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Gene Review

CREBBP  -  CREB binding protein

Homo sapiens

Synonyms: CBP, CREB-binding protein, KAT3A, RSTS, RTS
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Disease relevance of CREBBP


Psychiatry related information on CREBBP


High impact information on CREBBP

  • N-Cad/CTF2 binds the transcription factor CBP and promotes its proteasomal degradation, inhibiting CRE-dependent transactivation [11].
  • Mutations in PS-1 associated with Alzheimer's disease interfere with CBP proteolysis, leading to abnormal transcription [12].
  • In this issue of Cell, Marambaud et al. report that PS-1 cleaves the cell adhesion molecule N-cadherin, releasing a C-terminal fragment that promotes degradation of the transcriptional coactivator CBP [12].
  • Acetylation of histones by p300/CBP and PCAF is considered to be a critical step in transcriptional regulation [13].
  • Nucleosome acetylation in turn facilitates SWI/SNF recruitment by CBP, resulting in chromatin remodeling [14].

Chemical compound and disease context of CREBBP

  • The rescue function mapped to the cysteine-histidine rich domain CH3, a region of p300/CBP that we found to interact directly with the conserved COOH-terminal activation domain (AF-2) of ER-alpha. p300 and ER-alpha were also found to interact in vivo and to colocalize within the nucleus in breast cancer cells [15].
  • Intracellular Listeria induced time-dependent acetylation (lysine 8) of histone H4 and phosphorylation/acetylation (serine 10/lysine 14) of histone H3 globally and at the il8 promoter in HUVEC, as well as recruitment of the histone acetylase CREB-binding protein [16].
  • Taken together, our findings demonstrate the selective enhancement of agonistic action of the anti-androgen hydroxyflutamide by the transcriptional co-activator CBP, which is a new, potentially relevant mechanism contributing to the acquisition of therapy resistance in prostate cancer [17].
  • In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior [18].
  • Indeed, CBP suppressed the responsiveness of the mouse mammary tumor virus (MMTV) promoter to dexamethasone in a dose-dependent fashion in HeLa and A204 cells [19].

Biological context of CREBBP


Anatomical context of CREBBP

  • Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines [20].
  • A reconstitution experiment illustrated that optimum CREB-CBP interaction and CREB trans-activation were attained when these three kinase pathways were simultaneously activated in T cells [23].
  • Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation [24].
  • Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription [25].
  • In transfected HeLa cells, we show that the full-length ERalpha can interact physically and functionally with p160/SRCs and CBP in the absence of ligand and that mutation of Ser104/106/118 affects these interactions [26].

Associations of CREBBP with chemical compounds

  • Thus, polyglutamine-mediated interference with CBP-regulated gene transcription may constitute a genetic gain of function, underlying the pathogenesis of polyglutamine disorders [4].
  • We further present the three-dimensional nuclear magnetic resonance structure of the CBP bromodomain in complex with a lysine 382-acetylated p53 peptide [27].
  • Amino acid replacement in the sequences of CADs revealed a specific cysteine to be essential for their hypoxia-inducible interaction with CBP [5].
  • Control of CBP co-activating activity by arginine methylation [28].
  • One class of the nuclear receptor AF-2 coactivator complexes contains the SRC-1/TIF2 family, CBP/p300 and an RNA coactivator, SRA [29].

Physical interactions of CREBBP

  • Here we show that the human PR also interacts with p300/CBP-associated factor in vitro [30].
  • Whereas both the N terminus and ligand-binding domain of AR can interact with CBP, a short region in the N terminus of CBP is required for these interactions [31].
  • The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein [32].
  • The present study shows that FGFR1 accumulates and interacts with the transcriptional co-activator CREB-binding protein (CBP) in nuclear speckle domains in the developing brain and in neural progenitor-like cells in vitro, which accompanies differentiation and postmitotic growth [24].
  • The coactivator of transcription CREB-binding protein interacts preferentially with the glycosylated form of Stat5 [33].

Enzymatic interactions of CREBBP

  • Using purified components, we found that the MLL activation domain facilitated the binding of CBP to phosphorylated CREB [34].

Co-localisations of CREBBP

  • Finally, we show that Zta and CBP colocalize to viral immediate-early promoters in vivo and that overexpression of Zta leads to a robust increase in H3 and H4 acetylation at various regions of the EBV genome in vivo [35].
  • PIMT appeared to be co-localized in the nucleus with CBP, p300, and PBP [36].
  • The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding [37].

Regulatory relationships of CREBBP


Other interactions of CREBBP

  • ACTR also recruits two other nuclear factors, CBP and P/CAF, and thus plays a central role in creating a multisubunit coactivator complex [43].
  • Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha [3].
  • CREB-binding protein in androgen receptor-mediated signaling [38].
  • Ectopic expression of CBP or the related coactivator, p300, enhanced ER transcriptional activity by up to 10-fold in a receptor- and DNA-dependent manner [44].
  • CBP/p300 interact with and function as transcriptional coactivators of BRCA1 [39].
  • Such phosphorylation enhances NF-kappaB-mediated gene expression and suppresses p53-mediated gene expression by switching the binding preference of CBP from p53 to NF-kappaB, thus promoting cell growth [45].
  • We report three three-dimensional solution structures of the bromodomains of the human transcriptional coactivators CREB-binding protein (CBP) and p300/CBP-associated factor (PCAF) bound to peptides derived from histone acetylation sites at lysines 36 and 9 in H3, and lysine 20 in H4 [46].

Analytical, diagnostic and therapeutic context of CREBBP


  1. t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia. Vizmanos, J.L., Larráyoz, M.J., Lahortiga, I., Floristán, F., Alvarez, C., Odero, M.D., Novo, F.J., Calasanz, M.J. Genes Chromosomes Cancer (2003) [Pubmed]
  2. DNA sequencing of CREBBP demonstrates mutations in 56% of patients with Rubinstein-Taybi syndrome (RSTS) and in another patient with incomplete RSTS. Bartsch, O., Schmidt, S., Richter, M., Morlot, S., Seemanová, E., Wiebe, G., Rasi, S. Hum. Genet. (2005) [Pubmed]
  3. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Bhattacharya, S., Eckner, R., Grossman, S., Oldread, E., Arany, Z., D'Andrea, A., Livingston, D.M. Nature (1996) [Pubmed]
  4. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Nucifora , F.C., Sasaki, M., Peters, M.F., Huang, H., Cooper, J.K., Yamada, M., Takahashi, H., Tsuji, S., Troncoso, J., Dawson, V.L., Dawson, T.M., Ross, C.A. Science (2001) [Pubmed]
  5. Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. Ema, M., Hirota, K., Mimura, J., Abe, H., Yodoi, J., Sogawa, K., Poellinger, L., Fujii-Kuriyama, Y. EMBO J. (1999) [Pubmed]
  6. CBP/p300 are bimodal regulators of Wnt signaling. Li, J., Sutter, C., Parker, D.S., Blauwkamp, T., Fang, M., Cadigan, K.M. EMBO J. (2007) [Pubmed]
  7. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Alarcón, J.M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E.R., Barco, A. Neuron (2004) [Pubmed]
  8. Conjunction dysfunction: CBP/p300 in human disease. Giles, R.H., Peters, D.J., Breuning, M.H. Trends Genet. (1998) [Pubmed]
  9. Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. Rouaux, C., Loeffler, J.P., Boutillier, A.L. Biochem. Pharmacol. (2004) [Pubmed]
  10. Differential Role for CBP and p300 CREB-Binding Domain in Motor Skill Learning. Oliveira, A.M., Abel, T., Brindle, P.K., Wood, M.A. Behav. Neurosci. (2006) [Pubmed]
  11. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Marambaud, P., Wen, P.H., Dutt, A., Shioi, J., Takashima, A., Siman, R., Robakis, N.K. Cell (2003) [Pubmed]
  12. Secrets of a secretase: N-cadherin proteolysis regulates CBP function. Rao, V.R., Finkbeiner, S. Cell (2003) [Pubmed]
  13. Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Seo, S.B., McNamara, P., Heo, S., Turner, A., Lane, W.S., Chakravarti, D. Cell (2001) [Pubmed]
  14. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Agalioti, T., Lomvardas, S., Parekh, B., Yie, J., Maniatis, T., Thanos, D. Cell (2000) [Pubmed]
  15. p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Fan, S., Ma, Y.X., Wang, C., Yuan, R.Q., Meng, Q., Wang, J.A., Erdos, M., Goldberg, I.D., Webb, P., Kushner, P.J., Pestell, R.G., Rosen, E.M. Cancer Res. (2002) [Pubmed]
  16. Intracellular bacteria differentially regulated endothelial cytokine release by MAPK-dependent histone modification. Schmeck, B., Beermann, W., van Laak, V., Zahlten, J., Opitz, B., Witzenrath, M., Hocke, A.C., Chakraborty, T., Kracht, M., Rosseau, S., Suttorp, N., Hippenstiel, S. J. Immunol. (2005) [Pubmed]
  17. The transcriptional co-activator cAMP response element-binding protein-binding protein is expressed in prostate cancer and enhances androgen- and anti-androgen-induced androgen receptor function. Comuzzi, B., Lambrinidis, L., Rogatsch, H., Godoy-Tundidor, S., Knezevic, N., Krhen, I., Marekovic, Z., Bartsch, G., Klocker, H., Hobisch, A., Culig, Z. Am. J. Pathol. (2003) [Pubmed]
  18. Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats. Molenda-Figueira, H.A., Williams, C.A., Griffin, A.L., Rutledge, E.M., Blaustein, J.D., Tetel, M.J. Hormones and behavior. (2006) [Pubmed]
  19. Conditional modulation of glucocorticoid receptor activities by CREB-binding protein (CBP) and p300. Kino, T., Nordeen, S.K., Chrousos, G.P. J. Steroid Biochem. Mol. Biol. (1999) [Pubmed]
  20. Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines. Tillinghast, G.W., Partee, J., Albert, P., Kelley, J.M., Burtow, K.H., Kelly, K. Genes Chromosomes Cancer (2003) [Pubmed]
  21. Localization of human CREBBP (CREB binding protein) to 16p13.3 by fluorescence in situ hybridization. Chen, X.N., Korenberg, J.R. Cytogenet. Cell Genet. (1995) [Pubmed]
  22. Rubinstein-Taybi syndrome: clinical and molecular cytogenetic studies. Hou, J.W. Acta paediatrica Taiwanica = Taiwan er ke yi xue hui za zhi. (2005) [Pubmed]
  23. Multiple signals required for cyclic AMP-responsive element binding protein (CREB) binding protein interaction induced by CD3/CD28 costimulation. Yu, C.T., Shih, H.M., Lai, M.Z. J. Immunol. (2001) [Pubmed]
  24. Control of CREB-binding protein signaling by nuclear fibroblast growth factor receptor-1: a novel mechanism of gene regulation. Fang, X., Stachowiak, E.K., Dunham-Ems, S.M., Klejbor, I., Stachowiak, M.K. J. Biol. Chem. (2005) [Pubmed]
  25. Cooperative interaction of EWS with CREB-binding protein selectively activates hepatocyte nuclear factor 4-mediated transcription. Araya, N., Hirota, K., Shimamoto, Y., Miyagishi, M., Yoshida, E., Ishida, J., Kaneko, S., Kaneko, M., Nakajima, T., Fukamizu, A. J. Biol. Chem. (2003) [Pubmed]
  26. Ligand-independent interactions of p160/steroid receptor coactivators and CREB-binding protein (CBP) with estrogen receptor-alpha: regulation by phosphorylation sites in the A/B region depends on other receptor domains. Dutertre, M., Smith, C.L. Mol. Endocrinol. (2003) [Pubmed]
  27. Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mujtaba, S., He, Y., Zeng, L., Yan, S., Plotnikova, O., Sachchidanand, n.u.l.l., Sanchez, R., Zeleznik-Le, N.J., Ronai, Z., Zhou, M.M. Mol. Cell (2004) [Pubmed]
  28. Control of CBP co-activating activity by arginine methylation. Chevillard-Briet, M., Trouche, D., Vandel, L. EMBO J. (2002) [Pubmed]
  29. A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA. Watanabe, M., Yanagisawa, J., Kitagawa, H., Takeyama , K., Ogawa, S., Arao, Y., Suzawa, M., Kobayashi, Y., Yano, T., Yoshikawa, H., Masuhiro, Y., Kato, S. EMBO J. (2001) [Pubmed]
  30. Steroid receptor induction of gene transcription: a two-step model. Jenster, G., Spencer, T.E., Burcin, M.M., Tsai, S.Y., Tsai, M.J., O'Malley, B.W. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  31. CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1. Frønsdal, K., Engedal, N., Slagsvold, T., Saatcioglu, F. J. Biol. Chem. (1998) [Pubmed]
  32. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. Pitkänen, J., Doucas, V., Sternsdorf, T., Nakajima, T., Aratani, S., Jensen, K., Will, H., Vähämurto, P., Ollila, J., Vihinen, M., Scott, H.S., Antonarakis, S.E., Kudoh, J., Shimizu, N., Krohn, K., Peterson, P. J. Biol. Chem. (2000) [Pubmed]
  33. The coactivator of transcription CREB-binding protein interacts preferentially with the glycosylated form of Stat5. Gewinner, C., Hart, G., Zachara, N., Cole, R., Beisenherz-Huss, C., Groner, B. J. Biol. Chem. (2004) [Pubmed]
  34. MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Ernst, P., Wang, J., Huang, M., Goodman, R.H., Korsmeyer, S.J. Mol. Cell. Biol. (2001) [Pubmed]
  35. The CBP bromodomain and nucleosome targeting are required for Zta-directed nucleosome acetylation and transcription activation. Deng, Z., Chen, C.J., Chamberlin, M., Lu, F., Blobel, G.A., Speicher, D., Cirillo, L.A., Zaret, K.S., Lieberman, P.M. Mol. Cell. Biol. (2003) [Pubmed]
  36. Interaction of PIMT with transcriptional coactivators CBP, p300, and PBP differential role in transcriptional regulation. Misra, P., Qi, C., Yu, S., Shah, S.H., Cao, W.Q., Rao, M.S., Thimmapaya, B., Zhu, Y., Reddy, J.K. J. Biol. Chem. (2002) [Pubmed]
  37. The NeuroD1/BETA2 sequences essential for insulin gene transcription colocalize with those necessary for neurogenesis and p300/CREB binding protein binding. Sharma, A., Moore, M., Marcora, E., Lee, J.E., Qiu, Y., Samaras, S., Stein, R. Mol. Cell. Biol. (1999) [Pubmed]
  38. CREB-binding protein in androgen receptor-mediated signaling. Aarnisalo, P., Palvimo, J.J., Jänne, O.A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  39. CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Pao, G.M., Janknecht, R., Ruffner, H., Hunter, T., Verma, I.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  40. E1A-mediated repression of progesterone receptor-dependent transactivation involves inhibition of the assembly of a multisubunit coactivation complex. Xu, Y., Klein-Hitpass, L., Bagchi, M.K. Mol. Cell. Biol. (2000) [Pubmed]
  41. Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Fukuoka, M., Daitoku, H., Hatta, M., Matsuzaki, H., Umemura, S., Fukamizu, A. Int. J. Mol. Med. (2003) [Pubmed]
  42. Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. Zhang, Z., Teng, C.T. Nucleic Acids Res. (2003) [Pubmed]
  43. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Chen, H., Lin, R.J., Schiltz, R.L., Chakravarti, D., Nash, A., Nagy, L., Privalsky, M.L., Nakatani, Y., Evans, R.M. Cell (1997) [Pubmed]
  44. CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription. Smith, C.L., Oñate, S.A., Tsai, M.J., O'Malley, B.W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  45. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NF-kappaB. Huang, W.C., Ju, T.K., Hung, M.C., Chen, C.C. Mol. Cell (2007) [Pubmed]
  46. Structural basis of site-specific histone recognition by the bromodomains of human coactivators PCAF and CBP/p300. Zeng, L., Zhang, Q., Gerona-Navarro, G., Moshkina, N., Zhou, M.M. Structure (2008) [Pubmed]
  47. Analysis of CBP (CREBBP) gene deletions in Rubinstein-Taybi syndrome patients using real-time quantitative PCR. Coupry, I., Monnet, L., Attia, A.A., Taine, L., Lacombe, D., Arveiler, B. Hum. Mutat. (2004) [Pubmed]
  48. CREB-binding protein (CBP)/p300 and RNA polymerase II colocalize in transcriptionally active domains in the nucleus. von Mikecz, A., Zhang, S., Montminy, M., Tan, E.M., Hemmerich, P. J. Cell Biol. (2000) [Pubmed]
  49. Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome. Murata, T., Kurokawa, R., Krones, A., Tatsumi, K., Ishii, M., Taki, T., Masuno, M., Ohashi, H., Yanagisawa, M., Rosenfeld, M.G., Glass, C.K., Hayashi, Y. Hum. Mol. Genet. (2001) [Pubmed]
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