title: Human PC4 is a substrate-specific inhibitor of RNA polymerase II phosphorylation.
abstract: The activity of cyclin-dependent protein kinases (cdks) is physiologically regulated by phosphorylation, association with the specific cyclin subunits, and repression by specific cdk inhibitors. All three physiological regulatory mechanisms are specific for one or more cdks, but none is known to be substrate specific. In contrast, synthetic cdk peptide inhibitors that specifically inhibit cdk phosphorylation of only some substrates, "aptamers," have been described. Here, we show that PC4, a naturally occurring transcriptional coactivator, competitively inhibits cdk-1, -2, and -7-mediated phosphorylation of the largest subunit of RNA polymerase II (RNAPII), but it does not inhibit phosphorylation of other substrates of the same kinases. Interestingly, the phosphorylated form of PC4 is devoid of kinase inhibitory activity. We also show that wild-type PC4 but not the kinase inhibitory-deficient mutant of PC4 represses transcription in vivo. Our results point to a novel role for PC4 as a specific inhibitor of RNAPII phosphorylation.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Schang
authors.forename: G J
authors.initials: GJ
authors.lastname: Hwang
authors.forename: B D
authors.initials: BD
authors.lastname: Dynlacht
authors.forename: D W
authors.initials: DW
authors.lastname: Speicher
authors.forename: A
authors.initials: A
authors.lastname: Bantly
authors.forename: P A
authors.initials: PA
authors.lastname: Schaffer
authors.forename: A
authors.initials: A
authors.lastname: Shilatifard
authors.forename: H
authors.initials: H
authors.lastname: Ge
authors.forename: R
authors.initials: R
authors.lastname: Shiekhattar
mesh_terms: D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins; D007700:Kinetics; D008565:Membrane Proteins; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D012319:RNA Polymerase II / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000494:pharmacology*; D013379:Substrate Specificity; D015534:Trans-Activators / Q000235:genetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; C490043:IFRD2 protein, human; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II