CREB and the CRTC co-activators: Sensors for hormonal and metabolic signals
ABSTRACT The cyclic AMP-responsive element-binding protein (CREB) is phosphorylated in response to a wide variety of signals, yet target gene transcription is only increased in a subset of cases. Recent studies indicate that CREB functions in concert with a family of latent cytoplasmic co-activators called cAMP-regulated transcriptional co-activators (CRTCs), which are activated through dephosphorylation. A dual requirement for CREB phosphorylation and CRTC dephosphorylation is likely to explain how these activator-co-activator cognates discriminate between different stimuli. Following their activation, CREB and CRTCs mediate the effects of fasting and feeding signals on the expression of metabolic programmes in insulin-sensitive tissues.
- SourceAvailable from: My-Nhan Nguyen
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- "This finding may suggest a sequential signaling event leading to suppression of VEGF expression. According to the proposed " coactivator-poor " model, (Kasper et al. 2010; Altarejos and Montminy 2011) there is only one putative CRE palindrome in the VEGF promoter. Thus, recruitment of CBP and p300 to the CRE site as well as the phosphorylation of CREB are crucial to VEGF expression following b 2 AR-promoted CREB phosphorylation in cardiomyocytes. "
ABSTRACT: β-adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte-restricted overexpression of β2-adrenoceptors (β2-TG), and the effect of cardiac pressure overload. β2-TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2-TGs showed upregulated expression of vascular endothelial growth factor (VEGF), heightened phosphorylation of cAMP-responsive-element-binding protein (CREB), and increased recruitment of phospho-CREB, CREB-binding protein (CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction (TAC), angiogenic signaling in β2-TGs was inhibited within 1 week after TAC. β2-TG hearts, but not controls, exposed to pressure overload for 1–2 weeks showed significant increases from baseline in phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKIIδ) and protein expression of p53, reduction in CREB phosphorylation, and reduced abundance of phospho-CREB, p300 and CBP recruited to the CREB-responsive element (CRE) site of VEGF promoter. These changes were associated with reduction in both VEGF expression and capillary density. While non-TG mice with TAC developed compensatory hypertrophy, (2-TGs exhibited exaggerated hypertrophic growth at week-1 post-TAC, followed by LV dilatation and reduced fractional shortening measured by serial echocardiography. In conclusion, angiogenesis was enhanced by the cardiomyocyte (2AR/CREB/VEGF signaling pathway. Pressure overload rapidly inhibited this signaling, likely as a consequence of activated CaMKII and p53, leading to impaired angiogenesis and functional decompensation.03/2015; 3(3). DOI:10.14814/phy2.12340
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- "The PKA-dependent action of GLP-1R agonists is mediated by cAMP response elements (CREs) located in the human insulin gene (Hay et al. 2005). As illustrated in Fig. 3, CREs bind the cAMP response elementbinding protein (CREB), a basic region leucine zipper transcription factor (bZIP) that is regulated by PKA and co-activators p300 and CRTC in β-cells (Altarejos and Montminy 2011; Dalle et al. 2011b). These CREs also bind bZIPs that mediate Fig. 3 cAMP-stimulated gene expression in β-cells results from PKA holoenzyme activation with consequent translocation of PKA catalytic subunits to the nucleus where PKA phosphorylates CREB on Ser-133. "
ABSTRACT: Recent advances in conditional gene targeting and cyclic nucleotide research further our understanding of how the incretin hormone GLP-1 exerts a therapeutically important action to restore pancreatic insulin secretion in patients with type 2 diabetes mellitus (T2DM). These studies demonstrate that the pancreatic β-cell GLP-1 receptor has the capacity to signal through two distinct branches of the adenosine 3′,5′-cyclic monophosphate (cAMP) signal transduction network; one branch activates protein kinase A (PKA), and the second engages a cAMP-regulated guanine nucleotide exchange factor designated as Epac2. Under normal dietary conditions, specific activation of the cAMP-PKA branch in mice dramatically augments glucose-stimulated insulin secretion (GSIS). However, under conditions of diet-induced insulin resistance, cAMP-Epac2 signaling in the control of GSIS becomes prominent. This chapter provides an update on GLP-1 receptor signaling in the islets of Langerhans, with special emphasis on key molecular events that confer “plasticity” in the β-cell cAMP signal transduction network.Islets of Langerhans, Second edited by Md. Shahidul Islam, 01/2015: chapter 25: pages 565-603; Springer., ISBN: 978-94-007-6685-3
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- "Sustained phosphorylation of serine 133 (S133) is crucial for transcriptional activity of CREB (Shaywitz and Greenberg, 1999) because it enhances the transactivational properties of CREB by recruiting the co-activator CREB-binding protein (CBP/p300), which then results in the expression of plasticity-related genes such as brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc/ Arg3.1) (Yamamoto et al., 1988; Impey and Goodman, 2001; Patterson et al., 2001; Vanhoutte and Bading, 2003; Kalkhoven, 2004; Hardingham and Bading, 2010). However, additional phosphorylation sites on CREB like serine 117, 129, 142, 143 have also been implicated in regulating CREB's transcriptional activity (Johannessen et al., 2004, 2007; Altarejos and Montminy, 2011). CRTC1 was recently shown to be a synapse-to-nucleus transcriptional co-activator (Ch'ng et al., 2012), which specifically associates with the bZIP domain of promoter bound CREB (Luo et al., 2012). "
ABSTRACT: Long-lasting changes in neuronal excitability require activity-dependent gene expression and therefore the transduction of synaptic signals to the nucleus. Synaptic activity is rapidly relayed to the nucleus by membrane depolarization and the propagation of Ca(2+) -waves. However, it is unlikely that Ca(2+)-transients alone can explain the specific genomic response to the pleithora of extracellular stimuli that control gene expression. In recent years a steadily growing number of studies report the transport of proteins from synapse to nucleus. Potential mechanisms for active retrograde transport and nuclear targets for these proteins have been identified and recent reports assigned first functions to this type of long-distance signaling. In this review we will discuss how the dissociation of synapto-nuclear protein messenger from synaptic and extrasynaptic sites, their transport, nuclear import and the subsequent genomic response relate to the prevailing concept behind this signaling mechanism, the encoding of signals at their site of origin and their decoding in the nucleus.Neuroscience 09/2014; 280. DOI:10.1016/j.neuroscience.2014.09.011 · 3.33 Impact Factor