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Oncogene. 2005 Jan 10;24(2):306-12.

Sak/Plk4 and mitotic fidelity.

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1
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, Ontario, M5G 1X5, Canada.

Abstract

Sak/Plk4 differs from other polo-like kinases in having only a single polo box, which assumes a novel dimer fold that localizes to the nucleolus, centrosomes and the cleavage furrow. Sak expression increases gradually in S through M phase, and Sak is destroyed by APC/C dependent proteolysis. Sak-deficient mouse embryos arrest at E7.5 and display an increased incidence of apoptosis and anaphase arrest. Sak(+/-) mice are haploinsufficient for tumor suppression, with spontaneous tumors developing primarily in the liver with advanced age. During liver regeneration following partial hepatectomy, Sak(+/-) hepatocytes display a delay in reaching the first M phase, multipolar spindles, disorganized tissue morphology and loss of acuity for cyclin B1 expression. Similarly, Sak(+/-) MEF cells proliferate slowly, and show a high incidence of centrosome hyper-amplification. We suggest that Sak provides feedback to cell cycle regulators, and thereby precision to the switch-like transitions of centrosome duplication and exit-from-mitosis. Sak binds to p53, and studies are underway to provide a molecular context for the Sak-p53 interaction. Animal models of haploinsufficiency and more comprehensive models of cell cycle regulation should contribute to improvements in cancer risk assessment and novel therapies.

PMID:
15640847
DOI:
10.1038/sj.onc.1208275
[Indexed for MEDLINE]
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