Transcriptional Regulation via the cAMP Responsive Activator CREB

There are three principal cAMP responsive transcription factors in mammals, the cAMP responsive element binding protein (CREB), activating transcription factor (ATF-1), and cAMP responsive element modulator tau. Mammalian CREB has four main functional domains that include the basic/leucine zipper domain (bZIP), the Kinase Inducible Domain (KID), and two glutamine-rich domains (Q1, and Q2 or CAD). The bZIP provides dimerization and DNA binding activities but CREB bZIP has recently been shown to confer transactivation function by binding the TORC coactivators. The two glutamine-rich constitutive activation domains, Q1 and Q2, provide transactivation function in the absence of cAMP signaling and synergize with KID and bZIP to confer full activity to CREB in response to cAMP; however, ATF-1 lacks Q1, and Q2 is considered to be more critical for CREB function. The genes for CBP (Crebbp) and p300 (E1A binding protein p300, Ep300) encode highly related histone acetyltransferases that possess several conserved protein binding domains that bind a variety of transcriptional regulators and other proteins. The interaction between CBP/p300 and TORC appears to be important in determining which genes respond to different stimuli that result in Ser133 phosphorylation. The three TORC family members, TORC1, TORC2, and TORC3 (or CREB regulated transcription coactivator, Crtc1, Crtc2, Crtc3), are unrelated to CBP and p300. TORCs 1 and 2 are sequestered in the cytoplasm until activated by cAMP or calcium, whereupon they transit to the nucleus; TORC3 is constitutively nuclear and possesses an N-terminal coiled-coil domain that binds the CREB bZIP.