Modulation of p27 Kip1 levels by the cyclin encoded by Kaposi's sarcoma‐associated herpesvirus

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 p16 Ink4a , p21 Cip1 and p27 Kip1 cdk inhibitors. Here we investigate the mechanism involved in the subversion of a G 1 blockade imposed by overexpression of p27 Kip1 . 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 p27 Kip1 which is phosphorylated on Thr187. Expression of K cyclin in mammalian cells leads to p27 Kip1 downregulation, this being consistent with previous studies indicating that phosphorylation of p27 Kip1 on Thr187 triggers its downregulation. K cyclin expression is not able to prevent a G 1 arrest imposed by p27 Kip1 in which Thr187 is mutated to non‐phosphorylatable Ala. These results imply that K cyclin is able to bypass a p27 Kip1 ‐imposed G 1 arrest by facilitating phosphorylation and downregulation of p27 Kip1 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.