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Molecular and Cellular Biology, March 2006, p. 2430-2440, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2430-2440.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphorylation of the Cyclin-Dependent Kinase Inhibitor p21Cip1 on Serine 130 Is Essential for Viral Cyclin-Mediated Bypass of a p21Cip1-Imposed G1 Arrest

Annika Järviluoma,1,{dagger} Emma S. Child,2,{dagger} Grzegorz Sarek,1 Papinya Sirimongkolkasem,2 Gordon Peters,3 Päivi M. Ojala,1,{ddagger} and David J. Mann2,{ddagger}*

Molecular Cancer Biology Program, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, FIN-00014 University of Helsinki, Finland,1 Biochemistry Building, Division of Cell and Molecular Biology, Faculty of Life Sciences, Imperial College, South Kensington, London SW7 2AZ, United Kingdom,2 London Research Institute, Cancer Research United Kingdom, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom3

Received 19 August 2005/ Returned for modification 23 September 2005/ Accepted 20 December 2005

K cyclin encoded by Kaposi's sarcoma-associated herpesvirus confers resistance to the cyclin-dependent kinase (cdk) inhibitors p16Ink4A, p21Cip1, and p27Kip1 on the associated cdk6. We have previously shown that K cyclin expression enforces S-phase entry on cells overexpressing p27Kip1 by promoting phosphorylation of p27Kip1 on threonine 187, triggering p27Kip1 down-regulation. Since p21Cip1 acts in a manner similar to that of p27Kip1, we have investigated the subversion of a p21Cip1-induced G1 arrest by K cyclin. Here, we show that p21Cip1 is associated with K cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the K cyclin/cdk6 complex, resulting in phosphorylation of p21Cip1 on serine 130. This phosphoform of p21Cip1 appeared unable to associate with cdk2 in vivo. We further demonstrate that phosphorylation on serine 130 is essential for K cyclin-mediated release of a p21Cip1-imposed G1 arrest. Moreover, we show that under physiological conditions of cell cycle arrest due to elevated levels of p21Cip1 resulting from oxidative stress, K cyclin expression enabled S-phase entry and was associated with p21Cip1 phosphorylation and partial restoration of cdk2 kinase activity. Thus, expression of the viral cyclin enables cells to subvert the cell cycle inhibitory function of p21Cip1 by promoting cdk6-dependent phosphorylation of this antiproliferative protein.

* Corresponding author. Mailing address: Biochemistry Building, Division of Cell and Molecular Biology, Faculty of Life Sciences, Imperial College, South Kensington, London SW7 2AZ, United Kingdom. Phone: 020 7594 5302. Fax: 020 7594 5207. E-mail: d.mann{at}imperial.ac.uk.

{dagger} These authors made equal contributions to this work.

{ddagger} These authors made equal contributions to this work.

Molecular and Cellular Biology, March 2006, p. 2430-2440, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2430-2440.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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