Retinoid X receptor-specific ligands synergistically upregulate 1,25-dihydroxyvitamin D-3-dependent transcription in epidermal keratinocytes in vitro and in vivo

[摘要] We have examined the mechanism by which endogenous retinoid X receptor (RXR), vitamin D-3 receptor (VDR), and cognate ligands regulate nuclear 1,25-dihydroxyvitamin D-3 (D-3) Signaling in epidermal keratinocytes from skin, a physiologic D-3 target, In vitro, RXR and VDR-specific antibodies identified endogenous RXR and VDR bound to a vitamin D-3-responsive element (DR3) as heterodimers (VDR-RXR). In cultured keratinocytes, 9-cis retinoic acid (9cRA), a panagonist for RXR and retinoic acid receptor (RAR), and an RXR-selective agonist, SR11237, synergized with D-3 to activate DR3 via endogenous as well as overexpressed VDR-RXR, whereas both of these RXR agonists alone were ineffective. In contrast, SR11237 did not synergize with but antagonized an RAR-selective ligand activation of a retinoic acid-responsive element (DR5) via endogenous RAR-RXR, Furthermore, expression of RXR mutated in transactivation domain AF-2 inhibited endogenous VDR-RXR activity over DR3, This mutant efficiently bound to DR3 as VDR-RXR but showed reduced capacity to transactivate DR3 in response to D-3 and SR11237, In vivo, D-3 and SR11237 synergistically induced the naturally occurring D-3 responsive 24-hydroxylase gene in epidermis of mouse skin, whereas SR11237 alone was ineffective. Our data suggest that allosteric changes caused by VDR in DR3-bound VDR-RXR do not block access of ligands to RXR. RXR ligand-induced conformational changes permit VDR-RXR, via both VDR and RXR activation function domains, to mediate maximal D-3 signaling in keratinocytes.

[发布日期] 1997-04-01

[效力级别]  Proceedings Paper

[关键词] 9-cis retinoic acid;24-hydroxylase;vitamin D-3 receptor