Activation of cyclin A gene expression by the cyclin encoded by human herpesvirus-8.
Human herpesvirus-8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, encodes a protein, referred to as HHV8-Vcyc, with sequence similarity to human G1 cyclins, in particular of the D type. HHV8-Vcyc is expressed in Kaposi's sarcoma and functional analysis suggests that it can activate cyclin-dependent kinases (cdk) and thereby trigger inactivation of the retinoblastoma protein (pRb), indicating that HHV8-Vcyc may contribute to the oncogenic potential of HHV-8. We show here that HHV8-Vcyc can activate transcription of the human cyclin A gene in quiescent cells, a property shared with known transforming oncogenes. Transcriptional activation by HHV8-Vcyc depends on an E2F-binding site in the cyclin A promoter, and cdk6 kinase activity is required. The ability of HHV8-Vcyc to activate cyclin A gene expression is shared by D-type cyclins and cyclin E. Unlike D-type cyclins, HHV8-Vcyc is unable to trigger phosphorylation of the pRb-related protein p107 and fails to induce dissociation of p107 from E2F. Unlike cyclin E, HHV8-Vcyc fails to interact physically with E2F complexes on the cyclin A promoter. These results provide additional evidence for the notion that the HHV-8-encoded cyclin differs in several properties from cellular G1 cyclins.
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D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050704:E2F4 Transcription Factor; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D017386:Sequence Homology, Amino Acid; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D019925:Cyclin A; D016213:Cyclins; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; C118264:HHV8-Vcyc protein, Human herpesvirus 8; D009687:Nuclear Proteins; C493844:RBL1 protein, human; C489485:Rbl1 protein, mouse; D011993:Recombinant Fusion Proteins; D050720:Retinoblastoma-Like Protein p107; D050680:Transcription Factor DP1; D014157:Transcription Factors; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases