title: Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation.
abstract: p53 is the most frequently mutated tumor suppressor gene in human neoplasia and encodes a transcriptional coactivator. Identification of p53 target genes is therefore key to understanding the role of p53 in tumorigenesis. To identify novel p53 target genes, we first used a comparative genomics approach to identify p53 binding sequences conserved in the human and mouse genome. We hypothesized that potential p53 binding sequences that are conserved are more likely to be functional. Using stringent filtering procedures, 32 genes were newly identified as putative p53 targets, and their responsiveness to p53 in human cancer cells was confirmed by reverse transcription-PCR and real-time PCR. Among them, we focused on the vitamin D receptor (VDR) gene because vitamin D3 has recently been used for chemoprevention of human tumors. VDR is induced by p53 as well as several other p53 family members, and analysis of chromatin immunoprecipitation showed that p53 protein binds to conserved intronic sequences of the VDR gene in vivo. Introduction of VDR into cells resulted in induction of several genes known to be p53 targets and suppression of colorectal cancer cell growth. In addition, p53 induced VDR target genes in a vitamin D3-dependent manner. Our in silico approach is a powerful method for identification of functional p53 binding sites and p53 target genes that are conserved among humans and other organisms and for further understanding the function of p53 in tumorigenesis.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Fumio
authors.initials: F
authors.lastname: Aoki
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mita
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kimishige
authors.initials: K
authors.lastname: Akino
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ohe-Toyota
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Tatsumi
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D018390:Gene Targeting; D016158:Genes, p53; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol