title: Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.
abstract: Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.
authors: Department of Medicine and Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors: Li
authors: L
authors: Du
authors: Marvin
authors: M
authors: Bergsneider
authors: Leili
authors: L
authors: Mirsadraei
authors: Steven H
authors: SH
authors: Young
authors: Johan W
authors: JW
authors: Jonker
authors: Michael
authors: M
authors: Downes
authors: William H
authors: WH
authors: Yong
authors: Ronald M
authors: RM
authors: Evans
authors: Anthony P
authors: AP
authors: Heaney
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003345:Corticosterone / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C490515:NR2C2 protein, human; D009363:Neoplasm Proteins; C490514:Nr2c2 protein, mouse; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone
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