title: MDM2 binds and inhibits vitamin D receptor.
abstract: The E3 ubiquitin ligase and transcriptional repressor MDM2 is a potent inhibitor of the p53 family of transcription factors and tumor suppressors. Herein, we report that vitamin D receptor (VDR), another transcriptional regulator and probably, tumor suppressor, is also bound and inhibited by MDM2. This interaction was not affected by vitamin D ligand. VDR was ubiquitylated in the cell and its steady-state level was controlled by the proteasome. Strikingly, overproduced MDM2 reduced the level of VDR whereas knockdown of endogenous MDM2 increased the level of VDR. In addition to ubiquitin-marking proteins for degradation, MDM2, once recruited to promoters by DNA-binding interaction partners, can inhibit the transactivation of genes. Transient transfections with a VDR-responsive luciferase reporter revealed that low levels of MDM2 potently suppress VDR-mediated transactivation. Conversely, knockdown of MDM2 resulted in a significant increase of transcript from the CYP24A1 and p21 genes, noted cellular targets of transactivation by liganded VDR. Our findings suggest that MDM2 negatively regulates VDR in some analogy to p53.
authors.affiliation: a Internal Medicine I and José Carreras Center; University of Saarland Medical Center ; Homburg , Saar , Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Heyne
authors.forename: Tessa-Carina
authors.initials: TC
authors.lastname: Heil
authors.forename: Birgit
authors.initials: B
authors.lastname: Bette
authors.forename: Jörg
authors.initials: J
authors.lastname: Reichrath
authors.forename: Klaus
authors.initials: K
authors.lastname: Roemer
mesh_terms: D002460:Cell Line; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D018167:Receptors, Calcitriol; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; transcription; tumor suppression; vitamin D; vitamin D receptor