Nuclear receptor subfamily 2 group C member 2 (Testicular receptor 4) (TR4)

Testicular receptor 4 (TR4), also known as NR2C2, is an orphan nuclear receptor and transcription factor that serves as a critical regulator of diverse physiological processes, including metabolism, development, and cell survival. It is widely expressed across various tissues, with particularly high levels in the testes, prostate, and central nervous system. TR4 functions by binding to specific DNA response elements, such as direct repeats (DR1 and DR5), either as a homodimer or a heterodimer with its close relative TR2. It plays a significant role in the progression of several cancers, notably prostate and liver cancer, and is a key component of the DRED complex that represses fetal globin genes, making it a potential target for treating sickle cell disease and thalassemia. Additionally, TR4 is involved in glucose and lipid metabolism, where its activity often counteracts that of PPAR gamma. Recent pharmacological studies have identified several FDA-approved drugs, such as nilotinib and genistein, as potent modulators of TR4 activity, highlighting its emerging importance as a therapeutic target in oncology and metabolic disorders.

Other names

NR2C2TAK1hTAK1TR2R1Testicular orphan receptor 4

Acts as a ligand-activated transcription factor that binds to direct repeat (DR) response elements (e.g., DR1, DR5) in the promoters of target genes. It can form homodimers or heterodimers with TR2 (NR2C1) to recruit corepressors (e.g., LSD1, DNMT1 in the DRED complex) or coactivators (e.g., PGC-1α, SRC-1), thereby regulating genes involved in metabolism, erythropoiesis, and cell proliferation.