Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription.
Glucocorticoids rapidly and specifically inhibit transcription of the pro-opiomelanocortin (POMC) gene in the anterior pituitary, thus offering a model for studying negative control of transcription in mammals. We have defined an element within the rat POMC gene 5'-flanking region that is required for glucocorticoid inhibition of POMC gene transcription in POMC-expressing pituitary tumor cells (AtT-20). This element contains an in vitro binding site for purified glucocorticoid receptor. Site-directed mutagenesis revealed that binding of the receptor to this site located at position base pair -63 is essential for glucocorticoid repression of transcription. Although related to the well-defined glucocorticoid response element (GRE) found in glucocorticoid-inducible genes, the DNA sequence of the POMC negative glucocorticoid response element (nGRE) differs significantly from the GRE consensus; this sequence divergence may result in different receptor-DNA interactions and may account at least in part for the opposite transcriptional properties of these elements. Hormone-dependent repression of POMC gene transcription may be due to binding of the receptor over a positive regulatory element of the promoter. Thus, repression may result from mutually exclusive binding of two DNA-binding proteins to overlapping DNA sequences.
Drouin
J
J
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal, Quebec, Canada.
Trifiro
M A
MA
Plante
R K
RK
Nemer
M
M
Eriksson
P
P
Wrange
O
O
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D005796:Genes; D008969:Molecular Sequence Data; D009710:Nucleotide Mapping; D010903:Pituitary Gland, Anterior / Q000378:metabolism; D010957:Plasmids; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011485:Protein Binding; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015183:Restriction Mapping; D013489:Suppression, Genetic; D014158:Transcription, Genetic
D011965:Receptors, Glucocorticoid; D011333:Pro-Opiomelanocortin; D004247:DNA