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- Title
Modulation of p27<sup>Kip1</sup> levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus.
- Authors
Mann, David J.; Child, Emma S.; Swanton, Charles; Laman, Heike; Jones, Nic
- Abstract
DNA tumour viruses have evolved a number of mechanisms by which they deregulate normal cellular growth control. We have recently described the properties of a cyclin encoded by human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) which is able to resist the actions of p16Ink4a, p21Cip1 and p27Kip1 cdk inhibitors. Here we investigate the mechanism involved in the subversion of a G1 blockade imposed by overexpression of p27Kip1. We demonstrate that binding of K cyclin to cdk6 expands the substrate repertoire of this cdk to include a number of substrates phosphorylated by cyclin—cdk2 complexes but not cyclin D1—cdk6. Included amongst these substrates is p27Kip1 which is phosphorylated on Thr187. Expression of K cyclin in mammalian cells leads to p27Kip1 downregulation, this being consistent with previous studies indicating that phosphorylation of p27Kip1 on Thr187 triggers its downregulation. K cyclin expression is not able to prevent a G1 arrest imposed by p27Kip1 in which Thr187 is mutated to non-phosphorylatable Ala. These results imply that K cyclin is able to bypass a p27Kip1-imposed G1 arrest by facilitating phosphorylation and downregulation of p27Kip1 to enable activation of endogenous cyclin—cdk2 complexes. The extension of the substrate repertoire of cdk6 by K cyclin is likely to contribute to the deregulation of cellular growth by this herpesvirus-encoded cyclin.
- Publication
EMBO Journal, 1999, Vol 18, Issue 3, p654
- ISSN
0261-4189
- Publication type
Academic Journal
- DOI
10.1093/emboj/18.3.654