Sak/Plk4 and mitotic fidelity

Oncogene. 2005 Jan 10;24(2):306-12. doi: 10.1038/sj.onc.1208275.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chromosomal Instability / physiology
  • DNA Nucleotidyltransferases / physiology
  • Gene Dosage
  • Humans
  • Mice
  • Mitosis / physiology*
  • Neoplasms / enzymology
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Sequence Analysis, DNA

Substances

  • PLK4 protein, human
  • Plk4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • DNA Nucleotidyltransferases
  • cin recombinase