Cellular Senescence Requires CDK5 Repression of Rac1 Activity

Abstract

Cellular senescence is a tumor-suppressive process characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated β-galactosidase (SA-β-Gal). We report here a role for CDK5 in induction of senescent cytoskeletal changes. CDK5 activation is upregulated in senescing cells. The increased activity of CDK5 further reduces GTPase Rac1 activity and Pak activation. The repression of the activity of the GTPase Rac1 by CDK5 is required for expression of the senescent phenotype. CDK5 regulation of Rac1 activity is necessary for actin polymerization accompanying senescent morphology in response to expression of pRb, activated Ras, or continuous passage. Inhibition of CDK5 attenuates SA-β-Gal expression and blocks actin polymerization. These results point to a unique, nonneuronal role for CDK5 in regulation of Rac1 activity in senescence, illuminating the mechanisms underlying induction of senescence and the senescent shape change.

We thank Li-Huei Tsai and Maria Morabito for advice and critical CDK5-related reagents. We also thank Jeffery Settleman and Raffaela Sordella for advice on detecting Rac activity and plasmids. We are grateful to Yang Shi for the siRNA plasmid and instruction on constructing our siRNA plasmid of interest.

This work was supported by NIH grant AG20208 to P.W.H.