title: P-TEFb kinase complex phosphorylates histone H1 to regulate expression of cellular and HIV-1 genes.
abstract: Transcription of HIV-1 genes depends on the RNA polymerase II kinase and elongation factor positive transcription elongation factor b (P-TEFb), the complex of cyclin T1 and CDK9. Recent evidence suggests that regulation of transcription by P-TEFb involves chromatin binding and modifying factors. To determine how P-TEFb may connect chromatin remodeling to transcription, we investigated the relationship between P-TEFb and histone H1. We identify histone H1 as a substrate for P-TEFb involved in cellular and HIV-1 transcription. We show that P-TEFb interacts with H1 and that P-TEFb inhibition by RNAi, flavopiridol, or dominant negative CDK9 expression correlates with loss of phosphorylation and mobility of H1 in vivo. Importantly, P-TEFb directs H1 phosphorylation in response to wild-type HIV-1 infection, but not Tat-mutant HIV-1 infection. Our results show that P-TEFb phosphorylates histone H1 at a specific C-terminal phosphorylation site. Expression of a mutant H1.1 that cannot be phosphorylated by P-TEFb also disrupts Tat transactivation in an HIV reporter cell line as well as transcription of the c-fos and hsp70 genes in HeLa cells. We identify histone H1 as a novel P-TEFb substrate, and our results suggest new roles for P-TEFb in both cellular and HIV-1 transcription.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Siobhan K
authors.initials: SK
authors.lastname: O'Brien
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Robin
authors.initials: R
authors.lastname: Nathans
authors.forename: Akbar
authors.initials: A
authors.lastname: Ali
authors.forename: Tariq M
authors.initials: TM
authors.lastname: Rana
mesh_terms: D056906:Cyclin T / Q000235:genetics / Q000378:metabolism*; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology*; D005814:Genes, Viral / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D042925:Positive Transcriptional Elongation Factor B / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: C503684:CCNT1 protein, human; D056906:Cyclin T; D005419:Flavonoids; D018840:HSP70 Heat-Shock Proteins; D006657:Histones; D009097:Multienzyme Complexes; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D054322:tat Gene Products, Human Immunodeficiency Virus; C077990:alvocidib; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9