Sak/Plk4 and mitotic fidelity.
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.
Swallow
Carol J
CJ
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave. R988, Toronto, Ontario, M5G 1X5, Canada.
Ko
Michael A
MA
Siddiqui
Najeeb U
NU
Hudson
John W
JW
Dennis
James W
JW
D000818:Animals; D043171:Chromosomal Instability / Q000502:physiology; D004254:DNA Nucleotidyltransferases / Q000502:physiology; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017422:Sequence Analysis, DNA
C490219:PLK4 protein, human; C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004254:DNA Nucleotidyltransferases; C039930:cin recombinase