Characterization of CCAAT/enhancer-binding protein α 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 adipose differentiation and hepatic nutrient metabolism. Recently, our laboratory has characterized a role for C/EBP alpha in mediating hormonal responsiveness. For example, the cAMP responsiveness of the phosphoenolpyruvate carboxykinase gene promoter in liver requires synergism among the cAMP response element-binding protein (CREB), C/EBP alpha, and activator protein-1. in the present study, we show that C/EBP alpha can functionally substitute for CREB in this cAMP response unit, i.e. cAMP 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 identified 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 transactivation is distinct from that whereby it mediates cAMP responsiveness. These delta support the hypothesis that C/EBP alpha plays a critical role in metabolism, in part by participating in the hormonal regulation of expression of metabolically important genes.