Article
- The EMBO Journal (1999) 18, 644 - 653
- doi:10.1093/emboj/18.3.644
Degradation of p27Kip cdk inhibitor triggered by Kaposi's sarcoma virus cyclin–cdk6 complex
Mark Ellis1, Yat Peng Chew1, Lynn Fallis2, Steffen Freddersdorf2,3, Chris Boshoff1, Robin A. Weiss1, Xin Lu2 and Sibylle Mittnacht1
- Institute of Cancer Research, Chester Beatty Laboratory, London, UK
- Ludwig Institute of Cancer Research, St Mary's Branch, London, UK
- Present address: Biozentrum, University of Basel, Department of Biochemistry, Basel, Switzerland
Correspondence to:
Sibylle Mittnacht, E-mail: sibylle@icr.ac.uk
Received 21 May 1998; Accepted 9 December 1998; Revised 11 November 1998
Abstract
The Kaposi's sarcoma-associated human herpesvirus 8 (KSHV/HHV8) encodes a protein similar to cellular cyclins. This cyclin is most closely related to cellular D-type cyclins, but biochemically it behaves atypically in various respects. Complexes formed between the viral cyclin and the cyclin-dependent kinase subunit, cdk6, can phosphorylate a wider range of substrates and are resistant to cdk inhibitory proteins. We show here that the KSHV-cyclin–cdk6 complex phosphorylates p27Kip on a C-terminal threonine that is implicated in destabilization of this cdk inhibitor. Expression of the viral cyclin in tissue culture cells overcomes a cell cycle block by p27Kip. However, full cell-cycle transit of these cells appears to depend on C-terminal phosphorylation of p27Kip and seems to involve transactivation of other cellular cyclin-dependent kinases. A p27Kip-phosphorylating cdk6 complex exists in cell lines derived from primary effusion lymphoma and in Kaposi's sarcoma, this indicating that virally induced p27Kip degradation may occur in KSHV-associated tumours.
Keywords:
- cyclin,
- KSHV,
- HHV8,
- p27Kip,
- phosphorylation,
- protein degradation
