Ligand-triggered stabilization of vitamin D Receptor/Retinoid X receptor heterodimer conformations on DR4-type response elements

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• 作者：Quack ; Marcus ; Carlberg ; Carsten
• 关键词：transcriptional regulation ; orphan nuclear receptors ; synergistic ligand interaction ; gel shift clipping assay ; 4-ABB ; 4-amino-butyl-benzoate ; 9cRA ; 9-cis retinoic acid ; ANF ; atrial natriuretic factor ; atRA ; retinoic acid ; BXR ; benzoate X receptor ; c ; con
• 刊名：Journal of Molecular Biology
• 出版年：2000
• 出版时间：February 25, 2000
• 年：2000
• 卷：296
• 期：3
• 页码：743-756
• 全文大小：445 K

文摘

Nuclear receptors integrate an incoming signal in the form of a nuclear hormone by undergoing a conformational change that results via co-activator proteins in an activation of the basal transcriptional machinery. The vitamin D₃ receptor is the nuclear receptor for 1α,25-dihydroxy vitamin D₃ (1α,25(OH)₂D₃) and is known to function as a heterodimer with the retinoid X receptor on DR3-type 1α,25(OH)₂D₃ response elements. Here, it could be demonstrated that DR4-type response elements are at least as effective as DR3-type 1α,25(OH)₂D₃ response elements. Gel shift clipping analysis showed that vitamin D₃ receptor-retinoid X receptor heterodimers form in response to 1α,25(OH)₂D₃ and retinoid X receptor ligands, the pan-agonist 9-cis retinoic acid (9cRA) and the retinoid X receptor-selective retinoid CD2425, different conformations on the DR4-type element of the rat Pit-1 gene. Interestingly, on this response element the heterodimeric complexes of retinoid X receptor with the thyroid hormone receptor, the retinoic acid receptor and the benzoate ester receptor also displayed characteristic individual ligand-dependent complex formation. On the level of complex formation, utilizing DNA affinity and functional assays, only vitamin D₃ receptor-retinoid X receptor heterodimers showed a synergistic interaction of both ligands. However, the sensitivity of vitamin D₃ receptor-retinoid X receptor heterodimers to 1α,25(OH)₂D₃ was found to be much higher than to retinoid X receptor ligands. Taken together, this study demonstrates a unique interaction potential of vitamin D₃ receptor and retinoid X receptor but also establishes DR4-type response elements as multi-functional DNA binding sites with a potential to integrate various hormone signalling pathways.