期刊
JOURNAL OF CELLULAR PHYSIOLOGY
卷 214, 期 3, 页码 740-749出版社
WILEY
DOI: 10.1002/jcp.21267
关键词
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资金
- NIAMS NIH HHS [R01 AR049069, P01 AR48818] Funding Source: Medline
- NIDCR NIH HHS [DE12528] Funding Source: Medline
Binding of 1 alpha,25-dihydroxy vitamin D-3 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 p 160/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 (CC) gene in response to short and long exposures to 1 alpha,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-1 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 1 alpha,25-dihydroxy vitamin D-3-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 1 alpha,25-dihydroxy vitamin D-3, 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.
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