Tissue-specific activity of the pro-opiomelanocortin (POMC) gene and repression by glucocorticoids

Abstract

The gene encoding pro-opiomelanocortin (POMC) is specifically expressed in two different cell types of the pituitary gland. We have defined the regulatory DNA sequences of the POMC gene that are responsible for this cell-specific expression. In addition, we have defined a regulatory element, located in the proximal region of the POMC promoter, that confers glucocorticoid repression in the anterior pituitary. Using DNA-mediated gene transfer into transgenic mice and tissue culture cells, the POMC regulatory sequences required for cell-specific expression and glucocorticoid repression were localized within a 543-bp fragment in the 5′-flanking region of the gene. Multiple regulatory elements that bind nuclear proteins are present within this region. In particular, a sequence that binds the glucocorticoid receptor and behaves as a "negative glucocorticoid response element"; (nGRE) also binds nuclear proteins of the COUP (chicken ovalbumin upstream promoter) family of transcription factors. Thus, glucocorticoid repression of POMC transcription may result from the mutually exclusive binding of the glucocorticoid receptor and the COUP transcription factor to the POMC nGRE.Key words: pro-opiomelanocortin, steroid hormone action, repression, tissue-specific expression.