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Comparative Genome Analysis Identifies the Vitamin D Receptor Gene as a Direct Target of p53-Mediated Transcriptional Activation

¹ First Department of Internal Medicine; ² Department of Molecular Biology, Cancer Research Institute; ³ Information Center of Computer Communication; and ⁴ Department of Public Health, Sapporo Medical University, Sapporo, Japan; and ⁵ Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan

Requests for reprints: Takashi Tokino, Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan. Phone: 81-11-611-2111, ext. 2386; Fax: 81-11-618-3313; E-mail: tokino{at}sapmed.ac.jp.

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. (Cancer Res 2006; 66(9): 4574-83)

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