Signal transduction and gene regulation: the nuclear response to cAMP

Abstract

Transcription factors are recognized to be important nuclear targets for intracellular signal transduction systems.An increase in the intracellular levels of cyclic 3',5'-adenosine monophosphate (CAMP) is generated by the activation of adenylyl cyclase.This membrane-associated enzyme is stimulated upon the binding of specific receptors to their ligands via coupling with GTP-binding proteins (1).CAMP, in turn, binds cooperatively to two sites on the regulatory subunit of protein kinase A (PKA),l releasing the active catalytic subunit (2).This is translocated from its cytoplasmic and Golgi complex anchoring sites (3, 4) and phosphorylates its substrate (the serine in the context X-Arg-Arg-X-Ser-X) present in a number of cytoplasmic and nuclear proteins.It is remarkable that the elevation of intracellular CAMP levels can result in either stimulation or repression of specific gene expression (1, 5, 6), suggesting that complex, cell-specific molecular mechanisms must operate in the nucleus.The purpose of this review is to summarize the molecular aspects of the nuclear response to CAMP by connecting the biochemical and structural features of the regulatory factors with their physiological function.Activated PKA appears to modulate the function of nuclear factors that bind to DNA sequences present in the promoter regions of CAMP-inducible genes.Most of these genes contain one or a few CAMP-responsive elements (CREs) (1, 5, 6).The consensus CRE is constituted by the palindromic sequence TGACGTCA, which is strikingly similar to the binding site of the transcription factor AP-1 (1).Variations from the consensus CRE are common (1).The first nuclear factor to be cloned that binds to a CRE was CRE-binding protein (CREB) (7).CREB has been followed by many other proteins, which can be classified into several groups.They all belong to the basic region/ leucine zipper (bZip) transcription factor class (Fig. 1).In these proteins the DNA-binding domain is composed of a conserved region of about 30 amino acids, rich in basic residues.Immediately C-terminal to this basic region lies a region with a heptad leucine repeat.This can form a n amphipathic a-helix with the leucine residues aligned along one ridge, two of these helices associating in a coiled-coil conformation (leucine zipwhich will be available in December, 1994.Work in our laboratory is * This minireview will be reprinted in the Minireview Compendium, supported by the Institut de la