The regulation of gene expression during cellular differentiation is controlled by various classes of transcriptional factors. One such class consists of nuclear receptors and include the steroid and thyroid hormone, retinoid receptors and orphan receptors for which the ligand is unknown. Our laboratory has identified and cloned three novel receptors named TAK1, RTR and ROR gamma. These receptors exhibit 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 has a specific pattern of tissue-specific expression. The expression of the RTR receptor is the most restricted and is limited to testis and ovary. RTR expression in the testis is associated with a specific spermatogenesis. The ROR gamma receptor is highly expressed in skeletal muscle, kidney and liver. Although TAK1 is expressed in most tissue, it is expressed in a cell-type specific manner. In the testis it expressed at a specific stage of spermatogenesis and in the muscle its expression is associated with the muscle fiber rather then the connective tissue. These orphan receptors bind each to response elements containing the core motif AFFTCA. ROR gamma binds as a monomer to a single core motif whereas RTR and TAK1 bind as homodimers to direct repeats, DRO or DRO-DR5, respectively. We have demonstrated that TAK1 can antagonize the transactivation mediated by the thyroid hormone receptor (T#R) and the retinoid receptors (RARs and RXRs). This antagonism is due to the competition of the TAK1 homodimers with RAR-RXR and T3R-RXR heterodimers and RXR homodimers for the binding to their respective response elements. Future studies will concentrate on the further characterization of the function of these receptors and the identification of target genes that these receptors control.
| Ueda, Eiichiro; Kurebayashi, Shogo; Sakaue, Morito et al. (2002) High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORgamma. Cancer Res 62:901-9 |
| Kurebayashi, S; Sumitani, S; Kasayama, S et al. (2001) TNF-alpha inhibits 3T3-L1 adipocyte differentiation without downregulating the expression of C/EBPbeta and delta. Endocr J 48:249-53 |
| Jetten, A M; Kurebayashi, S; Ueda, E (2001) The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Prog Nucleic Acid Res Mol Biol 69:205-47 |
| Kurebayashi, S; Ueda, E; Sakaue, M et al. (2000) Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A 97:10132-7 |
