Testicular Receptor-4 (TR4) Modulates Proopiomelanocortin Gene Transcription By Binding the Glucocorticoid Receptor (GR) in Corticotroph Tumor Cells

Cushing’s disease is a life-threatening neuroendocrine disorder due to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH). No safe and effective medical therapy exists currently to target the corticotroph tumors. Glucorticoid resistance is a common yet largely unexplained phenomenon in many medical conditions and significantly limits therapeutic efficacy of administered glucocorticoids. We previously demonstrated that the orphan nuclear receptor TR4 (nuclear receptor subfamily 2, group C, member 2) binds the proopiomelanocortin (POMC) promoter to potently induce POMC expression and ACTH secretion form corticotroph tumor cells. Our further studies demonstrate that TR4 blocks both glucocorticoid and GR-mediated suppression of POMC transcription. Co-immunoprepicitation studies indicate that TR4 binds the GR in corticotroph tumor cells. In addition to abrogation of GR-directed POMC suppression, our quantitative RT-PCR studies show that TR4 modifies downstream expression of several GR target genes. Our results demonstrate that TR4 binds GR to play an important role in modulating GR actions. Further characterization of this pathway may offer important insights into glucocorticoid resistance.