1α,25-dihydroxy vitamin D3-enhanced expression of the osteocalcin gene involves increased promoter occupancy of basal transcription regulators and gradual recruitment of the 1α,25-dihydroxy vitamin D 3 receptor-SRC-1 coactivator complex

Loreto Carvallo, Berta Henríquez, Roberto Paredes, Juan Olate, Sergio Onate, Andre J. Van Wijnen, Jane B. Lian, Gary S. Stein, Janet L. Stein, Martin Montecino

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Binding of 1α,25-dihydroxy vitamin D3 to the C-terminal ligand-binding domain (LBD) of its receptor (VDR) induces a conformational change that enables interaction of VDR with transcriptional coactivators such as members of the p160/SRC family or the DRIP (vitamin D receptor-interacting complex)/Mediator complex. These interactions are critical for VDR-mediated transcriptional enhancement of target genes. The p160/SRC members contain intrinsic histone acetyl transferase (HAT) activities that remodel chromatin at promoter regulatory regions, and the DRIP/Mediator complex may establish a molecular bridge between the VDR complex and the basal transcription machinery. Here, we have analyzed the rate of recruitment of these coactivators to the bone-specific osteocalcin (OC) gene in response to short and long exposures to 1α,25-dihydroxy vitamin D3. We report that in intact osteoblastic cells VDR, in association with SRC-1, rapidly binds to the OC promoter in response to the ligand. The recruitment of SRC-I correlates with maximal transcriptional enhancement of the OC gene at 4 h and with increased histone acetylation at the OC promoter. In contrast to other 1α,25-dihydroxy vitamin D3-enhanced genes, binding of the DRIP205 subunit, which anchors the DRIP/Mediator complex to the VDR, is detected at the OC promoter only after several hours of incubation with 1α,25-dihydroxy vitamin D3, concomitant with the release of SRC-1. Together, our results support a model where VDR preferentially recruits SRC-1 to enhance bone-specific OC gene transcription.

Original languageEnglish (US)
Pages (from-to)740-749
Number of pages10
JournalJournal of Cellular Physiology
Volume214
Issue number3
DOIs
StatePublished - Mar 1 2008

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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