Transcription activation by the orphan nuclear receptor, chicken ovalbuminupstream promoter-transcription factor I (COUP-TFI) - Definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs), orpha n members of the nuclear receptor superfamily, play a key role in the regul ation of organogenesis, neurogenesis, and cellular differentiation during e mbryogenic development. COUP-TFs are also involved in the regulation of sev eral genes that encode metabolic enzymes. Although COUP-TFs function as pot ent transcription repressors, there are at least three different molecular mechanisms of activation of gene expression by COUP-TFs, First, as we have previously shown, COUP-TF is required as an accessory factor for the comple te induction of phosphoenolpyruvate carboxykinase gene transcription by glu cocorticoids, This action is mediated by the binding of COUP-TF to the gluc ocorticoid accessory factor 1 (gAF1) and 3 (gAF3) elements in the phosphoen olpyruvate carboxykinase gene glucocorticoid response unit. In addition, CO UP-TF1 binds to DNA elements in certain genes and transactivates directly. Finally, COUP-TF1 serves as a coactivator through DNA-bound hepatic nuclear factor 4, Here we show that the same region of COUP-TFI, located between a mino acids 184 and 423, is involved in these three mechanisms of transactiv ation by COUP-TFI, Furthermore, we show that GRIP1 and SRC-1 potentiate the activity of COUP-TFI and that COUP-TFI associates with these coactivators in vivo using the same region required for transcription activation. Finall y, overexpression of GRIP1 or SRC-1 does not convert COUP-TFI from a transc riptional repressor into a transcriptional activator in HeLa cells.