Journal
NUCLEIC ACIDS RESEARCH
Volume 33, Issue 17, Pages 5521-5532Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gki872
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Recently, insulin-like growth factor binding proteins (IGFBPs) have been found to be primary mediators of the anti-proliferative actions of the nuclear hormone 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)(2)D-3], but dependent on cellular context IGFBPs can also have a mitogenic effect. In this study, we performed expression profiling of all six human IGFBP genes in prostate and bone cancer cells and demonstrated that IGFBP1, 3 and 5 are primary 1 alpha,25(OH)(2)D-3 target genes. In silico screening of the 174 kb of genomic sequence surrounding all six IGFBP genes identified 15 candidate vitamin D response elements (VDREs) close to or in IGFBP1, 2, 3 and 5 but not in the IGFBP4 and 6 genes. The putative VDREs were evaluated in vitro by gelshift assays and in living cells by reporter gene and chromatin immuno-precipitation (ChIP) assays. Of these 10 VDREs appear to be functional. ChIP assays demonstrated for each of these an individual, stimulation time-dependent association profile not only with the vitamin D receptor, but also with first heterodimeric partner the retinoid X receptor, other regulatory complex components and phosphorylated RNA polymerase II. Some of the VDREs are located distantly from the transcription start sites of IGFBP1, 3 and 5, but all 10 VDREs seem to contribute to the regulation of the genes by 1 alpha,25(OH)(2)D-3. In conclusion, IGFBP1, 3 and 5 are primary 1 alpha,25(OH)(2)D-3 target genes that in intact cells are each under the control of multiple VDREs.
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