Eukaryotic gene transcription is regulated by sequence-specific transcription factors that bind modular cis acting promoter and enhancer elements. The ATF/CREB transcription factor family binds the palindromic cAMP response element (CRE) octanucleotide TGACGTCA. The ATF/CREB family includes CREB-1, CREB-2 (also designated ATF-4), ATF-1, ATF-2 and ATF-3. This family of proteins contains highly divergent N-terminal domains, but shares a C-terminal leucine zipper for dimerization and DNA binding. Although CREB can bind to DNA in an unphosphorylated state, it cannot activate transcription.Phosphorylation of CREB on Ser 133 by protein kinase A facilitates its interaction with the CREB-binding protein (CBP) and activates the basal transcription complex. CREB functions in neoglucogenesis through interactions with the nuclear coactivator PGC-1. CREB may play a role in the pathogenesis of type II diabetes and dilated cardiomyopathy.