Alexander Kamilah, Yang Hai-Su, Hinds Philip W
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mol Cell Biol. 2004 Apr;24(7):2808-19. doi: 10.1128/MCB.24.7.2808-2819.2004.
Cellular senescence is a tumor-suppressive process characterized by an irreversible cell cycle exit, a unique morphology, and expression of senescence-associated beta-galactosidase (SA-beta-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-beta-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.
细胞衰老 是一种肿瘤抑制过程，其特征为不可逆的细胞周期停滞、独特的形态以及衰老相关β-半乳糖苷酶（SA-β-Gal）的表达。我们在此报告CDK5在诱导衰老细胞骨架变化中的作用。CDK5激活在衰老细胞中上调。CDK5活性增加进一步降低GTP酶Rac1活性和Pak激活。CDK5对GTP酶Rac1活性的抑制是衰老表型表达所必需的。CDK5对Rac1活性的调节对于响应pRb表达、激活的Ras或连续传代时伴随衰老形态的肌动蛋白聚合是必要的。抑制CDK5可减弱SA-β-Gal表达并阻断肌动蛋白聚合。这些结果表明CDK5在衰老过程中对Rac1活性的调节具有独特的非神经元作用，阐明了衰老诱导和衰老形状变化的潜在机制。
