Mechanisms of transcriptional activation of cAMP-responsive element-binding protein CREB

  • Philipp Haus-Seuffert
  • Michael Meisterernst
Part of the Developments in Molecular and Cellular Biochemistry book series (DMCB, volume 33)


The CREB-CREM transcription factors are the main gene regulatory effectors of the cAMP signaling pathway. The investigations of this family of transcription factors had a profound impact on the understanding of signaling-induced gene transcription. Here we discuss some key aspects of the underlying biology, review transcriptional activation by CREB proteins through transcription cofactors and present novel insights into the context-and position-specific function of CREB on complex genes. (Mol Cell Biochem 212: 5–9, 2000)

Key words

transcriptional regulation gene expression coactivator repressor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Sassone CP: Transcription factors responsive to cAMP. Annu Rev Cell Dev Biol 11: 355–377, 1995CrossRefGoogle Scholar
  2. 2.
    Qian JF, Wang TT, Wu XH, Wu J, Ge C, Lachance S, Carriere S, Chan JS: Angiotensinogen gene expression is stimulated by the cAMP-responsive element-binding protein in opossum kidney cells. J Am Soc Nephrol 8: 1072–1079, 1997PubMedGoogle Scholar
  3. 3.
    Wang TT, Chen X, Wu XH, Zhang SL, Chan JS: Molecular mechanism(s) of action of isoproterenol on the expression of the angiotensinogen gene in opossum kidney proximal tubular cells. Kidney Int 55: 1713–1723, 1999PubMedCrossRefGoogle Scholar
  4. 4.
    Esther CJ, Semeniuk D, Marino EM, Zhou Y, Overbeek PA, Bernstein KE: Expression of testis angiotensin-converting enzyme is mediated by a cyclic AMP responsive element. Lab Invest 77: 483–488, 1997PubMedGoogle Scholar
  5. 5.
    Nahman NJ, Rothe KL, Falkenhain ME, Frazer KM, Dacio LE, Madia JD, Leonhart KL, Kronenberger JC, Stauch DA: Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: Association with CREB transcription factor activation. J Lab Clin Med 127: 599–611, 1996PubMedCrossRefGoogle Scholar
  6. 6.
    Funakoshi Y, Ichiki T, Ito K, Takeshita A: Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells. Hypertension 34: 118–125, 1999PubMedCrossRefGoogle Scholar
  7. 7.
    Kim EL, Esparza FM, Stachowiak MK: The roles of CRE, TRE, and TRE-adjacent S1 nuclease sensitive element in the regulation of tyrosine hydroxylase gene promoter activity by angiotensin II. J Neurochem 67: 26–36, 1996PubMedCrossRefGoogle Scholar
  8. 8.
    Dudai Y, Jan YN, Byers D, Quinn WG, Benzer S: Dunce, a mutant of Drosophila deficient in learning. Proc Natl Acad Sci USA 73: 1684–1688, 1976PubMedCrossRefGoogle Scholar
  9. 9.
    Dubnau J, Tully T: Gene discovery in Drosophila: New insights for learning and memory. Annu Rev Neurosci 21: 407–444, 1998PubMedCrossRefGoogle Scholar
  10. 10.
    Davis HP, Squire LR: Protein synthesis and memory: Areview. Psychol Bull 96: 518–559, 1984PubMedCrossRefGoogle Scholar
  11. 11.
    Dash PK, Hochner B, Kandel ER: Injection of the cAMP-responsive element into the nucleus ofAplysia sensory neurons blocks long-term facilitation. Nature 345: 718–721, 1990PubMedCrossRefGoogle Scholar
  12. 12.
    Mayford M, Kandel ER: Genetic approaches to memory storage. Trends Genet 15: 463–470, 1999PubMedCrossRefGoogle Scholar
  13. 13.
    Muthusamy N, Leiden JM: A protein kinase C-, Ras-, and RSK2-dependent signal transduction pathway activates the cAMP-responsive element-binding protein transcription factor following T cell receptor engagement. J Biol Chem 273: 22841–22847, 1998PubMedCrossRefGoogle Scholar
  14. 14.
    Mayall TP, Sheridan PL, Montminy MR, Jones KA: Distinct roles for P-CREB and LEF-1 in TCR alpha enhancer assembly and activation on chromatin templates in vitro. Genes Dev 11: 887–899, 1997PubMedCrossRefGoogle Scholar
  15. 15.
    Gottschalk LR, Leiden JM: Identification and functional characterization of the human T-cell receptor beta gene transcriptional enhancer: Common nuclear proteins interact with the transcriptional regulatory elements of the T-cell receptor alpha and beta genes. Mol Cell Biol 10: 5486–5495, 1990PubMedGoogle Scholar
  16. 16.
    Gupta A, Terhorst C: CD3-delta enhancer. CREB interferes with the function of a murine CD3-delta A binding factor (M delta AF). J Immunol 152: 3895–3903, 1994PubMedGoogle Scholar
  17. 17.
    Lee MR, Chung CS, Liou ML, Wu M, Li WF, Hsueh YP, Lai MZ: Isolation and characterization of nuclear proteins that bind to T cell receptor V beta decamer motif. J Immunol 148: 1906–1912, 1992PubMedGoogle Scholar
  18. 18.
    Rudolph D, Tafuri A, Gass P, Hammerling GJ, Arnold B, Schutz G: Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP-response element-binding protein. Proc Natl Acad Sci USA 95: 4481–4486, 1998PubMedCrossRefGoogle Scholar
  19. 19.
    Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden JM: Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Nature 379: 81–85, 1996PubMedCrossRefGoogle Scholar
  20. 20.
    Lee KA, Masson N: Transcriptional regulation by CREB and its relatives. Biochim Biophys Acta 1174: 221–233, 1993PubMedCrossRefGoogle Scholar
  21. 21.
    Hoeffler JP, Meyer TE, Yun Y, Jameson JL, Habener JF: Cyclic AMP-responsive DNA-binding protein: Structure based on a cloned placental eDNA. Science 242: 1430–1433, 1988PubMedCrossRefGoogle Scholar
  22. 22.
    Hai T, Curran T: Cross-family dimerization of transcription factors Fos/ Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88: 3720–3724, 1991PubMedCrossRefGoogle Scholar
  23. 23.
    Yamamoto KK, Gonzalez GA, Biggs WD, Montminy MR: Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature 334: 494–498, 1988PubMedCrossRefGoogle Scholar
  24. 24.
    Deutsch PJ, Hoeffler JP, Jameson JL, Lin JC, Habener JF: Structural determinants for transcriptional activation by cAMP-responsive DNA elements. J Biol Chem 263: 18466–18472, 1988PubMedGoogle Scholar
  25. 25.
    Gonzalez GA, Montminy MR: Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59: 675–680, 1989PubMedCrossRefGoogle Scholar
  26. 26.
    de GR, Ballou LM, Sassone CP: Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: An alternative route to mitogen-induced gene expression. Cell 79: 81–91, 1994PubMedCrossRefGoogle Scholar
  27. 27.
    Nakajima T, Uchida C, Anderson SF, Parvin JD, Montminy M: Analysis of a cAMP-responsive activator reveals a two-component mechanism for transcriptional induction via signal-dependent factors. Genes Dev 11: 738–747, 1997PubMedCrossRefGoogle Scholar
  28. 28.
    Rehfuss RP, Walton KM, Loriaux MM, Goodman RH: The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A. J Biol Chem 266: 18431–18434,1991PubMedGoogle Scholar
  29. 29.
    Laoide BM, Foulkes NS, Schlotter F, Sassone CP: The functional versatility of CREM is determined by its modular structure. Embo J 12: 1179–1191, 1993PubMedGoogle Scholar
  30. 30.
    Bartsch D, Casadio A, Karl KA, Serodio P, Kandel ER: CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. Cell 95: 211–223, 1998PubMedCrossRefGoogle Scholar
  31. 31.
    Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH: Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci USA 83: 6682–6686, 1986PubMedCrossRefGoogle Scholar
  32. 32.
    Hyman SE, Comb M, Lin YS, Pearlberg J, Green MR, Goodman HM: A common trans-acting factor is involved in transcriptional regulation of neurotransmitter genes by cyclic AMP. Mol Cell Biol 8: 4225–4233, 1988PubMedGoogle Scholar
  33. 33.
    Lee CQ, Yun YD, Hoeffler JP, Habener JF: Cyclic-AMP-responsive transcriptional activation of CREB-327 involves interdependent phosphorylated subdomains (retracted by Y Yun, JP Hoeffler, JF Habener. In EMBO J 13: 2736, 1994). Embo J 9: 4455–4465, 1990PubMedGoogle Scholar
  34. 34.
    Bito H, Deisseroth K, Tsien RW: CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87: 1203–1214, 1996PubMedCrossRefGoogle Scholar
  35. 35.
    De CD, Fimia GM, Sassone CP: Signaling routes to CREM and CREB: Plasticity in transcriptional activation. Trends Biochem Sci 24: 281–285, 1999PubMedCrossRefGoogle Scholar
  36. 36.
    Parker D, Jhala US, Radhakrishnan I, Yaffe MB, Reyes C, Shulman AI, Cantley LC, Wright PE, Montminy M: Analysis of an activator:coactivator complex reveals an essential role for secondary structure in transcriptional activation. Mol Cell 2: 353–359, 1998PubMedCrossRefGoogle Scholar
  37. 37.
    Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH: Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365: 855–859, 1993PubMedCrossRefGoogle Scholar
  38. 38.
    Nakajima T, Uchida C, Anderson SF, Lee CG, Hurwitz J, Parvin JD, Montminy M: RNA helicase A mediates association of CBP with RNA polymerase II. Cell 90: 1107–1112, 1997PubMedCrossRefGoogle Scholar
  39. 39.
    Kouzarides T: Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 9: 40–48, 1999PubMedCrossRefGoogle Scholar
  40. 40.
    Xu L, Glass CK, Rosenfeld MG: Coactivator and corepressor complexes in nuclear receptor function. Curr Opin Genet Dev 9: 140–147, 1999PubMedCrossRefGoogle Scholar
  41. 41.
    Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R, McInerney EM, Mullen TM, Glass CK, Rosenfeld MG: Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 279: 703–707, 1998PubMedCrossRefGoogle Scholar
  42. 42.
    Fimia GM, De CD, Sassone CP: CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature 398: 165–169, 1999PubMedCrossRefGoogle Scholar
  43. 43.
    Felinski EA, Quinn PG: The CREB constitutive activation domain interacts with TATA-binding protein-associated factor 110 (TAF110) through specific hydrophobic residues in one of the three subdomains required for both activation and TAF110 binding. J Biol Chem 274: 11672–11678,1999PubMedCrossRefGoogle Scholar
  44. 44.
    Halle JP, Haus SP, Woltering C, Stelzer G, Meisteremst M: A conserved tissue-specific structure at a human T-cell receptor beta-chain core promoter. Mol Cell Biol 17: 4220–4229, 1997PubMedGoogle Scholar
  45. 45.
    Haus-Seuffert P, Halle JP, Sanner S, Meisterernst M: Conserved cAMP-responsive element and core promoter complex are critical for specificity of the distal T-cell receptor beta chain enhancer for its native promoter. Gene 236: 209–219, 1999PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Philipp Haus-Seuffert
    • 1
  • Michael Meisterernst
    • 1
    • 2
  1. 1.Institute of Molecular Immunology, Department for ProteinbiochemistryGSFMünchenGermany
  2. 2.Institute of Molecular Immunology, Department for ProteinbiochemistryGSFMünchenGermany

Personalised recommendations