title: Transcriptional repressor NIR interacts with the p53-inhibiting ubiquitin ligase MDM2.
abstract: NIR (novel INHAT repressor) can bind to p53 at promoters and inhibit p53-mediated gene transactivation by blocking histone acetylation carried out by p300/CBP. Like NIR, the E3 ubiquitin ligase MDM2 can also bind and inhibit p53 at promoters. Here, we present data indicating that NIR, which shuttles between the nucleolus and nucleoplasm, not only binds to p53 but also directly to MDM2, in part via the central acidic and zinc finger domain of MDM2 that is also contacted by several other nucleolus-based MDM2/p53-regulating proteins. Like some of these, NIR was able to inhibit the ubiquitination of MDM2 and stabilize MDM2; however, unlike these nucleolus-based MDM2 regulators, NIR did not inhibit MDM2 to activate p53. Rather, NIR cooperated with MDM2 to repress p53-induced transactivation. This cooperative repression may at least in part involve p300/CBP. We show that NIR can block the acetylation of p53 and MDM2. Non-acetylated p53 has been documented previously to more readily associate with inhibitory MDM2. NIR may thus help to sustain the inhibitory p53:MDM2 complex, and we present evidence suggesting that all three proteins can indeed form a ternary complex. In sum, our findings suggest that NIR can support MDM2 to suppress p53 as a transcriptional activator.
authors.affiliation: José Carreras Research Center and Internal Medicine I, University of Saarland Medical Center, 66421 Homburg/Saar, Germany and Department of Urology, Center for Clinical Research, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Heyne
authors.forename: Juliane
authors.initials: J
authors.lastname: Förster
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
authors.forename: Klaus
authors.initials: K
authors.lastname: Roemer
mesh_terms: D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D054875:Ubiquitination
chemical_list: C507220:NOC2L protein, human; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2