Cdc42 promotes G1 progression through p70 S6 kinase-mediated induction of cyclin E expression.
The Rho family GTPase Cdc42 is recognized for its role in cellular proliferation and transformation. However, the mechanism by which it promotes cell cycle progression has remained undefined. Using an inducible expression system, we show that constitutively active Cdc42 (Cdc42V12) is sufficient by itself to induce anchorage-independent but not mitogen-independent growth in NIH3T3 cells. However, Cdc42V12 markedly accelerates activation of cyclin E-Cdk2 in response to mitogen. These effects were highly specific, as the kinetics of cyclin D-Cdk4 activation was unaltered. Cdc42V12 promotes Cdk2 activation by selectively inducing cyclin E expression without affecting other regulatory proteins such as the p27 Cdk inhibitor or Cdc25A. Furthermore, Cdc42V12 was able to activate a reporter gene driven by the cyclin E promoter in the absence of exogenous mitogen or adhesion. Cyclin E induction was sensitive to rapamycin but not inhibitors of mitogen-activated protein kinases, implicating p70 S6 kinase (p70S6k) as the relevant mediator. Consistent with this notion, wild type and constitutively active alleles of p70S6k were sufficient to activate the cyclin E promoter. In sum, these studies provide novel insights into the mechanism by which Cdc42 promotes G1 progression.
Chou
Margaret M
MM
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. mmc@mail.med.upenn.edu
Masuda-Robens
Jeffrey M
JM
Gupta
Meryl L
ML
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019927:Cyclin E / Q000235:genetics*; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*
D019927:Cyclin E; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020764:cdc42 GTP-Binding Protein