Barry M. Forman

Identification of a nuclear receptor that is activated by farnesol metabolites.

Nuclear hormone receptors comprise a superfamily of ligand-modulated transcription factors that mediate the transcriptional activities of steroids, retinoids, and thyroid hormones. A growing number of related proteins have been identified that possess the structural features of hormone receptors, but that lack known ligands. Known as orphan receptors, these proteins represent targets for novel signaling molecules. We have isolated a mammalian orphan receptor that forms a heterodimeric complex with the retinoid X receptor. A screen of candidate ligands identified farnesol and related metabolites as effective activators of this complex. Farnesol metabolites are generated intracellularly and are required for the synthesis of cholesterol, bile acids, steroids, retinoids, and farnesylated proteins. Intermediary metabolites have been recognized as transcriptional regulators in bacteria and yeast. Our results now suggest that metabolite-controlled intracellular signaling systems are utilized by higher organisms.

Unique response pathways are established by allosteric interactions among nuclear hormone receptors

Heterodimerization is a common paradigm among eukaryotic transcription factors. The 9-cis retinoic acid receptor (RXR) serves as a common heterodimerization partner for several nuclear receptors, including the thyroid hormone receptor (T3R) and retinoic acid receptor (RAR). This raises the question as to whether these complexes possess dual hormonal responsiveness. We devised a strategy to examine the transcriptional properties of each receptor individually or when tethered to a heterodimeric partner. We find that the intrinsic binding properties of RXR are masked in T3R-RXR and RAR-RXR heterodimers. In contrast, RXR is active as a non-DNA-binding cofactor with the NGFI-B/Nurr1 orphan receptors. Heterodimerization of RXR with constitutively active NGFI-B/Nurr1 creates a novel hormone-dependent complex. These findings suggest that allosteric interactions among heterodimers create complexes with unique properties. We suggest that allostery is a critical feature underlying the generation of diversity in hormone response networks.

The Peroxisome Proliferator‐activated Receptors: Ligands and Activators

PPAR alpha and PPAR gamma represent related but distinct members of the nuclear receptor superfamily. PPAR alpha signaling is modulated by long-chain fatty acids, whereas PPAR gamma ligands are potent antidiabetic agents.

Nuclear hormone receptors activate direct, inverted, and everted repeats.

Nuclear hormone receptors comprise a family of ligand-modulated transcription factors that link cellular responses to extracellular and intracellular signals. Receptors for retinoids, thyroid hormone, vitamin D3 and fatty acids/peroxisome proliferators bind their response elements as heterodimers with the retinoid X receptor. Naturally occurring response elements are composed of core-motifs that are organized as direct, inverted, and/or everted repeats. The structural mechanisms that facilitate binding of a single receptor heterodimer to such diverse binding sites remain unknown.