Atp

CBP/P,GG

Basal transcription machinery

Basal transcription machinery

Transcription

Transcription

CREB Links cAMP Signals to Transcription

In mammalian cells, an elevation in the cytosolic cAMP level stimulates the expression of many genes. For instance, increased cAMP in certain endocrine cells induces production of somatostatin, a peptide that inhibits release of various hormones; in liver cells, cAMP induces synthesis of several enzymes involved in converting three-carbon compounds to glucose.

All genes regulated by cAMP 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. As discussed previously, binding of neurotransmitters and hormones to Gs protein-coupled receptors activates adenylyl cyclase, leading to an increase in cAMP and subsequent release of the active catalytic subunit of PKA. Some of the catalytic subunits then translocate to the nucleus and phosphorylate serine-133 on CREB protein.

Phosphorylated CREB protein binds to CRE-containing target genes and also interacts with a co-activator termed CBP/300, which links CREB to the basal transcriptional machinery, thereby permitting CREB to stimulate transcription (Figure 13-32). Earlier studies suggested that phosphoryla-tion induced a conformational change in CREB protein, but more recent work indicates that CBP/P300 binds specifically to phosphoserine-133 in activated CREB. As discussed in Chapter 11, other signal-regulated transcription factors rely on CBP/P300 to exert their activating effect. Thus this co-activator plays an important role in integrating signals from multiple signaling pathways that regulate gene transcription.

GPCR-Bound Arrestin Activates Several Kinase Cascades That Control Gene Expression

We saw earlier that binding of p-arrestin to phosphorylated serines in the cytosolic domain of G protein-coupled receptors both blocks activation of Ga and mediates endocytosis of the GPCR-arrestin complex. Perhaps surprisingly, the GPCR-arrestin complex also acts as a scaffold for binding and activating several cytosolic kinases (see Figure 13-19). These include c-Src, which activates the MAP kinase pathway and other pathways leading to transcription of genes needed for cell division. A complex of three arrestin-bound proteins, including a Jun N-terminal kinase (JNK-1), initiates a kinase cascade that ultimately activates the c-Jun transcription factor. Activated c-Jun promotes expression of certain growth-promoting enzymes and other proteins that help cells respond to some stresses.

Binding of epinephrine to the p-adrenergic receptors in heart muscle stimulates glycogenolysis and enhances the rate of muscle contraction. Prolonged treatment with epinephrine, however, induces proliferation of these cardiac muscle cells. In extreme cases, such cardiac hypertrophy causes failure of the heart muscle, a major cause of heart disease. This epinephrine-induced cell proliferation results in part from activation of the MAP kinase cascade. As just described, the GPCR-arrestin complex can trigger this cascade.

Another, perhaps more important, way that activation of p-adrenergic receptors promotes cardiac hypertrophy involves another type of receptor. The Gs protein activated by p-adrenergic receptors can somehow lead to activation of a specific extracellular metal-containing protease that, in turn, cleaves the transmembrane precursor of epidermal growth factor (EGF). The soluble EGF released into the extracellular space binds to and activates EGF receptors on the same cell in an autocrine fashion. As we learn in the next chapter, the EGF receptor belongs to the receptor tyrosine ki-nase (RTK) class of receptors, which commonly trigger the MAP kinase cascade leading to cell proliferation. Similar cross-talk between two types of receptors occurs in many other signaling systems. Just as no cell lives in isolation, no receptor and no signal-transduction pathway function by themselves. I

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