PMID:21555514

Citation	Khan, SZ and Mitra, D (2011) Cyclin K inhibits HIV-1 gene expression and replication by interfering with cyclin-dependent kinase 9 (CDK9)-cyclin T1 interaction in Nef-dependent manner. J. Biol. Chem. 286:22943-54
Abstract	Human immunodeficiency virus-1 (HIV-1) exploits a number of host cellular factors for successful survival and propagation. The viral protein Nef plays an important role in HIV-1 pathogenesis by interacting with various cellular proteins. In the present work, we identified Cyclin K (CycK) as a novel Nef-interacting protein, and for the first time, we showed that CycK inhibits HIV-1 gene expression and replication in a Nef-dependent manner. The positive elongation factor b complex comprising cyclin-dependent kinase 9 (CDK9) and Cyclin T1 is a critical cellular complex required for viral gene expression and replication. Enhanced expression of CycK in the presence of Nef induced CycK-CDK9 binding, which prevented CDK9-Cyclin T1 complex formation and nuclear translocation of CDK9, resulting in inhibition of HIV-1 long terminal repeat-driven gene expression. Furthermore, this effect of CycK was not observed with Nef-deleted virus, indicating the importance of Nef in this phenomenon. Finally, silencing of CycK in HIV-1-infected cells resulted in increased translocation of CDK9 into the nucleus, leading to increased viral gene expression and replication. These data also suggest that endogenous CycK might act as an inhibitory factor for HIV-1 gene expression and replication in T-cells. Thus, our results clearly demonstrate that CycK utilizes HIV-1 Nef protein to displace CycT1 from the positive elongation factor b complex, resulting in inhibition of HIV-1 gene expression and replication.
Links	PubMed PMC3123062 Online version:10.1074/jbc.M110.201194
Keywords	Active Transport, Cell Nucleus/genetics; Cell Line; Cell Nucleus/genetics; Cell Nucleus/metabolism; Cell Nucleus/virology; Cyclin T/genetics; Cyclin T/metabolism; Cyclin-Dependent Kinase 9/genetics; Cyclin-Dependent Kinase 9/metabolism; Cyclins/genetics; Cyclins/metabolism; Gene Expression Regulation, Viral/physiology; HIV-1/physiology; Humans; Multiprotein Complexes/genetics; Multiprotein Complexes/metabolism; Protein Binding/physiology; Virus Replication/physiology; nef Gene Products, Human Immunodeficiency Virus/genetics; nef Gene Products, Human Immunodeficiency Virus/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:CCNK	involved_in	GO:0044828: negative regulation by host of viral genome replication	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:CCNK		GO:0044828: negative regulation by host of viral genome replication	ECO:0000314:		P		Figure 2B shows that Cyclin K inhibits HIV-1 gene replication in the presence of Nef.	complete CACAO 10250

References

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