title: Cdk9 phosphorylates Pirh2 protein and prevents degradation of p53 protein.
abstract: Several reports have pointed to the negative involvement of p53 in transcriptional regulation of the human immunodeficiency virus type 1 long-terminal repeat (HIV-1 LTR). We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on Ser-392, leading to p53 stability and accumulation. As a result, p53 stalled transcriptional elongation of the HIV-1 LTR and significantly reduced HIV-1 replication in primary microglia and astrocytes. Therefore, we sought to identify the mechanisms used by cdk9 to allow this p53 function. Using western blot analysis, we found that cdk9 promotes inhibition and phosphorylation of Mdm2 on Ser-395, thus preventing degradation of p53, a protein that is directly involved in promoting p53 ubiquitination. On the other hand, we showed that cdk9 phosphorylates Pirh2 on Ser-211 and Thr-217 residues through their physical interaction. Phosphorylation of Pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the HIV-1 LTR. Hence, we suggest that phosphorylation of Pirh2 may be a novel target for the inhibition of HIV-1 gene expression.
authors.affiliation: Molecular Studies of Neurodegenerative Diseases Lab, The Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Asen
authors.initials: A
authors.lastname: Bagashev
authors.forename: Shongshan
authors.initials: S
authors.lastname: Fan
authors.forename: Ruma
authors.initials: R
authors.lastname: Mukerjee
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Claudio
authors.forename: Tinatin
authors.initials: T
authors.lastname: Chabrashvili
authors.forename: Roger P
authors.initials: RP
authors.lastname: Leng
authors.forename: Samuel
authors.initials: S
authors.lastname: Benchimol
authors.forename: Bassel E
authors.initials: BE
authors.lastname: Sawaya
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C485369:RCHY1 protein, human; D044767:Ubiquitin-Protein Ligases; D042863:Cyclin-Dependent Kinase 9
keywords: Cdk9; HIV-1; Pirh2; p53; transcription