A 5′-Distal Element Mediates Vitamin D-Inducibility of PDGF-A Gene Transcription

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Abstract
Expression of the platelet-derived growth factor-A subunit (PDGF-A) is regulated to a significant degree by DNA elements located in the 5′-distal region of the gene. A potent basal enhancer (ACE66) located approximately 7 kb upstream of the transcription start site contains a number of half-sites for nuclear receptor binding, two of which are arranged in the form of direct repeat-3 motif that corresponds to a consensus vitamin D response element (VDRE). Electrophoretic mobility shift assays confirmed that the ACE66 sequence was recognized as a high affinity target for binding of heterodimers of recombinant vitamin D receptor (VDR) and its partner, retinoid-X receptor-α (RXRα). VDRE activity was localized by transient transfection analysis to a direct repeat-3 motif within the 5′-portion of the ACE66 element. Moreover, 1,25-(OH)2D3 was validated as a regulator of the endogenous PDGF-A gene by the vitamin D-stimulated upregulation of PDGF-A mRNA levels in a VDR-expressing clone of JEG-3 cells. Thus, PDGF-A represents a novel mitogenic target of 1,25-(OH)2D3 whose expression is induced via binding of hormone-activated VDR to a response element located far upstream of the transcription start site.