Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy Ϸ4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.cAMP ͉ cAMP-response element binding protein-binding protein ͉ DNA methylation T he concept of a transcription code that dictates gene expression by means of the concerted action of multiple promoter elements has served as a useful paradigm for understanding specificity in gene regulation. The ability of multiple transcription factors to recruit RNA polymerase II to the promoter by means of low affinity interactions with components of the transcriptional machinery has been documented extensively (1).By contrast with this model, other studies suggest that some activators per se are sufficient to mediate transcriptional responses to hormonal signals depending on the occupancy of relevant sites (1). Indeed, genome-wide studies comparing binding patterns of hepatic nuclear factors in the liver and endocrine pancreas indicate that selective occupancy may often explain how different genetic programs are activated in distinct cell types (2).The cAMP-response element binding protein (CREB) family of activators stimulates cellular gene expression after phosphorylation at a conserved serine (Ser-133 in CREB1) in response to cAMP (3). Ser-133 phosphorylation promotes target gene activation in part by means of recruitment of the coactivator paralogs CREB-binding protein (CBP)͞p300 (4). Recruitment of CBP by phospho-CREB (P-CREB) appears sufficient for induction of cellular genes in response to cAMP (5, 6); in vitro transcription studies indicate that P-CREB is capable of promoting assembly of the transcriptional apparatus independent of other regulatory inputs (7).By contrast, some reports suggest that other upstream activators in addition to CREB are required for cellular gene induction by cAMP (8). Indeed, the notion that CREB coordinates with other transcription factors is supported by recent animal studies in which CREB appeared to elicit the expressi...

through a cAMP-dependent mechanism (Hui et al., John R. Yates III, 2 Hiroshi Takemori, 3, * 2003). The ability of GLP-1 to modulate islet cell gene

The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pan-creatic-cells, develop diabetes secondary to-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2 by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival. Supplemental material is available at http://www.genesdev.org.