Minireview: Pathophysiological roles of the TR4 nuclear receptor: lessons learned from mice lacking TR4.
Testicular nuclear receptor 4 (TR4), also known as NR2C2, belongs to the nuclear receptor superfamily and shares high homology with the testicular nuclear receptor 2. The natural ligands of TR4 remained unclear until the recent discoveries of several energy/lipid sensors including the polyunsaturated fatty acid metabolites, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, and their synthetic ligands, thiazolidinediones, used for treatment of diabetes. TR4 is widely expressed throughout the body and particularly concentrated in the testis, prostate, cerebellum, and hippocampus. It has been shown to play important roles in cerebellar development, forebrain myelination, folliculogenesis, gluconeogenesis, lipogenesis, muscle development, bone development, and prostate cancer progression. Here we provide a comprehensive summary of TR4 signaling including its upstream ligands/activators/suppressors, transcriptional coactivators/repressors, downstream targets, and their in vivo functions with potential impacts on TR4-related diseases. Importantly, TR4 shares similar ligands/activators with another key nuclear receptor, peroxisome proliferator-activated receptor γ, which raised several interesting questions about how these 2 nuclear receptors may collaborate with or counteract each other's function in their related diseases. Clear dissection of such molecular mechanisms and their differential roles in various diseases may help researchers to design new potential drugs with better efficacy and fewer side effects to battle TR4 and peroxisome proliferator-activated receptor γ involved diseases.
George Whipple Laboratory for Cancer Research (S.-J.L., Y.Z., N.-C.L., C.C.), Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14646; Department of Urology (D.-R.Y.), the Second Affiliated Hospital of Suzhou University, Suzhou, 215004 China; Chawnshang Chang Liver Cancer Center and Department of Urology (G.L.), Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016 China; and Sex Hormone Research Center (C.C.), China Medical University/Hospital, Taichung, 404 Taiwan.
Shin-Jen
SJ
Lin
Yanqing
Y
Zhang
Ning-Chun
NC
Liu
Dong-Rong
DR
Yang
Gonghui
G
Li
Chawnshang
C
Chang
D000375:Aging; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics; D006801:Humans; D007246:Infertility / Q000235:genetics; D024821:Metabolic Syndrome / Q000235:genetics; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics; D011499:Protein Processing, Post-Translational; D011987:Receptors, Steroid / Q000235:genetics* / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction
C490514:Nr2c2 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone