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.
"cAMP-responsive element-binding (CREB) protein CREB is a transcription factor that binds to an 8-bp element known as the cAMP-response element (CRE) in the promoter regions of target genes (Altarejos and Montminy, 2011). CREB is expressed in several tissues that regulate the expression of genes related to neuronal differentiation, adipocyte differentiation, hepatic glucose levels, and lipid metabolism (Altarejos and Montminy, 2011; Ravnskjaer et al., 2013). Suppressing CREB using antisense-oligonucleotides (ASOs) prevents hepatic insulin resistance and steatosis-associated T2DM (Erion et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Post-translational modifications (PTMs) of transcription factors play a crucial role in regulating metabolic homeostasis. These modifications include phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. Recent studies have shed light on the importance of lysine acetylation at nonhistone proteins including transcription factors. Acetylation of transcription factors affects subcellular distribution, DNA affinity, stability, transcriptional activity, and current investigations are aiming to further expand our understanding of the role of lysine acetylation of transcription factors. In this review, we summarize recent studies that provide new insights into the role of protein lysine-acetylation in the transcriptional regulation of metabolic homeostasis.
Protein & Cell 09/2015; DOI:10.1007/s13238-015-0204-y · 3.25 Impact Factor
"We then verified that glucagon signaling was induced efficiently in response to hypoglycemia. Glucagon leads to an increase in cyclic AMP (cAMP) that activates protein kinase A (PKA), which, in turn, phosphorylates CREB, a key transcription factor controlling gluconeogenic gene expression (Altarejos and Montminy, 2011). The basal cAMP levels and PKA activity were increased in the liver of Rab5KD animals compared to control (Figures 5A and 5B). "
"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. "
[Show abstract][Hide abstract] 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.
Note: This list is based on the publications in our database and might not be exhaustive.
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