Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

Du L.; Bergsneider M.; Mirsadraei L.Young S.H.Jonker J.W.Downes M.Yong W.H.Evans R.M.Heaney A.P.

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Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

机译：Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

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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.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第21期|8555-8560|共6页
作者
Du L.; Bergsneider M.; Mirsadraei L.Young S.H.Jonker J.W.Downes M.Yong W.H.Evans R.M.Heaney A.P.;
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作者单位

Departments of Medicine and Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, United States;

Center for Liver, Digestive, and Metabolic Diseases, Department of Pediatrics, University of Groningen, 9713 GZ, Groningen, Netherlands;

Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA 92037, United States;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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正文语种英语
中图分类自然科学总论;
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Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease

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