We have examined how retinoic acid receptors (RARs) and retinoid X receptors (RXRs) at physiological concentrations regulate distinct retinoid-responsive elements, hRAR2/RARE (DR5) and rCRBPII/RXRE (DR1), in keratinocytes from human skin, a major retinoid target. In vitro, endogenous RAR and RXRs bound to these elements as heterodimers (RARRXR) but not homodimers (RARRAR or RXRRXR). In cultured keratinocytes, all-trans retinoic acid, 9-cis retinoic acid, and CD367 activated RARE but not RXRE via endogenous RARRXR (ED = 2.3, 3.8, and 0.3 nM, respectively) whereas SR11237 showed no significant effect. All-trans retinoic acid, 9-cis retinoic acid, and SR11237 activated RXRE via overexpressed RXRRXR (ED = 110, 120, and 11 nM, respectively), indicating interconversion between retinoic acid isomers, whereas co-overexpression of RAR or RAR suppressed this activation. Unlike 9cRA, CD367 neither induced formation of nor activated RXRRXR. Overexpression of RAR or RXR mutated in transactivation domain AF-2 suppressed endogenous receptor activity over RARE. Our data suggest that 1) in keratinocytes, RARRXR-mediated pathway dominates over that mediated by RXRRXR; 2) RAR-selective CD367 and RXR-selective SR11237 can be used to identify these two distinct pathways, respectively; 3) RARE is mainly regulated by RARRXR, in which RAR alone confers ligand inducibility whereas AF-2 of unliganded RXR is required for transactivation by liganded RAR AF-2; 4) lack of RXRE activity in keratinocytes is due to low endogenous levels of RXRRXR and inhibition by RARRXR; and 5) interaction among RXRs is much lower than that between RAR and RXR.

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