Identification of glucocorticoid-responsive elements that control transcription of rat glutamine synthetase

Basal expression of glutamine synthetase (GS) is very low in rat lung and m uscle and remarkably enhanced by glucocorticoid hormones during trauma and catabolic states. Although this response is believed to be transcriptionall y regulated, the genetic elements responsible for tissue-specific glucocort icoid induction of GS expression have not been identified. A rat lung epith elial cell line (L2) and a glucocorticoid receptor-deficient human prostate cancer cell line (PC3), together with GS reporter gene constructs, were ut ilized in gene transfer experiments to identify two regions within the rat genomic clone gGS3 that imparted dexamethasone (Dex) responsiveness to both the homologous GS promoter and the heterologous herpes simplex virus thymi dine kinase promoter in glucocorticoid receptor-dependent fashions. One reg ion lies nearly 6 kb upstream of the GS transcription initiation site, and the other lies within the first intron of the GS gene. Dex responsiveness w as localized to a 325-bp fragment of the intron region containing a canonic al glucocorticoid response element and to a 225-bp fragment of the far-upst ream region containing three separate glucocorticoid response element half- sites. The GS promoter exhibited relatively high basal activity that was re pressed by inclusion of the far-upstream or the intron glucocorticoid-respo nsive region. Dex treatment negated this repression. A model is suggested i n which the glucocorticoid-receptor unit causes derepression of lung and mu scle GS transcription during trauma and catabolic states.