MECHANISM OF ACTION AND FUNCTION OF NUCLEAR RECEPTORS

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Summary of Work: The nuclear receptor superfamily constitutes a class of ligand-dependent transcriptional factors that regulate gene expression during many biological processes, including development, cellular proliferation and differentiation. This family includes the steroid hormone and retinoid receptors and orphan receptors for which the ligand is unknown. The activity of these receptors is also relevant to disease since alterations in certain receptor signaling path- ways have been linked to various disease processes. Our laboratory has identified and cloned three novel receptors named TAK1, RTR and ROR gamma. These receptors contain the characteristic structure of other members of this family and contain a DNA-binding domain consisting of two "zinc-fingers" and a putative ligand-binding domain. Each of these receptors exhibit a specific pattern of tissue- and cell type-specific expression suggesting that these receptors play a regulatory role in specific biological processes. RTR expression is highly restricted to the testis and associated with a specific stage of spermatogen- esis. RTR is also highly expressed in embryonal carcinoma and embryonic stem cells suggesting a role in early embryogenesis. RTR bind most optimally as a homodimer to response elements (DR0) containing a direct repeat of the core motif AGGTCA. The protamine 2 gene which is expressed at the same stage of spermatogenesis as RTR, contains a DR0 in its promoter flanking region and a putative target gene for RTR. RORg binds as a monomer to a single core motif preceded by an AT-rich sequence. ROR gamma receptor mRNA is induced during adipocyte differentiation and also highly expressed in T- lymphocytes. The genomic structure of RORg was characterized and shown to consist of 11 exons.