cAMP activates transcription of the human glucocorticoid receptor gene promoter

Glucocorticoids and cAMP regulate, either in a synergistic or additive fash ion, the transcription of multiple genes, although some antagonistic effect s of dexamethasone on cAMP-activated transcription have been described. The increased glucocorticoid receptor (GR) mediated response of some cell type s, as a result of augmented cAMP, has been considered to be mainly due to a n increased stability of GR mRNA, although other plausible explanations sho uld not be ruled out. We studied the possibility that GR transcription itse lf could be affected by cAMP levels. HeLa cells were transfected with human GR (hGR) promoter constructs and their transcriptional activity determined after inducing a cAMP increase with forskolin. We found that forskolin alm ost doubled the transcriptional activity of the promoter construct spanning -2995 to +38 of the hGR, whereas no significant variations were observed w ith shorter chimeras containing sequences downstream -979. Shift mobility s howed binding of CREB in vitro to a putative cAMP responsive element locate d at -1000, suggesting that hGR may be upregulated by cAMP at the transcrip tional level, thus adding a new mechanism ascribable to this second messeng er, which in conjunction with the cAMP-induced GR mRNA increased stability, would lead to a more precise control of the amount of GR protein within th e cell. (C) 1998 Elsevier Science Ltd. All rights reserved.