p27(Kip1) controls cytokinesis via the regulation of citron kinase activation

J Clin Invest. 2012 Mar;122(3):844-58. doi: 10.1172/JCI60376. Epub 2012 Feb 1.

Abstract

p27(Kip1) (p27) acts as a tumor suppressor by inhibiting cyclin-cyclin-dependent kinase (cyclin-CDK) activity. However, mice expressing a form of p27 that is unable to bind or inhibit cyclin-CDK complexes (p27(CK-)) have increased incidence of tumor development as compared with wild-type and p27(-/-) mice, revealing an oncogenic role for p27. Here, we identified a phenotype of multinucleation and polyploidy in p27(CK-) mice not present in p27(-/-) animals, suggesting a role for p27 in G2/M that is independent of cyclin-CDK regulation. Further analysis revealed that p27(CK-) expression caused a cytokinesis and abscission defect in mouse embryonic fibroblasts. We identified the Rho effector citron kinase (citron-K) as a p27-interacting protein in vitro and in vivo and found that p27 and citron-K colocalized at the contractile ring and mid-body during telophase and cytokinesis. Moreover, overexpression of the minimal p27-binding domain of citron-K was sufficient to rescue the phenotype caused by p27(CK-). Conversely, expression of a mutant p27(CK-) unable to bind citron-K did not induce multinucleation. Finally, by binding to citron-K, p27 prevented the interaction of citron-K with its activator RhoA. Taken together, these data suggest a role for p27 during cytokinesis via the regulation of citron-K activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p27 / physiology*
  • Cytokinesis
  • Enzyme Activation
  • Fibroblasts / cytology
  • Genotype
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Mitosis
  • Models, Biological
  • Polyploidy
  • Protein Serine-Threonine Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • citron-kinase
  • Protein Serine-Threonine Kinases
  • rhoA GTP-Binding Protein