GLUCOCORTICOID RECEPTOR-BETA, A POTENTIAL ENDOGENOUS INHIBITOR OF GLUCOCORTICOID ACTION IN HUMANS

Alternative splicing of the human glucocorticoid receptor (hGR) pre-mR NA generates two highly homologous isoforms, termed hGR alpha and hGR beta. hGR alpha is a ligand-activated transcription factor which, in t he hormone-bound state, modulates the expression of glucocorticoid-res ponsive genes by binding to specific glucocorticoid response element ( GRE) DNA sequences, In contrast, hGR beta does not bind glucocorticoid s and is transcriptionally inactive, We demonstrate here that hGR beta is able to inhibit the effects of hormone-activated hGR alpha on a gl ucocorticoid-responsive reporter gene in a concentration-dependent man ner. [H-3]-Dexamethasone binding studies indicate that hGR beta does n ot alter the affinity of hGR alpha for its hormonal ligand, The presen ce of hGR beta in nuclear extracts and its ability to bind to a radiol abeled GRE oligonucleotide suggest that its inhibitory effect may be d ue to competition for GRE target sites, Reverse transcription-PCR anal ysis shows expression of hGR beta mRNA in multiple human tissues, Thes e results indicate that hGR beta may be a physiologically and pathophy siologically relevant endogenous inhibitor of glucocorticoid action, w hich may participate in defining the sensitivity of target tissues to glucocorticoids, They also underline the importance of distinguishing between the two receptor isoforms in all future studies of hGR functio n and the need to revisit old data,