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D cyclins (D1, D2 and D3) and their catalytic subunits (cyclin-dependent kinases cdk4 and cdk6) have a facilitating, but nonessential, role in cell cycle entry. Tissue-specific functions for D-type cyclins and cdks have been reported; however, the biochemical properties of these kinases are indistinguishable. We report that an F box protein, Fbxo7, interacted with cellular and viral D cyclins and distinguished among the cdks that bind D-type cyclins, specifically binding cdk6, in vitro and in vivo. Fbxo7 specifically regulated D cyclin/cdk6 complexes: Fbxo7 knockdown decreased cdk6 association with cyclin and its overexpression increased D cyclin/cdk6 activity and E2F activity. Fbxo7 interacted with p27, but its enhancement of cyclin D/cdk6 activity was p21/p27 independent. Fbxo7 overexpression transformed murine fibroblasts, rendering them tumorigenic in athymic nude mice. Transformed phenotypes were dependent on cdk6, as knockdown of cdk6 reversed them. Fbxo7 was highly expressed in epithelial tumors, but not in normal tissues, suggesting that it may have a proto-oncogenic role in human cancers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]