MECHANISM OF ACTION AND FUNCTION OF NUCLEAR RECEPTORS

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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 pathways 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. This is further indicated by observations showing that the expression of RTR and TAK1 in the testis is associated with a specific stage of spermatogenesis. Moreover, RTR expression is down-regulated during differentiation of embryonal carcinoma cells while ROR gamma receptor mRNA is induced during adipocyte differentiation. TAK1, RTR and ROR gamma bind each to response elements containing the core motif AGGTCA. ROR gamma binds as a monomer to a single core motif preceded by an AT- rich sequence whereas RTR and TAK1 bind as homodimers to direct repeats, DRO and DR1-DR5, respectively. The characterization of the response element has been helpful in identifying putative target genes for these orphan receptors. The protamine 2 gene which is expressed at the same stage of spermatogenesis as RTR and contains a DR0 in its promoter flanking region, has been identified as a target gene for RTR. Cross-talk between different receptor signaling pathways plays an important role in the control of gene expression. We have demonstrated that TAK1 can antagonize the transactivation mediated by the thyroid hormone receptor (T3R) and the retinoid receptors (RARs and RXRs). This antagonism is due to the competition of the TAK1 homodimers with RAR-RXR heterodimers and RXR homodimers for the binding to their respective response elements.