Details

Autor(en) / Beteiligte

• Swallow, Carol J
• Ko, Michael A
• Siddiqui, Najeeb U
• Hudson, John W
• Dennis, James W

Titel

Sak Plk4 and mitotic fidelity

Ist Teil von

• Oncogene, 2005-01, Vol.24 (2), p.306-312

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2005

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.