title: Hdm2 recruits a hypoxia-sensitive corepressor to negatively regulate p53-dependent transcription.
abstract: The transcription factor p53 lies at the center of a protein network that controls cell cycle progression and commitment to apoptosis. p53 is inactive in proliferating cells, largely because of negative regulation by the Hdm2/Mdm2 oncoprotein, with which it physically associates. Release from this negative regulation is sufficient to activate p53 and can be triggered in cells by multiple stimuli through diverse pathways. This diversity is achieved in part because Hdm2 uses multiple mechanisms to inactivate p53; it targets p53 for ubiquitination and degradation by the proteosome, shuttles it out of the nucleus and into the cytoplasm, prevents its interaction with transcriptional coactivators, and contains an intrinsic transcriptional repressor activity. Here we show that Hdm2 can also repress p53 activity through the recruitment of a known transcriptional corepressor, hCtBP2. This interaction, and consequent repression of p53-dependent transcription, is relieved under hypoxia or hypoxia-mimicking conditions that are known to increase levels of intracellular NADH. CtBP proteins can undergo an NADH-induced conformational change, which we show here results in a loss of their Hdm2 binding ability. This pathway represents a novel mechanism whereby p53 activity can be induced by cellular stress.
authors.affiliation: Cancer Sciences Division, School of Medicine, University of Southampton, MP 824, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Mirnezami
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Campbell
authors.forename: Matthew
authors.initials: M
authors.lastname: Darley
authors.forename: John N
authors.initials: JN
authors.lastname: Primrose
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Johnson
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Blaydes
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D015966:Gene Expression Regulation, Fungal; D000860:Hypoxia / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D009243:NAD; D051736:Proto-Oncogene Proteins c-mdm2