RAR-related orphan receptor gamma
|RAR-related orphan receptor C|
Crystallographic structure of the ligand binding domain of RORγ (rainbow colored, N-terminus = blue, C-terminus = red) complexed with 25-hydroxycholesterol (space-filling model (carbon = white, oxygen = red) and the NCOA2 coactivator (magneta).
|External IDs||IUPHAR: ChEMBL: GeneCards:|
RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC (RAR-related orphan receptor C) gene. RORγ is member of the nuclear receptor family of transcription factors.
- RORγ (also referred to as RORγ1) – produced from an mRNA containing exons 1 to 11.
- RORγt (also known as RORγ2) – produced from an mRNA identical to that of RORγ, except that the two 5'-most exons are replaced by an alternative exon, located downstream in the gene. This causes a different, shorter N-terminus.
The mRNA of the first isoform, RORγ is expressed in many tissues, including thymus, lung, liver, kidney, muscle, and brown fat. While RORγ mRNA is abundantly expressed, attempts to detect RORγ protein have not been successful therefore it is not clear whether RORγ protein is actually expressed. Consistent with this, the main phenotypes identified in RORγ-/- knockout mice (where neither isoform is expressed) are those associated with RORγt immune system function and an isoform specific RORγt knockout displayed a phenotype identical to the RORγ-/- knockout. On the other hand, circadian phenotypes of RORγ-/- mice in tissues where the RORγt isoform is expressed in minute amounts argues for the expression of functional RORγ isoform. Absent protein in previous studies may be due to the high amplitude circadian rhythm of expression of this isoform in some tissues.
The tissue distribution of the second isoform, RORγt, appears to be highly restricted to the thymus where it is expressed exclusively in immature CD4+/CD8+ thymocytes and in lymphoid tissue inducer (LTi) cells. RORγt inhibitors are under development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis.
The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear receptors. Although the specific functions of this nuclear receptor have not been fully characterized yet, some roles emerge from the literature on the mouse gene.
The RORγ isoform appears to be involved in the regulation of circadian rhythms. This protein can bind to and activate the promoter of the ARNTL (BMAL1) gene, a transcription factor central to the generation of physiological circadian rhythms. Also, since the levels of RORγ are rhythmic in some tissues (liver, kidney), it has been proposed to impose a circadian pattern of expression on a number of clock-controlled genes, for example the cell cycle regulator p21.
RORγt is the more studied of the two isoforms. Its best understood functionality is in the immune system. The transcription factor is essential for lymphoid organogenesis, in particular lymph nodes and Peyer's patches, but not the spleen. RORγt also plays an important regulatory role in thymopoiesis, by reducing apoptosis of thymocytes and promoting thymocyte differentiation into pro-inflammatory T helper 17 (Th17) cells. It also plays a role in inhibiting apoptosis of undifferentiated T cells and promoting their differentiation into Th17 cells, possibly by down regulating the expression of Fas ligand and IL2, respectively .
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- Hirose T, Smith RJ, Jetten AM (December 1994). "ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle". Biochemical and Biophysical Research Communications 205 (3): 1976–83. doi:10.1006/bbrc.1994.2902. PMID 7811290.
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- Villey I, de Chasseval R, de Villartay JP (December 1999). "RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORgamma / TOR, is up-regulated by signaling through the pre-T cell receptor and binds to the TEA promoter". European Journal of Immunology 29 (12): 4072–80. doi:10.1002/(SICI)1521-4141(199912)29:12<4072::AID-IMMU4072>3.0.CO;2-E. PMID 10602018.
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- Medvedev A, Chistokhina A, Hirose T, Jetten AM (November 1997). "Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene". Genomics 46 (1): 93–102. doi:10.1006/geno.1997.4980. PMID 9403063.
- Medvedev A, Yan ZH, Hirose T, Giguère V, Jetten AM (November 1996). "Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element". Gene 181 (1–2): 199–206. doi:10.1016/S0378-1119(96)00504-5. PMID 8973331.
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- Guillaumond F, Dardente H, Giguère V, Cermakian N (October 2005). "Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors". Journal of biological rhythms 20 (5): 391–403. doi:10.1177/0748730405277232. PMID 16267379.
- Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (July 2002). "The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell 110 (2): 251–60. doi:10.1016/S0092-8674(02)00825-5. PMID 12150932.
- Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR (June 2000). "Requirement for RORgamma in thymocyte survival and lymphoid organ development". Science 288 (5475): 2369–73. doi:10.1126/science.288.5475.2369. PMID 10875923.
- Eberl G, Littman DR (July 2004). "Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells". Science 305 (5681): 248–51. doi:10.1126/science.1096472. PMID 15247480.
- "Merck and Lycera to Develop Oral Autoimmune Disease Drugs Targeting Th17 Cells". Mar 2011.
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- Akashi M, Takumi T (May 2005). "The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1". Nature structural & molecular biology 12 (5): 441–8. doi:10.1038/nsmb925. PMID 15821743.
- Gréchez-Cassiau A, Rayet B, Guillaumond F, Teboul M, Delaunay F (February 2008). "The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation". The Journal of Biological Chemistry 283 (8): 4535–42. doi:10.1074/jbc.M705576200. PMID 18086663.
- Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, Jetten AM (August 2000). "Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis". Proceedings of the National Academy of Sciences of the United States of America 97 (18): 10132–7. doi:10.1073/pnas.97.18.10132. PMC 27750. PMID 10963675.
- Dong C (May 2008). "TH17 cells in development: an updated view of their molecular identity and genetic programming". Nature Reviews Immunology 8 (5): 337–48. doi:10.1038/nri2295. PMID 18408735.
- orphan nuclear receptor ROR-gamma at the US National Library of Medicine Medical Subject Headings (MeSH)