Nur77 is a member of the steroid receptor superfamily and is known to be expressed in animals under stress. We studied the role of nur77 in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis during the stress response using a murine pituitary corticotrope cell line, AtT-20. Corticotropin-releasing hormone (CRH), a stress mediator in the HPA axis, induced the expression of nur77 transiently in AtT-20 cells. Gel shift assay showed that nur77 bound to negative glucocorticoid responsive element (nGRE) in the promoter of the human proopiomelanocortin (POMC) gene and the formation of the nur77-nGRE complex increased after treatment of the cells with CRH. Negative GRE is known to be necessary for the negative regulation by glucocorticoid of the POMC gene expression. In stable transformants of AtT-20 cells expressing a human homolog of nur77, NAK-1, at a high level, glucocorticoid-mediated inhibition of both POMC mRNA induction and ACTH secretion was significantly lower than that in the NAK-1-non-expressing cells (P < 0.001). These results strongly suggest that nur77 antagonizes the negative feedback effect of glucocorticoid on the synthesis and secretion of ACTH in pituitary corticotropes. This suggests that nur77 plays an important role in the pituitary gland in the biological adaptation to overcome stress.

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