CREB Links cAMP and PKA to Activation of Gene Transcription
Activation of PKA also stimulates the expression of many genes, leading to long-term effects on cells. For instance, in hepatic cells, PKA induces the expression of several enzymes involved in gluconeogenesis—the conversion of three-carbon compounds such as pyruvate (see Figure 12-3) to glucose—thus increasing the concentration of glucose in the blood and enhancing the short-term effects of activated PKA.
All genes regulated by PKA contain a cis-acting DNA sequence, the cAMP-response element (CRE), that binds the phosphorylated form of a transcription factor called CRE-binding (CREB) protein, which is found only in the nucleus. Following the elevation of cAMP levels and the release of active PKA catalytic subunits, some of the catalytic subunits translocate to the nucleus. There they phosphorylate serine-133 on the CREB protein. Phosphorylated CREB binds to CRE-containing target genes and also binds to a co-activator termed CBP/P300 (see Figure 9-31). CBP/P300 links CREB to RNA polymerase II and other gene regulatory proteins, thereby stimulating gene transcription (Figure 15-30).
FIGURE 15-30 Activation of CREB transcription factor following ligand binding to Gαs-coupled GPCRs. Receptor stimulation 1 leads to activation of PKA 2. Catalytic subunits of PKA translocate to the nucleus 3 and there phosphorylate and activate the CREB transcription factor 4. Phosphorylated CREB associates with the co-activator CBP/P300 5 and other proteins to stimulate transcription of the various target genes controlled by a CRE regulatory element. See K. A. Lee and N. Masson, 1993, Biochim. Biophys. Acta 1174:221, and D. Parker et al., 1996, Mol. Cell Biol. 16(2):694.