THE ORPHAN RECEPTORS COUP-TF AND HNF-4 SERVE AS ACCESSORY FACTORS REQUIRED FOR INDUCTION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE-TRANSCRIPTION BY GLUCOCORTICOIDS

Glucocorticoids stimulate hepatic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) gene expression, thereby increasing the rate of gluconeogenesis. The effect of glucocorticoids on PEPCK gene expression is mediated by a set of promoter elements collectively referred to as the glucocorticoid response unit. The response unit spans a 100-bp segment and includes two glucocorticoid receptor binding sites (GR1 and GR2) and two accessory factor binding sites (AF1 and AF2), all of which are required for a maximal glucocorticoid response, The AF1 element also serves as a retinoic acid response element and may be involved in developmental and tissue-specific expression of the gene, In this study we report that COUP-TF and HNF-4, two orphan members of the nuclear receptor superfamily, bind to the AF1 element and function as accessory factors for the glucocorticoid response of the PEPCK gene.