CHARACTERIZATION OF CCAAT ENHANCER-BINDING PROTEIN-ALPHA AS A CYCLIC AMP-RESPONSIVE NUCLEAR REGULATOR/

The alpha isoform of CCAAT/enhancer-binding protein (C/EBP alpha) is a transcription factor that regulates expression of genes linked to adi pose differentiation and hepatic nutrient metabolism. Recently, our la boratory has characterized a role for C/EBP alpha in mediating hormona l responsiveness. For example, the cAMP responsiveness of the phosphoe nolpyruvate carboxykinase gene promoter in liver requires synergism am ong the cAMP response element-binding protein (CREB), C/EBP alpha, and activator protein-1. in the present study, we show that C/EBP alpha c an functionally substitute for CREB in this cAMP response unit, i.e. c AMP responsiveness can occur in the absence of CREB. This observation is physiologically relevant since both CREB and C/EBP alpha have been shown to hind with high affinity to the cAMP response element in this particular promoter. Structure/function analysis of C/EBP alpha identi fied specific mutations that differentially affected its constitutive and protein kinase A-inducible activities. This finding suggests that the mechanism whereby C/EBP alpha mediates constitutive transactivatio n is distinct from that whereby it mediates cAMP responsiveness. These delta support the hypothesis that C/EBP alpha plays a critical role i n metabolism, in part by participating in the hormonal regulation of e xpression of metabolically important genes.