Ligand-Independent Coregulator Recruitment by the Triply Activatable OR1/Retinoid X Receptor- Nuclear Receptor Heterodimer

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Abstract
OR1 is a member of the superfamily of steroid/ thyroid hormone nuclear receptors and recognizes DNA as a heterodimer with the 9-cis-retinoic acid receptor RXR (retinoid X receptor). The het- erodimeric complex has been shown to be tran- scriptionally activatable by the RXR ligand as well as certain oxysterols via OR1, but to date uniquely also by heterodimerization itself. Recent studies on other members of the superfamily of nuclear receptors have led to the identification of a number of nuclear receptor-interacting proteins that medi- ate their regulatory effects on transcription. Here, we address the question of involvement of some of these cofactors in the three modes of activation by the OR1/RXRa complex. We show that in vitro the steroid receptor coactivator SRC-1 can be re- cruited by RXRa upon addition of its ligand, and to OR1 upon addition of 22(R)-OH-cholesterol, dem- onstrating that the latter can act as a direct ligand to OR1. Additionally, heterodimerization is suffi- cient to recruit SRC-1 to OR1/RXRa, indicating SRC-1 as a molecular mediator of dimerization- induced activation. In transfection experiments, coexpression of a nuclear receptor-interacting fragment of SRC-1 abolishes constitutive activa- tion by OR1/RXRa, which can be restored by over- expression of full-length SRC-1. This constitutes evidence for an in vivo role of SRC-1 in dimeriza- tion-induced activation by OR1/RXRa. Additionally, we show that the nuclear receptor- interacting protein RIP140 binds in vitro to OR1 and RXRa with requirements distinct from those of SRC-1, and that binding of the two cofactors is competitive. Taken together, our results suggest a complex modulation of differentially induced trans- activation by OR1/RXR coregulatory molecules. (Molecular Endocrinology 13: 1105-1118, 1999)

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