Novel properties of the cyclin encoded by Human Herpesvirus 8 that facilitate exit from quiescence.
Viral DNA replication is generally dependent upon circumventing host cell cycle control to force S phase entry in an otherwise quiescent cell. Here we describe novel attributes of the cyclin encoded by Human Herpesvirus 8 (K cyclin) that enable it to subvert the quiescent state. K cyclin is most similar to the mammalian D-type cyclins in primary sequence but displays properties more akin to those of cyclin E. K cyclin (like cyclin E) can autonomously couple with its cognate cdk subunit and localize to the nucleus. D-type cyclins require mitogen stimulated accessory factors (such as p21(Cip1) and p27(Kip1)) to facilitate both of these processes. A striking difference between K cyclin and mammalian cyclins is that K cyclin binding to cdk6 can substantially activate the catalytic activity of the complex without the requirement for cyclin H/cdk7 phosphorylation of the cdk T-loop; this phosphorylation is obligatory for endogenous cyclin/cdk activity. However, K cyclin/cdk6 complexes are not totally immune from cell cycle control since CAK phosphorylation is necessary for complete activation. Thus, CAK phosphorylated K cyclin/cdk6 targets multiple sites in the retinoblastoma protein (pRb) whereas the unphosphorylated complex targets a single site. The restricted substrate specificity of the non-CAK phosphorylated K cyclin/cdk6 complex is insufficient to enable K cyclin-mediated S phase entry. Thus, the viral K cyclin is reliant upon endogenous CAK activity to subvert the quiescent state.
Child
E S
ES
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, SW7 2AY, UK.
Mann
D J
DJ
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D002384:Catalysis; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000737:chemistry / Q000145:classification; D000070819:Discoidin Domain Receptor 1; D004789:Enzyme Activation; D005822:Genetic Vectors / Q000235:genetics; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D046911:Macromolecular Substances; D008322:Mammals / Q000378:metabolism; D051379:Mice; D017924:Nucleopolyhedroviruses / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D013045:Species Specificity; D018411:Spodoptera / Q000166:cytology; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D016895:Culture Media, Serum-Free; D016213:Cyclins; C118264:HHV8-Vcyc protein, Human herpesvirus 8; D006657:Histones; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D014764:Viral Proteins; D007544:Isopropyl Thiogalactoside; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases