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Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.
Du, Li; Bergsneider, Marvin; Mirsadraei, Leili; Young, Steven H; Jonker, Johan W; Downes, Michael; Yong, William H; Evans, Ronald M; Heaney, Anthony P.
Afiliação
  • Du L; Department of Medicine and Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A ; 110(21): 8555-60, 2013 May 21.
Article em En | MEDLINE | ID: mdl-23653479
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores dos Hormônios Tireóideos / Receptores de Esteroides / Hormônio Adrenocorticotrópico / Hipersecreção Hipofisária de ACTH / Adenoma Hipofisário Secretor de ACT / Proteínas de Neoplasias Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores dos Hormônios Tireóideos / Receptores de Esteroides / Hormônio Adrenocorticotrópico / Hipersecreção Hipofisária de ACTH / Adenoma Hipofisário Secretor de ACT / Proteínas de Neoplasias Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article