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. The TAK1 receptor was shown to bind with highest affinity to DR1 hormone response elements and to inhibit the transcriptional activation by PPAR.RXR heterodimers. ROR gamma binds as a monomer to a single core motif preceded by an AT-rich sequence. ROR gamma interacts with several co-activators including CBP and RIP-140. ROR gamma receptor mRNA is highly expressed in brown fat cells and also in the thymus suggesting specific roles in these tissues. The genomic structure of ROR gamma was determined and shown to consist of 11 exons. A knock-out vector has been constructed and is used in generating ROR gamma-null mice.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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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