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Synthesis of rat alpha 1-acid glycoprotein (AGP), one of the major inflammation-induced plasma proteins, is positively regulated by dexamethasone. To define the dexamethasone-responsive genetic element, we isolated and tested AGP gene sequences for the ability to confer glucocorticoid induction to the bacterial chloramphenicol acetyltransferase (CAT) gene in L cells. A 141-base-pair region of the AGP gene, including 120 base pairs of DNA upstream from the start site of transcription and 21 base pairs of the 5' untranslated region, was sufficient for maximal CAT gene induction by dexamethasone. To localize more precisely the AGP glucocorticoid-responsive element, parts of this 141-base-pair region were inserted 5' to either an AGP promoter-CAT gene or a human triosephosphate isomerase promoter-CAT gene, both of which lacked a response to the steroid. The AGP gene region between 120 and 42 base pairs upstream from the start site of transcription was found to mediate maximal dexamethasone induction of CAT enzyme levels. This result was unexpected because this region does not contain sequence homologies to known glucocorticoid receptor-binding sites and those AGP gene regions that lay further upstream and were homologous to other glucocorticoid receptor-binding sites were inactive in the CAT assay. The fact that the AGP gene region mediating dexamethasone regulation was distinct from the transcribed region indicates that glucocorticoids increase AGP gene expression primarily at the transcriptional rather than the posttranscriptional level.