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

Key Points

  • Cyclic AMP-responsive element-binding protein (CREB) mediates induction of cAMP-responsive genes following its phosphorylation at Ser133 by protein kinase A (PKA). CREB phosphorylation increases its activity by promoting an association with the co-activator paralogues CREB-binding protein (CBP) and p300.

  • The cAMP-regulated transcriptional co-activators (CRTCs) mediate CREB target gene activation following their dephosphorylation and nuclear translocation, when they bind to CREB over relevant promoters. CRTCs are selectively activated by cAMP and calcium signals, perhaps explaining why only a subset of stimuli that promote CREB phosphorylation also increase target gene expression.

  • CRTC1 is expressed almost exclusively in the hypothalamus, where it mediates effects of leptin on satiety. CRTC1 reduces food intake by stimulating the expression of the neuropeptide cocaine- and amphetamine-regulated transcript 1 (CART1) in arcuate cells.

  • CRTC2 mediates effects of glucagon on induction of the gluconeogenic programme in the liver during fasting. CREB and CRTC2 activities are increased in insulin resistance, in which they contribute to the attendant hyperglycaemia.

  • CRTC3 is expressed in white and brown adipose tissue, where it promotes obesity by inhibiting catecholamine signalling. Inheritance of a gain-of-function CRTC3 mutant in certain human populations is associated with obesity.

  • The CRTCs are conserved in lower organisms, including Drosophila melanogaster and Caenorhabditis elegans, in which they mediate effects of fasting and feeding signals on glucose and lipid metabolism, as well as lifespan.

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.

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Figure 1: cAMP stimulates CREB phosphorylation.
Figure 2: Modular organization of CREB and its co-activators.
Figure 3: CRTC nuclear shuttling is regulated by phosphorylation.
Figure 4: CREB stimulates the gluconeogenic programme.
Figure 5: Glucagon and insulin antagonism.
Figure 6: Leptin promotes lipolysis and energy expenditure.

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References

  1. Gonzalez, G. A. & Montminy, M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at Serine 133. Cell 59, 675–680 (1989).

    CAS  PubMed  Google Scholar 

  2. Chrivia, J. C. et al. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855–859 (1993). Characterizes the role of CBP as a CREB co-activator.

    Article  CAS  PubMed  Google Scholar 

  3. Kwok, R. et al. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370, 223–226 (1994).

    CAS  PubMed  Google Scholar 

  4. Arias, J. et al. Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370, 226–228 (1994).

    CAS  PubMed  Google Scholar 

  5. Dash, P. K., Karl, K. A., Colicos, M. A., Prywes, R. & Kandel, E. R. cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase. Proc. Natl Acad. Sci. USA 88, 5061–5065 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sheng, M., Thompson, M. A. & Greenberg, M. E. CREB: a Ca-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430 (1991).

    CAS  PubMed  Google Scholar 

  7. Deak, M., A. Clifton, Lucocq, J. & Alessi, D. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 17, 4426–4441 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Tan, Y. et al. FGF and stress regulate CREB and ATF-1 via a pathway involvin p38 MAP kinase and MAPKAP kinase-2. EMBO J. 15, 4629–4642 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bonni, A., Ginty, D., Dudek, H. & Greenberg, M. Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals. Mol. Cell. Neurosci. 6, 168–183 (1995).

    CAS  PubMed  Google Scholar 

  10. Xing, J., Ginty, D. D. & Greenberg, M. E. Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273, 959–963 (1996).

    CAS  PubMed  Google Scholar 

  11. Iordanov, M. et al. CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J. 16, 1009–1022 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Michael, L. F., Asahara, H., Shulman, A., Kraus, W. & Montminy, M. The phosphorylation status of a cyclic AMP-responsive activator is modulated via a chromatin-dependent mechanism. Mol. Cell. Biol. 20, 1596–1603 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Canettieri, G. et al. Attenuation of a phosphorylation-dependent activator by an HDAC–PP1 complex. Nature Struct. Biol. 10, 175–181 (2003).

    CAS  PubMed  Google Scholar 

  14. Hagiwara, M. et al. Coupling of hormonal stimulation and transcription via cyclic AMP-responsive factor CREB is rate limited by nuclear entry of protein kinase A. Mol. Cell. Biol. 13, 4852–4859 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hagiwara, M. et al. Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell 70, 105–113 (1992).

    CAS  PubMed  Google Scholar 

  16. Alberts, A. S., Arias, J., Hagiwara, M., Montminy, M. R. & Feramisco, J. R. Recombinant cyclic AMP response element binding protein (CREB) phosphorylated on Ser-133 is transcriptionally active upon its introduction into fibroblast nuclei. J. Biol. Chem. 269, 7623–7630 (1994).

    CAS  PubMed  Google Scholar 

  17. Wadzinski, B. et al. Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Mol. Cell. Biol. 13, 2822–2834 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Montminy, M. R., Sevarino, K. A., Wagner, J. A., Mandel, G. & Goodman, R. H. Identification of a cyclic-AMP responsive element within the rat somatostatin gene. Proc. Natl Acad. Sci. USA 83, 6682–6686 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Short, J. M., Wynshaw-Boris, A., Short, H. P. & Hanson, R. W. Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. II. Identification of cAMP and glucocorticoid regulatory domains. J. Biol. Chem. 261, 9721–9726 (1986).

    CAS  PubMed  Google Scholar 

  20. Comb, M., Birnberg, N. C., Seasholtz, A., Herbert, E. & Goodman, H. M. A cyclic AMP- and phorbol ester-inducible DNA element. Nature 323, 353–356 (1986).

    CAS  PubMed  Google Scholar 

  21. Iourgenko, V. et al. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc. Natl Acad. Sci. USA 100, 12147–12152 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hornbuckle, L. A. et al. Selective stimulation of G-6-Pase catalytic subunit but not G-6-P transporter gene expression by glucagon in vivo and cAMP in situ. Am. J. Physiol. Endocrinol. Metab. 286, E795–E808 (2004).

    CAS  PubMed  Google Scholar 

  23. Iguchi-Ariga, S. M. & Schaffner, W. CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes Dev. 3, 612–619 (1989).

    CAS  PubMed  Google Scholar 

  24. Zhang, X. et al. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc. Natl Acad. Sci. USA 102, 4459–4464 (2005). Provides a genome-wide characterization of CREB occupancy and activity in different tissues.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Impey, S. et al. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 1041–1054 (2004). Describes the genome-wide characterization of CREB target genes.

    CAS  PubMed  Google Scholar 

  26. Mayr, B. & Montminy, M. Tanscriptional regulation by the phosphorylation dependent factor CREB. Nature Rev. Mol. Cell Biol. 2, 599–609 (2001).

    CAS  Google Scholar 

  27. Conkright, M. D. et al. Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol. Cell 11, 1101–1108 (2003).

    CAS  PubMed  Google Scholar 

  28. Brindle, P., Nakajima, T. & Montminy, M. Multiple protein kinase A-regulated events are required for transcriptional induction by cAMP. Proc. Natl Acad. Sci. USA 92, 10521–10525 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Conkright, M. D. et al. TORCs: transducers of regulated CREB activity. Mol. Cell 12, 413–423 (2003).

    CAS  PubMed  Google Scholar 

  30. Shaywitz, A. J. & Greenberg, M. E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68, 821–861 (1999).

    CAS  PubMed  Google Scholar 

  31. Quinn, P. G. Distinct activation domains within cAMP response element-binding protein (CREB) mediate basal and cAMP-stimulated transcription. J. Biol. Chem. 268, 16999–17009 (1993).

    CAS  PubMed  Google Scholar 

  32. Brindle, P., Linke, S. & Montminy, M. Protein-kinase-A-dependent activator in CREB reveals a new role for the CREM family of repressors. Nature 364, 821–824 (1993).

    CAS  PubMed  Google Scholar 

  33. Ferreri, K., Gill, G. & Montminy, M. The cAMP-regulated transcription factor CREB interacts with a component of the TFIID complex. Proc. Natl Acad. Sci. USA 91, 1210–1213 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Saluja, D., Vassallo, M. & Tanese, N. Distinct subdomains of human TAFII130 are required for interactions with glutamine-rich transcriptional activators. Mol. Cell. Biol. 18, 5734–5743 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mengus, G. et al. TAF4 inactivation in embryonic fibroblasts activates TGFβ signalling and autocrine growth. EMBO J. 24, 2753–2767 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Shimohata, T. et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nature Genet. 26, 29–36 (2000).

    CAS  PubMed  Google Scholar 

  37. Lundblad, J. R., Kwok, R. P., Laurance, M. E., Harter, M. L. & Goodman, R. H. Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP. Nature 374, 85–88 (1995).

    CAS  PubMed  Google Scholar 

  38. Parker, D. et al. Phosphorylation of CREB at Ser133 induces complex formation with CBP via a direct mechanism. Mol. Cell. Biol. 16, 694–703 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000).

    CAS  PubMed  Google Scholar 

  40. Bannister, A. J. & Kouzarides, T. The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643 (1996).

    CAS  PubMed  Google Scholar 

  41. Ogryzko, V. V., Schiltz, S. R., Russanova, V., Howard, B. H. & Nakatani, M. The transcriptional coactivators p300 and CBP are histone acetytransferases. Cell 87, 953–959 (1996).

    CAS  PubMed  Google Scholar 

  42. Asahara, H., Santoso, B., Du, K., Cole, P. & Montminy, M. Chromatin-dependent cooperativity between constitutive and inducible activation domains in CREB. Mol. Cell. Biol. 21, 7892–7900 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, T. & Maniatis, T. Efficient recruitment of TFIIB and CBP-RNA polymerase II holoenzyme by an interferon-β enhanceosome in vitro. Proc. Natl Acad. Sci. USA 95, 12191–12196 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kee, B., Arias, J. & Montminy, M. Adaptor-mediated recruitment of RNA polymerase II to a signal-dependent activator. J. Biol. Chem. 271, 2373–2375 (1996).

    CAS  PubMed  Google Scholar 

  45. Radhakrishnan, I. et al. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell 91, 741–752 (1997). Describes the solution structure of the CREB–CBP complex and the role of CREB phosphorylation in promoting the CREB–CBP association.

    CAS  PubMed  Google Scholar 

  46. Parker, D. et al. Analysis of an activator:coactivator complex reveals an essential role for secondary structure in transcriptional activation. Mol. Cell 2, 353–359 (1998).

    CAS  PubMed  Google Scholar 

  47. Shaywitz, A. J., Dove, S. L., Kornhauser, J. M., Hochschild, A. & Greenberg, M. E. Magnitude of the CREB-dependent transcriptional response is determined by the strength of the interaction between the kinase-inducible domain of CREB and the KIX domain of CREB-binding protein. Mol. Cell. Biol. 20, 9409–9422 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kasper, L. H. et al. A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis. Nature 419, 738–743 (2002).

    CAS  PubMed  Google Scholar 

  49. Cardinaux, J. R. et al. Recruitment of CREB-binding protein is sufficient for CREB-mediated gene activation. Mol. Cell. Biol. 20, 1546–1552 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Best, J. L. et al. Identification of small-molecule antagonists that inhibit an activator:coactivator interaction. Proc. Natl Acad. Sci. USA 101, 17622–17627 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wagner, B., Bauer, A., Schutz, G. & Montminy, M. Stimulus-specific interaction between activator–coactivator cognates revealed with a novel complex-specific antiserum. J. Biol. Chem. 275, 8263–8266 (2000).

    CAS  PubMed  Google Scholar 

  52. Ravnskjaer, K. et al. Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression. EMBO J. 26, 2880–2889 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Sun, P., Enslen, H., Myung, P. & Maurer, R. Differential activation of CREB by Ca2+/calmodulin-dependent protein kinase type II and type IV involves phosphorylation of a site that negatively regulates activity. Genes Dev. 8, 2527–2539 (1994).

    CAS  PubMed  Google Scholar 

  54. Shi, Y. et al. Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress. Proc. Natl Acad. Sci. USA 101, 5898–5903 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Shanware, N. P., Trinh, A. T., Williams, L. M. & Tibbetts, R. S. Coregulated ataxia telangiectasia-mutated and casein kinase sites modulate cAMP-response element-binding protein-coactivator interactions in response to DNA damage. J. Biol. Chem. 282, 6283–6291 (2007).

    CAS  PubMed  Google Scholar 

  56. Bittinger, M. A. et al. Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins. Curr. Biol. 14, 2156–2161 (2004). Characterizes the mechanism by which calcium signals regulate the CRTC co-activators.

    CAS  PubMed  Google Scholar 

  57. Screaton, R. A. et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004). Describes the role of AMPK family members and calcineurin in regulating CRTC activity.

    CAS  PubMed  Google Scholar 

  58. Wang, B. et al. The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila. Cell Metab. 7, 434–444 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Mair, W. et al. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404–408 (2011). Shows that CRTC-1 and CRH-1 mediate effects of AMPK and calcineurin pathways on lifespan in C. elegans.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, Y. et al. Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proc. Natl Acad. Sci. USA 107, 3087–3092 (2010). Demonstrates that CRTC expression in the brain regulates energy balance in D. melanogaster.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kasper, L. H. et al. CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation. EMBO J. 29, 3660–3672 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Riccio, A. et al. A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol. Cell 21, 283–294 (2006).

    CAS  PubMed  Google Scholar 

  63. Amelio, A. L., Caputi, M. & Conkright, M. D. Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation. EMBO J. 28, 2733–2747 (2009). Describes a novel role for the CRTC family in alternative splicing of CREB target genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Amelio, A. L. et al. A coactivator trap identifies NONO (p54nrb) as a component of the cAMP-signaling pathway. Proc. Natl Acad. Sci. USA 104, 20314–20319 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lee, M. W. et al. Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH. Cell Metab. 11, 331–339 (2010).

    CAS  PubMed  Google Scholar 

  66. Canettieri, G. et al. The coactivator CRTC1 promotes cell proliferation and transformation via AP-1. Proc. Natl Acad. Sci. USA 106, 1445–1450 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang, Y., Vera, L., Fischer, W. H. & Montminy, M. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460, 534–537 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Goodman, M. N., McElaney, M. A. & Ruderman, N. B. Adaptation to prolonged starvation in the rat: curtailment of skeletal muscle proteolysis. Am. J. Physiol. 241, E321–E327 (1981).

    CAS  PubMed  Google Scholar 

  69. Cahill, G. F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).

    CAS  PubMed  Google Scholar 

  70. Goodman, M. N. et al. Starvation in the rat. II. Effect of age and obesity on protein sparing and fuel metabolism. Am. J. Physiol. 239, E277–E286 (1980).

    CAS  PubMed  Google Scholar 

  71. Herzig, S. et al. CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413, 179–183 (2001).

    CAS  PubMed  Google Scholar 

  72. Ahn, S. et al. A dominant-negative inhibitor of CREB reveals that it is a general mediator stimulus-dependent transcription of c-fos. Mol. Cell. Biol. 18, 967–977 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Quinn, P. G. & Granner, D. K. Cyclic AMP-dependent protein kinase regulates transcription of the phosphoenolpyruvate carboxykinase gene but not binding of nuclear factors to the cyclic AMP regulatory element. Mol. Cell. Biol. 10, 3357–3364 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Wynshaw-Boris, A., Short, J. M., Loose, D. S. & Hanson, R. W. Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. I. Multiple hormone regulatory elements and the effects of enhancers. J. Biol. Chem. 261, 9714–9720 (1986).

    CAS  PubMed  Google Scholar 

  75. Haeusler, R. A., Kaestner, K. H. & Accili, D. FoxOs function synergistically to promote glucose production. J. Biol. Chem. 285, 35245–35248 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pei, L. et al. NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nature Med. 12, 1048–55 (2006).

    CAS  PubMed  Google Scholar 

  77. Ramsey, K. M., Marcheva, B., Kohsaka, A. & Bass, J. The clockwork of metabolism. Annu. Rev. Nutr. 27, 219–240 (2007).

    CAS  PubMed  Google Scholar 

  78. Green, C. B., Takahashi, J. S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang, E. et al. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Med. 16, 1152–1156 (2010).

    CAS  PubMed  Google Scholar 

  80. Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005). Describes a role for CRTC2 and CREB in regulating hepatic gluconeogenesis.

    CAS  PubMed  Google Scholar 

  81. Saberi, M. et al. Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 297, E1137–E1146 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Uebi, T., Tamura, M., Horike, N., Hashimoto, Y. K. & Takemori, H. Phosphorylation of the CREB-specific coactivator TORC2 at Ser307 regulates its intracellular localization in COS-7 cells and in the mouse liver. Am. J. Physiol. Endocrinol. Metab. 299, E413–E425 (2010).

    CAS  PubMed  Google Scholar 

  83. Yoon, Y. S. et al. Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis. Proc. Natl Acad. Sci. USA 107, 17704–17709 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Dentin, R. et al. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449, 366–369 (2007).

    CAS  PubMed  Google Scholar 

  86. Yuan, L. W. & Gambee, J. E. Phosphorylation of p300 at serine 89 by protein kinase C. J. Biol. Chem. 275, 40946–40951 (2000).

    CAS  PubMed  Google Scholar 

  87. Yang, W. et al. Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. J. Biol. Chem. 276, 38341–38344 (2001).

    CAS  PubMed  Google Scholar 

  88. He, L. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137, 635–646 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhou, X. Y. et al. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein. Nature Med. 10, 633–637 (2004).

    CAS  PubMed  Google Scholar 

  90. Berglund, E. D. et al. Hepatic energy state is regulated by glucagon receptor signaling in mice. J. Clin. Invest. 119, 2412–2422 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Imai, S. & Guarente, L. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol. Sci. 31, 212–220 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Canto, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Daitoku, H. et al. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl Acad. Sci. USA 101, 10042–10047 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Rodgers, J. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    CAS  PubMed  Google Scholar 

  97. Veerababu, G. et al. Overexpression of glutamine:fructose-6-phosphate amidotransferase in the liver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity, and impaired glucose tolerance. Diabetes 49, 2070–2078 (2000).

    CAS  PubMed  Google Scholar 

  98. Dentin, R., Hedrick, S., Xie, J., Yates, J. & Montminy, M. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319, 1402–1405 (2008).

    CAS  PubMed  Google Scholar 

  99. Erion, D. M. et al. Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein. Cell Metab. 10, 499–506 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Le Lay, J. et al. CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required for the maintenance of glucose homeostasis. Cell Metab. 10, 55–62 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Inada, A. et al. Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic β cells. Mol. Cell. Biol. 24, 2831–2841 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Jhala, U. S. et al. cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2. Genes Dev. 17, 1575–1580 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Jansson, D. et al. Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. Proc. Natl Acad. Sci. USA 105, 10161–10166 (2008).

    PubMed  PubMed Central  Google Scholar 

  104. Aramburu, J. et al. Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol. Cell 1, 627–637 (1998).

    CAS  PubMed  Google Scholar 

  105. Qi, L. et al. Adipocyte CREB promotes insulin resistance in obesity. Cell Metab. 9, 277–286 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Song, Y. et al. CRTC3 links catecholamine signaling to energy balance. Nature 468, 933–939 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Landsberg, L. Feast or famine: the sympathetic nervous system response to nutrient intake. Cell. Mol. Neurobiol. 26, 497–508 (2006).

    CAS  PubMed  Google Scholar 

  108. Berdeaux, R. et al. SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes. Nature Med. 13, 597–603 (2007).

    CAS  PubMed  Google Scholar 

  109. Wu, Z. et al. Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1α transcription and mitochondrial biogenesis in muscle cells. Proc. Natl Acad. Sci. USA 103, 14379–14384 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Altarejos, J. Y. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nature Med. 14, 1112–1117 (2008).

    CAS  PubMed  Google Scholar 

  111. Lerner, R. G., Depatie, C., Rutter, G. A., Screaton, R. A. & Balthasar, N. A role for the CREB co-activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation. EMBO Rep. 10, 1175–1181 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Choi, S., Kim, W. & Chung, J. Drosophila salt-inducible kinase (SIK) regulates starvation resistance through CREB-regulated transcription coactivator (CRTC). J. Biol. Chem. 286, 2658–2664 (2010).

    PubMed  PubMed Central  Google Scholar 

  113. Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Schwartz, M. W. & Porte, D. Jr. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge support from the US National Institutes of Health, the Clayton Foundation for Medical Research, The Helmsley Foundation and the Kieckhefer Foundation.

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Correspondence to Marc Montminy.

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CREB Target Gene Database

Glossary

Second messenger

An intracellular molecule that mediates effects of extracellular signals on cellular function.

TATA box

An A/T-rich sequence usually located 30 nucleotides upstream from the transcriptional start site of RNA polymerase II-dependent promoters. TATA boxes specify transcriptional initiation; they are recognized by TATA-binding protein (TBP), the DNA-binding component of transcription factor IID (TFIID).

KIX domain

A domain of three helices in CREB-binding protein (CBP) and p300 that mediates binding to phosphorylated cyclic AMP-responsive element-binding protein (CREB) and other transcription factors.

Spliceosome

A multi-protein complex that mediates splicing of nascent transcripts.

Glycogenolysis

The breakdown of glycogen into glucose monomers. This occurs in liver and muscle tissues following stimulation with glucagon or catecholamines.

Gluconeogenesis

The hepatic production of 'new glucose' from glycerol, pyruvate or Ala in response to glucagon, catecholamines and cortisol.

Heterotrimeric G protein

A membrane-associated protein complex, composed of α-, β- and γ-subunits, that associates with G protein-coupled receptors and mediates induction of intracellular signalling pathways in response to ligand binding.

β-oxidation

A fatty acid metabolic pathway that occurs in mitochondria and peroxisomes. Fatty acids are metabolized to acetyl-coA and then processed through the tricarboxylic acid (TCA) cycle.

Ketogenesis

A metabolic pathway in liver tissue that generates ketones (acetoacetate and β-hydroxybutyrate) using acetyl-coA from the β-oxidation pathway. Ketones provide an important fuel source for the brain and other tissues during long term fasting.

O-glycosylation

The enzymatic addition of a glycan to Ser or Thr residues in proteins. O-glycosylation is thought to compete with phosphorylation in regulating protein function.

Hexosamine biosynthetic pathway

(HBP). An offshoot of the glycolytic pathway that normally accounts for 2–5% of glucose flux. The HBP generates UDP-glucosamine, which is used for O-glycosylation of proteins. Glucose flux through the HBP is increased in diabetes, in which it is thought to contribute to insulin resistance through the O-glycosylation of key proteins in the insulin signalling pathway.

Incretin hormones

A family of gastrointestinal hormones that are released into the circulation in response to oral feeding. They promote insulin release from β-cells of the pancreatic islets.

Sympathetic outflow

Activity of the sympathetic nervous system, which receives regulatory input from the hypothalamus. Among other functions, sympathetic nerve activity regulates heart rate, blood pressure and fat burning.

Hepatic steatosis

Pathological increases in hepatic lipid content that are often associated with obesity and insulin resistance. Also referred to as 'fatty liver'.

Arcuate cell

One of a group of neurons in the hypothalamus that mediate effects of leptin and other signals on appetite through the expression of specific neuropeptides.

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Altarejos, J., Montminy, M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12, 141–151 (2011). https://doi.org/10.1038/nrm3072

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