Survivin-Induced Aurora-B Kinase Activation A Mechanism by Which APC Mutations Contribute to Increased Mitoses during Colon Cancer Development

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 Be cause 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 be tween 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 (Am J Pathol 2010 177 2816-2826, DOI 10 2353/ajpath 2010 100047)