CREB and the CRTC co-activators: Sensors for hormonal and metabolic signals

Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, Florida 32827, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 03/2011; 12(3):141-51. DOI: 10.1038/nrm3072
Source: PubMed


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.

81 Reads
  • Source
    • "We have described a molecular circuitry that regulates NSC proliferation and self-renewal in response to changes in glucose concentration. Although the main components of this nutrientsensing switch, CREB and Sirt-1, have well recognized roles at the crossroads of nutrient sensing, energy metabolism, and cell or tissue aging (Altarejos and Montminy, 2011;Fusco et al., 2012a) and have already been implicated in the regulation of NSC renewal, survival, and differentiation (Dworkin et al., 2009;Hisahara et al., 2008;Prozorovski et al., 2008;Saharan et al., 2013;Ma et al., 2014), we identified a key role for the glucose-sensing CREB-Sirt1-Hes1 network in the regulation of NSC behavior. Most current protocols recommend NSC cultivation in the presence of supra-physiological concentrations of glucose, close to those employed in studies of cell hyperglycemic damage (Du et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis.
    Full-text · Article · Jan 2016 · Cell Reports
    • "While this approach can provide robust control of a given target gene, it does not adequately mimic transcriptional control by endogenous factors such as CREB. Approximately 5,000 functional CREB binding sites occur in promoter regions of human genes (Zhang et al., 2005), and CREB activation typically leads to transcriptional changes in $100 of these in a given cell type (Altarejos and Montminy, 2011; Barco and Marie, 2011). The subset of responsive genes varies considerably between cell types (Zhang et al., 2005), and which genes become cAMP responsive in a given situation depends both on CREB and a family of co-activator proteins (Altarejos and Montminy , 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN-CREB, a blue-light-controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light-driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events.
    No preview · Article · Nov 2015 · Chemistry & biology
  • Source
    • "The association of CRTCs and CBP with CREB is not mutually self-exclusive. CRTCs interact with the bZIP domain, unlike CBP, which interacts with the KID domain [4]. Although the phosphorylation of CREB is not required for CRTCs and CREB to interact, both phosphorylation and dephosphorylation events must nevertheless occur, albeit at another level. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sodium reabsorption by the kidney is regulated by locally produced natriuretic and anti-natriuretic factors, including dopamine and norepinephrine, respectively. Previous studies indicated that signaling events initiated by these natriuretic and anti-natriuretic factors achieve their effects by altering the phosphorylation of Na,K-ATPase in the renal proximal tubule, and that Protein Kinase A (PKA) and Calcium mediated signaling pathways are involved. The same signaling pathways also control the transcription of the Na,K-ATPase β subunit gene atp1b1 in renal proximal tubule cells. In this report, evidence is presented that 1) both the recently discovered cAMP-Regulated Transcriptional Coactivators (CRTCs), and Salt Inducible Kinase 1 (SIK1) contribute to the transcriptional regulation of atp1b1 in renal proximal tubule (RPT) cells, and 2) that renal effectors including norepinephrine, dopamine, prostaglandins and sodium play a role. Exogenously expressed CRTCs stimulate atp1b1 transcription. Evidence for a role of endogenous CRTCs includes the loss of transcriptional regulation of atp1b1 by a dominant negative CRTC, as well as by a CREB mutant, with an altered CRTC binding site. In a number of experimental systems, SIK phosphorylates CRTCs, which are then sequestered in the cytoplasm, preventing their nuclear effects. Consistent with such a role of SIK in primary RPT cells, atp1b1 transcription increased in the presence of a dominant negative SIK1, and in addition, regulation by dopamine, norepinephrine and monensin was disrupted by a dominant negative SIK1. These latter observations can be explained, if SIK1 is phosphorylated and inactivated in the presence of these renal effectors. Our results support the hypothesis that Na,K-ATPase in the renal proximal tubule is regulated at the transcriptional level via SIK1 and CRTCs by renal effectors, in addition to the previously reported control of the phosphorylation of Na,K-ATPase.
    Full-text · Article · Oct 2015 · Cellular Signalling
Show more