title: p27(Kip1) controls cytokinesis via the regulation of citron kinase activation.
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.
authors.affiliation: INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France.
authors.forename: Murielle P
authors.initials: MP
authors.lastname: Serres
authors.forename: Uta
authors.initials: U
authors.lastname: Kossatz
authors.forename: Yong
authors.initials: Y
authors.lastname: Chi
authors.forename: James M
authors.initials: JM
authors.lastname: Roberts
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besson
mesh_terms: D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology*; D048749:Cytokinesis; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D008954:Models, Biological; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases; D020742:rhoA GTP-Binding Protein