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Gene Review

CREB1  -  cAMP responsive element binding protein 1

Homo sapiens

Synonyms: CREB-1, Cyclic AMP-responsive element-binding protein 1, cAMP-responsive element-binding protein 1
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Disease relevance of CREB1


Psychiatry related information on CREB1


High impact information on CREB1

  • This review discusses the molecular mechanisms by which Ser133-phosphorylated CREB activates transcription, intracellular signaling pathways that lead to phosphorylation of CREB at Ser133, and features of each signaling pathway that impart specificity at the level of CREB activation [11].
  • In some cases, signaling pathways target additional sites on CREB or proteins associated with CREB, permitting CREB to regulate distinct programs of gene expression under different conditions of stimulation [11].
  • Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation [12].
  • The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector [13].
  • Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB [13].

Chemical compound and disease context of CREB1


Biological context of CREB1

  • TORC1 potently induced known CREB1 target genes, bound CREB1, and activated expression through a potent transcription activation domain [19].
  • In this study, we observed increased ATF-2 and CREB1 phosphorylation mediated by the HDACIs in K562 cells, in conjunction with histone H4 hyperacetylation [20].
  • Exposure of prostate epithelial phenotypes to cAMP alters the expression of lumbo-sacral HOX D genes located on the chromosomal region 2q31-33 where the cAMP effector genes CREB1, CREB2, and cAMP-GEFII are present [21].
  • Interaction between the activator type of cyclic AMP response element binding protein (CREB1) and the repressor type (CREB2) results in determining the emergence of long-lasting synaptic enhancement involved in memory consolidation [22].
  • Furthermore Wp activity in B cell, but not in non-B cell, lines could be inhibited by cotransfection of expression plasmids expressing dominant negative forms of CREB1 and ATF1 [23].

Anatomical context of CREB1


Associations of CREB1 with chemical compounds


Physical interactions of CREB1

  • Gel retardation and chromatin immunoprecipitation assays confirm that POU forms a complex with CREB bound to the cyclin D1 CRE [30].
  • This synergy also partially occurred when hGABPalpha was used alone in place of the combination of hGABPalpha and hGABPbeta. hGABP activated an artificial promoter containing only ATF/CREB-binding sites under coexistence of ATF1 or CREB [31].
  • Both in vitro and in vivo DNA binding assay revealed that the CREB binding activity was low in EGF-starved cells, whereas it was induced within 30 min after EGF treatment of A431 cells [32].
  • Finally, the addition of the CREB-binding transcriptional coactivator p300 leads to a dramatic CREB-dependent increase in both mitogen- and CD28-mediated transactivation of the CD28RE-TRE [33].
  • A second CREB motif closely linked to the S-ATG showed a similar binding pattern involving ATF2 and CREB1, without appearing essential for basal promoter activity [34].

Enzymatic interactions of CREB1

  • RSK1 was found to directly phosphorylate cAMP-response element-binding protein (CREB), and this event led to the stimulation of subsequent CRE-mediated gene transcription [35].
  • RSK-B phosphorylates the cAMP response element-binding protein (CREB) and c-Fos peptides [36].
  • Exposure of 1-LN cells to alpha2M* significantly raised the levels of phosphorylated CREB by about 15-20 min and phosphorylated p53 by about 60-90 min of incubation [37].
  • In addition, Dyrk1 directly phosphorylates CREB, leading to the stimulation of subsequent CRE-mediated gene transcription during the neuronal differentiation in H19-7 cells [38].
  • Next, we utilized activators and inhibitors of protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase kinase (MAPKK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to determine which kinases might be involved in phosphorylating the CREB in PZHPV-7 cells [39].

Regulatory relationships of CREB1


Other interactions of CREB1

  • Experiments conducted with mutants in the E1A or CREB components support a model whereby E1A 243R transactivates the PCNA promoter via a CBP-CREB-PERE pathway [2].
  • A protein, termed transducer of regulated cAMP response element-binding protein (CREB) (TORC1), was identified that activated expression through the variant CRE and consensus CRE sites [19].
  • Here we show that HDAC1 associates with and blocks Ser133 phosphorylation of CREB during pre-stimulus and attenuation phases of the cAMP response [44].
  • We describe an alternative mechanism for CREB-driven cyclin D1 induction that involves the ubiquitous POU domain protein Oct-1 [30].
  • Oct-1/CREB synergy is not diminished by the adenovirus E1A 12S protein, a repressor of CBP coactivator function [30].
  • The effect of TORC2 on CBP/p300 promoter occupancy appears pivotal because a gain of function mutant CREB polypeptide with increased affinity for CBP restored CRE-mediated transcription in cells exposed to stress signals [45].

Analytical, diagnostic and therapeutic context of CREB1


  1. Protein domains involved in both in vivo and in vitro interactions between human T-cell leukemia virus type I tax and CREB. Yin, M.J., Paulssen, E.J., Seeler, J.S., Gaynor, R.B. J. Virol. (1995) [Pubmed]
  2. Transcriptional coactivator cAMP response element binding protein mediates induction of the human proliferating cell nuclear antigen promoter by the adenovirus E1A oncoprotein. Lee, B.H., Mathews, M.B. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  3. CREB and its associated proteins act as survival factors for human melanoma cells. Jean, D., Harbison, M., McConkey, D.J., Ronai, Z., Bar-Eli, M. J. Biol. Chem. (1998) [Pubmed]
  4. Critical role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-alpha. Taylor, C.T., Fueki, N., Agah, A., Hershberg, R.M., Colgan, S.P. J. Biol. Chem. (1999) [Pubmed]
  5. Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK. Nishihara, H., Hwang, M., Kizaka-Kondoh, S., Eckmann, L., Insel, P.A. J. Biol. Chem. (2004) [Pubmed]
  6. Molecular characterization of the Tax-containing HTLV-1 enhancer complex reveals a prominent role for CREB phosphorylation in Tax transactivation. Kim, Y.M., Ramírez, J.A., Mick, J.E., Giebler, H.A., Yan, J.P., Nyborg, J.K. J. Biol. Chem. (2007) [Pubmed]
  7. Sequence variations in CREB1 cosegregate with depressive disorders in women. Zubenko, G.S., Hughes, H.B., Stiffler, J.S., Brechbiel, A., Zubenko, W.N., Maher, B.S., Marazita, M.L. Mol. Psychiatry (2003) [Pubmed]
  8. The gene transcription factor cyclic AMP-responsive element binding protein: role in positive and negative affective states of alcohol addiction. Pandey, S.C. Pharmacol. Ther. (2004) [Pubmed]
  9. CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Barco, A., Pittenger, C., Kandel, E.R. Expert Opin. Ther. Targets (2003) [Pubmed]
  10. Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Zubenko, G.S., Maher, B., Hughes, H.B., Zubenko, W.N., Stiffler, J.S., Kaplan, B.B., Marazita, M.L. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2003) [Pubmed]
  11. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Shaywitz, A.J., Greenberg, M.E. Annu. Rev. Biochem. (1999) [Pubmed]
  12. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Horvath, A., Boikos, S., Giatzakis, C., Robinson-White, A., Groussin, L., Griffin, K.J., Stein, E., Levine, E., Delimpasi, G., Hsiao, H.P., Keil, M., Heyerdahl, S., Matyakhina, L., Libè, R., Fratticci, A., Kirschner, L.S., Cramer, K., Gaillard, R.C., Bertagna, X., Carney, J.A., Bertherat, J., Bossis, I., Stratakis, C.A. Nat. Genet. (2006) [Pubmed]
  13. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Screaton, R.A., Conkright, M.D., Katoh, Y., Best, J.L., Canettieri, G., Jeffries, S., Guzman, E., Niessen, S., Yates, J.R., Takemori, H., Okamoto, M., Montminy, M. Cell (2004) [Pubmed]
  14. Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. Bébien, M., Salinas, S., Becamel, C., Richard, V., Linares, L., Hipskind, R.A. Oncogene (2003) [Pubmed]
  15. Nitric oxide protects neuroblastoma cells from apoptosis induced by serum deprivation through cAMP-response element-binding protein (CREB) activation. Ciani, E., Guidi, S., Della Valle, G., Perini, G., Bartesaghi, R., Contestabile, A. J. Biol. Chem. (2002) [Pubmed]
  16. The 3',5'-cyclic adenosine monophosphate response element binding protein (CREB) is functionally reduced in human toxic thyroid adenomas. Brunetti, A., Chiefari, E., Filetti, S., Russo, D. Endocrinology (2000) [Pubmed]
  17. Growth stimulation of human pulmonary adenocarcinoma cells and small airway epithelial cells by beta-carotene via activation of cAMP, PKA, CREB and ERK1/2. Al-Wadei, H.A., Takahashi, T., Schuller, H.M. Int. J. Cancer (2006) [Pubmed]
  18. Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Pradeep, C.R., Kuttan, G. Int. Immunopharmacol. (2004) [Pubmed]
  19. Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Iourgenko, V., Zhang, W., Mickanin, C., Daly, I., Jiang, C., Hexham, J.M., Orth, A.P., Miraglia, L., Meltzer, J., Garza, D., Chirn, G.W., McWhinnie, E., Cohen, D., Skelton, J., Terry, R., Yu, Y., Bodian, D., Buxton, F.P., Zhu, J., Song, C., Labow, M.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  20. Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves {gamma}-globin activation by CREB1 and ATF-2. Sangerman, J., Lee, M.S., Yao, X., Oteng, E., Hsiao, C.H., Li, W., Zein, S., Ofori-Acquah, S.F., Pace, B.S. Blood (2006) [Pubmed]
  21. cAMP induced modifications of HOX D gene expression in prostate cells allow the identification of a chromosomal area involved in vivo with neuroendocrine differentiation of human advanced prostate cancers. Cantile, M., Kisslinger, A., Cindolo, L., Schiavo, G., D'Antò, V., Franco, R., Altieri, V., Gallo, A., Villacci, A., Tramontano, D., Cillo, C. J. Cell. Physiol. (2005) [Pubmed]
  22. De Novo synthesis of CREB in a presynaptic neuron is required for synaptic enhancement involved in memory consolidation. Wagatsuma, A., Azami, S., Sakura, M., Hatakeyama, D., Aonuma, H., Ito, E. J. Neurosci. Res. (2006) [Pubmed]
  23. The activity of the Epstein-Barr virus BamHI W promoter in B cells is dependent on the binding of CREB/ATF factors. Kirby, H., Rickinson, A., Bell, A. J. Gen. Virol. (2000) [Pubmed]
  24. CREB in the pond snail Lymnaea stagnalis: cloning, gene expression, and function in identifiable neurons of the central nervous system. Sadamoto, H., Sato, H., Kobayashi, S., Murakami, J., Aonuma, H., Ando, H., Fujito, Y., Hamano, K., Awaji, M., Lukowiak, K., Urano, A., Ito, E. J. Neurobiol. (2004) [Pubmed]
  25. Assignment of the human gene for CREB1 to chromosome 2q32.3-q34. Taylor, A.K., Klisak, I., Mohandas, T., Sparkes, R.S., Li, C., Gaynor, R., Lusis, A.J. Genomics (1990) [Pubmed]
  26. Identification and characterization of a cAMP-responsive element in the region upstream from promoter 1.3 of the human aromatase gene. Zhou, D., Chen, S. Arch. Biochem. Biophys. (1999) [Pubmed]
  27. Effects of vitamin E and prostaglandin E2 on expression of CREB1 and CREB2 proteins by human T lymphocytes. Valenti, A., Venza, I., Venza, M., Fimiani, V., Teti, D. Physiological research / Academia Scientiarum Bohemoslovaca. (2000) [Pubmed]
  28. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Xing, J., Kornhauser, J.M., Xia, Z., Thiele, E.A., Greenberg, M.E. Mol. Cell. Biol. (1998) [Pubmed]
  29. Ceramide and cyclic adenosine monophosphate (cAMP) induce cAMP response element binding protein phosphorylation via distinct signaling pathways while having opposite effects on myeloid cell survival. Scheid, M.P., Foltz, I.N., Young, P.R., Schrader, J.W., Duronio, V. Blood (1999) [Pubmed]
  30. Oct-1 potentiates CREB-driven cyclin D1 promoter activation via a phospho-CREB- and CREB binding protein-independent mechanism. Boulon, S., Dantonel, J.C., Binet, V., Vié, A., Blanchard, J.M., Hipskind, R.A., Philips, A. Mol. Cell. Biol. (2002) [Pubmed]
  31. Synergistic transcriptional activation by hGABP and select members of the activation transcription factor/cAMP response element-binding protein family. Sawada, J., Simizu, N., Suzuki, F., Sawa, C., Goto, M., Hasegawa, M., Imai, T., Watanabe, H., Handa, H. J. Biol. Chem. (1999) [Pubmed]
  32. Induction of human NF-IL6beta by epidermal growth factor is mediated through the p38 signaling pathway and cAMP response element-binding protein activation in A431 cells. Wang, J.M., Tseng, J.T., Chang, W.C. Mol. Biol. Cell (2005) [Pubmed]
  33. Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB2. Butscher, W.G., Powers, C., Olive, M., Vinson, C., Gardner, K. J. Biol. Chem. (1998) [Pubmed]
  34. CREB/PKA sensitive signalling pathways activate and maintain expression levels of the hepatitis B virus pre-S2/S promoter. Tacke, F., Liedtke, C., Bocklage, S., Manns, M.P., Trautwein, C. Gut (2005) [Pubmed]
  35. Induction of MUC8 gene expression by interleukin-1 beta is mediated by a sequential ERK MAPK/RSK1/CREB cascade pathway in human airway epithelial cells. Song, K.S., Seong, J.K., Chung, K.C., Lee, W.J., Kim, C.H., Cho, K.N., Kang, C.D., Koo, J.S., Yoon, J.H. J. Biol. Chem. (2003) [Pubmed]
  36. RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). Pierrat, B., Correia, J.S., Mary, J.L., Tomás-Zuber, M., Lesslauer, W. J. Biol. Chem. (1998) [Pubmed]
  37. Potentiation of signal transduction mitogenesis and cellular proliferation upon binding of receptor-recognized forms of alpha2-macroglobulin to 1-LN prostate cancer cells. Misra, U.K., Pizzo, S.V. Cell. Signal. (2004) [Pubmed]
  38. Protein kinase Dyrk1 activates cAMP response element-binding protein during neuronal differentiation in hippocampal progenitor cells. Yang, E.J., Ahn, Y.S., Chung, K.C. J. Biol. Chem. (2001) [Pubmed]
  39. Vitamin D autocrine system and prostate cancer. Wang, L., Whitlatch, L.W., Flanagan, J.N., Holick, M.F., Chen, T.C. Recent Results Cancer Res. (2003) [Pubmed]
  40. Tissue transglutaminase directly regulates adenylyl cyclase resulting in enhanced cAMP-response element-binding protein (CREB) activation. Tucholski, J., Johnson, G.V. J. Biol. Chem. (2003) [Pubmed]
  41. HLA-G transactivation by cAMP-response element-binding protein (CREB). An alternative transactivation pathway to the conserved major histocompatibility complex (MHC) class I regulatory routes. Gobin, S.J., Biesta, P., de Steenwinkel, J.E., Datema, G., van den Elsen, P.J. J. Biol. Chem. (2002) [Pubmed]
  42. Regulation of mucin gene expression by CREB via a nonclassical retinoic acid signaling pathway. Kim, S.W., Hong, J.S., Ryu, S.H., Chung, W.C., Yoon, J.H., Koo, J.S. Mol. Cell. Biol. (2007) [Pubmed]
  43. cAMP-responsive element-binding protein regulates vascular endothelial growth factor expression: implication in human prostate cancer bone metastasis. Wu, D., Zhau, H.E., Huang, W.C., Iqbal, S., Habib, F.K., Sartor, O., Cvitanovic, L., Marshall, F.F., Xu, Z., Chung, L.W. Oncogene (2007) [Pubmed]
  44. Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. Canettieri, G., Morantte, I., Guzmán, E., Asahara, H., Herzig, S., Anderson, S.D., Yates, J.R., Montminy, M. Nat. Struct. Biol. (2003) [Pubmed]
  45. Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression. Ravnskjaer, K., Kester, H., Liu, Y., Zhang, X., Lee, D., Yates, J.R., Montminy, M. EMBO J. (2007) [Pubmed]
  46. Identification of a novel cyclic AMP-response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene. Majumder, S., Varadharaj, S., Ghoshal, K., Monani, U., Burghes, A.H., Jacob, S.T. J. Biol. Chem. (2004) [Pubmed]
  47. Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1{alpha} transcription and mitochondrial biogenesis in muscle cells. Wu, Z., Huang, X., Feng, Y., Handschin, C., Feng, Y., Gullicksen, P.S., Bare, O., Labow, M., Spiegelman, B., Stevenson, S.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  48. Two CGTCA motifs and a GHF1/Pit1 binding site mediate cAMP-dependent protein kinase A regulation of human growth hormone gene expression in rat anterior pituitary GC cells. Shepard, A.R., Zhang, W., Eberhardt, N.L. J. Biol. Chem. (1994) [Pubmed]
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