title: PKC phosphorylates HEXIM1 and regulates P-TEFb activity.
abstract: The positive transcription elongation factor b (P-TEFb) regulates RNA polymerase II elongation. In cells, P-TEFb partitions between small active and larger inactive states. In the latter, HEXIM1 binds to 7SK snRNA and recruits as well as inactivates P-TEFb in the 7SK snRNP. Several stimuli can affect this P-TEFb equilibrium. In this study, we demonstrate that protein kinase C (PKC) phosphorylates the serine at position158 (S158) in HEXIM1. This phosphorylated HEXIM1 protein neither binds to 7SK snRNA nor inhibits P-TEFb. Phorbol esters or the engagement of the T cell antigen receptor, which activate PKC and the expression of the constitutively active (CA) PKCθ protein, which is found in T cells, inhibit the formation of the 7SK snRNP. All these stimuli increase P-TEFb-dependent transcription. In contrast, the kinase-negative PKCθ and the mutant HEXIM1 (S158A) proteins block effects of these PKC-activating stimuli. These results indicate that the phosphorylation of HEXIM1 by PKC represents a major regulatory step of P-TEFb activity in cells.
authors: Departments of Medicine, Microbiology and Immunology, Rosalind Russell Research Center, University of California, San Francisco, San Francisco, CA 94143-0703, USA.
authors: Koh
authors: K
authors: Fujinaga
authors: Matjaz
authors: M
authors: Barboric
authors: Qintong
authors: Q
authors: Li
authors: Zeping
authors: Z
authors: Luo
authors: David H
authors: DH
authors: Price
authors: B Matija
authors: BM
authors: Peterlin
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D012342:RNA, Small Nuclear / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors
chemical_list: C476123:HEXIM1 protein, human; D016328:NF-kappa B; D012342:RNA, Small Nuclear; D016601:RNA-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D012694:Serine; D042925:Positive Transcriptional Elongation Factor B; D011493:Protein Kinase C; D051745:Protein Kinase C-delta