In eukaryotes, transcriptional regulation on stimulation of the adenylate cyclase signaling pathway is mediated by a family of cyclic AMP-responsive nuclear factors, including CREB, CREM, and ATF-1. These factors contain the basic domain/leucine zipper motifs and bind as dimers to cAMP-responsive elements (CREs). The activation function of CRE-binding proteins is modulated by phosphorylation by several kinases and is mediated by coactivators such as CBP and p300. Activation might also be independent of CBP and phosphorylation in some specific cell types, such as male germ cells, wherein the protein ACT confers a powerful activation function to CREM. The inducible cAMP early repressor (ICER) protein is the only inducible member of this family. The induction of this powerful repressor is likely to be important for the transient nature of cAMP-induced gene expression. CRE-binding proteins have been found to play an important role in the physiology of the pituitary gland, in regulating spermatogenesis, in the response to circadian rhythms, and in the molecular basis of memory.