OCT4 modulates Pomc gene transcription by interfering with specific corticotroph transcription factors.

backgroundCorticotroph cells produce and secrete adrenocorticotropic hormone (ACTH) from the pro-opiomelanocortin (Pomc) gene. Corticotroph function is controlled by hypothalamic signals through the action of corticotrophin-releasing hormone (CRH) through Nur77 nuclear factor and by feedback repression by glucocorticoids (GC) from adrenal gland acting through the glucocorticoid receptor (GR). Corticotroph adenomas, a pituitary neoplasm, exhibit multiple potential sites of altered signaling, with regulation of the Pomc gene being particularly critical. During differentiation, stem cell markers are silenced, however, some pituitary tumors present expression of progenitor factors. Although some reports show the expression of OCT4 in corticotrophs, its function remains unknow.

methodsWe performed immunoblotting, subcellular fractionation and histochemistry to determine the protein expression of OCT4 in corticothoph cells and in corticotrophic human samples. To study the transcriptional modulation of Pomc promoter by OCT4 and the mechanistic interaction between knowing regulators of ACTH-secreting cells and OCT4, we performed luciferase reporter and immunoprecipitation assays.

resultsOCT4 is expressed in AtT-20 corticotroph cells, in human tumoral samples of patients with an ACTH-secreting tumor, and to a much lesser extent in normal pituitary, showing an expression predominantly nuclear. OCT4 inhibits the transcription of the Pomc gene not by binding to the Pomc promoter, but through its interaction with the transcription factor Nur77. OCT4 also interacts with the negative Pomc regulator GR.

conclusionOur study allows to identify that progenitor marker OCT4 is not only expressed in corticotroph pituitary cells but acts on Pomc regulation through the functional interaction with Nur77 and GR.