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Molecular and Cellular Biology, June 2007, p. 4273-4282, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.02286-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

CDK4 and CDK6 Delay Senescence by Kinase-Dependent and p16^INK4a-Independent Mechanisms ^,

Margarida Ruas, Fiona Gregory, Rebecca Jones,^¶ Robert Poolman,^|| Maria Starborg,^# Janice Rowe, Sharon Brookes, and Gordon Peters^*

Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Received 7 December 2006/ Returned for modification 28 December 2006/ Accepted 30 March 2007

Replicative senescence of human diploid fibroblasts (HDFs) is largely implemented by the cyclin-dependent kinase (CDK) inhibitors p16^INK4a and p21^CIP1. Their accumulation results in a loss of CDK2 activity, and cells arrest with the retinoblastoma protein (pRb) in its hypophosphorylated state. It has become standard practice to bypass the effects of p16^INK4a by overexpressing CDK4 or a variant form that is unable to bind to INK4 proteins. Although CDK4 and CDK6 and their INK4-insensitive variants can extend the life span of HDFs, they also cause a substantial increase in the levels of endogenous p16^INK4a. Here we show that CDK4 and CDK6 can extend the life span of HDFs that have inactivating mutations in both alleles of INK4a or in which INK4a levels are repressed, indicating that overexpression of CDK4/6 is not equivalent to ablation of p16^INK4a. However, catalytically inactive versions of these kinases are unable to extend the replicative life span, suggesting that the impact of ectopic CDK4/6 depends on their ability to phosphorylate as yet unidentified substrates rather than to sequester CDK inhibitors. Since p16^INK4a deficiency, CDK4 expression, and p53 or p21^CIP1 ablation have additive effects on replicative life span, our results underscore the idea that senescence is an integrated response to diverse signals.

Published ahead of print on 9 April 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom.

Present address: Linklaters, One Silk Street, London FC2Y 8HQ, United Kingdom.

^¶ Present address: Veterinary Laboratories Agency, Addlestone KT15 3NB, Surrey, United Kingdom.

^|| Present address: Novartis International AG, Horsham, United Kingdom.

^# Present address: Swedish Research Council-Medicine, SE-103 Stockholm, Sweden.

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