as cells migrate up neoplastic crypts, transitions between cell phenotypes (eg, from stem to proliferating) appear delayed. In CRC cell lines, increasing wild-type APC, inhibiting TCF-4, or decreasing survivin expression down-regulated ABK activity. Thus, APC mutation-induced up-regulation of the survivin/ABK cascade can explain delayed crypt cell maturation, expansion of proliferative cell populations (including mitotic figures), and promotion of colon tumorigenesis.

SUBMITTER: Zhang T 

PROVIDER: S-EPMC2993266 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature