title: Vitamin D directly regulates Mdm2 gene expression in osteoblasts.
abstract: While Mdm2 is an important negative regulator of the p53 tumor suppressor, it also possesses p53-independent functions in cellular differentiation processes. Mdm2 expression is alternatively regulated by two P1 and P2 promoters. In this study we show that the P2-intiated transcription of Mdm2 gene is activated by 1,25-dihydroxy vitamin D3 in MC3T3 cells. By using P1 and P2-specific reporters, we demonstrate that only the P2-promoter responds to vitamin D treatment. We have further identified a potential vitamin D receptor responsive element proximal to the two p53 response elements within the Mdm2 P2 promoter. Using cell lines that are p53-temperature sensitive and p53-null, we show requirement of p53 for VDR-mediated up regulation of Mdm2 expression. Our results indicate that 1,25-dihydroxy vitamin D3 and its receptor have a role in the regulation of P2-initiated Mdm2 gene expression in a p53-dependent way.
authors.affiliation: Department of Biochemistry, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, United States.
authors.forename: Hankui
authors.initials: H
authors.lastname: Chen
authors.forename: Grant
authors.initials: G
authors.lastname: Reed
authors.forename: Janete
authors.initials: J
authors.lastname: Guardia
authors.forename: Sandeep
authors.initials: S
authors.lastname: Lakhan
authors.forename: Oliver
authors.initials: O
authors.lastname: Couture
authors.forename: Emily
authors.initials: E
authors.lastname: Hays
authors.forename: Nalini
authors.initials: N
authors.lastname: Chandar
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D005786:Gene Expression Regulation; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D030181:Vitamin D Response Element / Q000187:drug effects / Q000235:genetics*
chemical_list: D018167:Receptors, Calcitriol; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D002117:Calcitriol