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 p27(Kip) 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 p27(Kip). However, full cell-cycle transit of these cells appears to depend on C-terminal phosphorylation of p27(Kip) and seems to involve transactivation of other cellular cyclin-dependent kinases. A p27(Kip)-phosphorylating cdk6 complex exists in cell lines derived from primary effusion lymphoma and in Kaposi's sarcoma, this indicating that virally induced p27(Kip) degradation may occur in KSHV-associated tumours.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Binding Sites
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CDC2-CDC28 Kinases*
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Cell Cycle
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Cell Cycle Proteins*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism
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Cyclins / genetics
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Cyclins / metabolism*
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DNA Primers / genetics
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Enzyme Inhibitors / metabolism*
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Herpesvirus 8, Human / genetics
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Herpesvirus 8, Human / metabolism*
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Herpesvirus 8, Human / pathogenicity
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Humans
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Sarcoma, Kaposi / metabolism
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Sarcoma, Kaposi / pathology
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Sarcoma, Kaposi / virology
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Tumor Cells, Cultured
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Tumor Suppressor Proteins*
Substances
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Cell Cycle Proteins
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Cyclins
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DNA Primers
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Enzyme Inhibitors
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Microtubule-Associated Proteins
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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CDK6 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases