A Novel Mechanism for 1,25-(OH)2-D3-Mediated Gene Transcription

• Main Authors: Yu-Chun Huang, 黃郁淳
• Other Authors: 洪文俊
• Format: Others
• Language: zh-TW
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/36038772160597197158

博士 === 高雄醫學大學 === 醫學研究所博士班 === 94 === Vitamin D3 is a conditionally required nutrient traditionally thought to exert its physiological activity via the binding of its active metabolite, 1,25-(OH)2-D3, to the vitamin D receptor (VDR) .VDR is a ligand-activated transcription factor that plays a central role in calcium/phosphorus homeostasis and has been implicated in regulating diverse biological functions, including cellular proliferation and differentiation. The classical pathway for VDR signaling is mediated by receptor binding to vitamin D response elements (VDREs) located within the promoters of vitamin D3- responsive genes. In this study, we demenstrate that VDR can alter gene transcription via a novel mechanism that does not require direct VDR binding to the VDRE. Interaction between the VDR and the transcription factor Sp1, leads to changes in the transcription of target genes. Vitamin D3 may suppress proliferation of human prostate cancer cells. Therefore, we used the human prostate cancer cell line LNCaP to examine the effect of vitamin D3 on gene expression. In this study, we elucidate the underlying mechanism by which vitamin D3 activates p27Kip1 and inhibits p45Skp2. Reporter assay, DNA affinity precipitation assay (DAPA) and chromatin immunoprecipitation (ChIP) assay reveal that VDR and Sp1 form a complex and bind to the promoter of VDRE-lacking genes. The VDR/Sp1 complex acts via Sp1 binding site to regulate gene transcription. Thus, our study elucidates the molecular mechanism by which VDR regulates gene activation or suppression via interaction with Sp1. We also reveal the particular cofactors that involved in gene activation or repression. These results may be of important clinical significance and provide a new strategy for the treatment of prostate cancer.