CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBPgene.[5][6]
The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more CREB domains: the nuclear receptor interaction domain (RID), the KIX domain (CREB and MYB interaction domain), the cysteine/histidine regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The CREB protein domains, KIX, TAZ1 and TAZ2, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.[7][8]
This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein [Ref] that binds to cAMP-response element-binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity [9] and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein EP300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain.[10] Recent results suggest that novel CBP-mediated post-translational N-glycosylation activity alters the conformation of CBP-interacting proteins, leading to regulation of gene expression, cell growth and differentiation,[11]
Posttranslational modification[]
Homeodomain interacting protein kinase 2 (HIPK2) phosphorylates several regions of CBP close to the N-terminal and close to the C-terminal region as well. Out of the described phosphoacceptor sites, serines 2361, 2363, 2371, 2376, and 2381 are responsible for the HIPK2-induced mobility shift of the CBP C-terminal activation domain that is also visible in Polyacrylamide gel electrophoresis (PAGE) experiments. However, activation of CBP by HIPK2 is not mediated by this phosphorylation but rather by counteracting the repressive action of the cell cycle regulatory domain 1 (CRD1) of CBP, located between amino acids 977 and 1076.[12]
Clinical significance[]
Mutations in this gene cause Rubinstein-Taybi syndrome (RTS).[13] Chromosomal translocations involving this gene have been associated with acute myeloid leukemia.[10][14] Hypothalamic expression of this gene in mice correlates with mouse lifespan, and when CBP is inhibited in C. elegans by RNAi, there is a proportional fold-change decrease in lifespan.
Small molecule inhibition[]
A small molecule inhibitor (I-CBP112) binding to the bromodomain domain of CBP/p300 has been developed for leukemia therapy.[15]
Interactions[]
CREB-binding protein has been shown to interact with:
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, Goodman RH (October 1993). "Phosphorylated CREB binds specifically to the nuclear protein CBP". Nature. 365 (6449): 855–9. Bibcode:1993Natur.365..855C. doi:10.1038/365855a0. PMID8413673. S2CID4302589.
^Wydner KL, Bhattacharya S, Eckner R, Lawrence JB, Livingston DM (November 1995). "Localization of human CREB-binding protein gene (CREBBP) to 16p13.2-p13.3 by fluorescence in situ hybridization". Genomics. 30 (2): 395–6. PMID8586450.
^Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ (July 1995). "Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP". Nature. 376 (6538): 348–51. Bibcode:1995Natur.376..348P. doi:10.1038/376348a0. PMID7630403. S2CID4254507.
^Vizmanos JL, Larráyoz MJ, Lahortiga I, Floristán F, Alvarez C, Odero MD, Novo FJ, Calasanz MJ (April 2003). "t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia". Genes, Chromosomes & Cancer. 36 (4): 402–5. doi:10.1002/gcc.10174. hdl:10171/19610. PMID12619164. S2CID7842547.
^Picaud S, Fedorov O, Thanasopoulou A, Leonards K, Jones K, Meier J, Olzscha H, Monteiro O, Martin S, Philpott M, Tumber A, Filippakopoulos P, Yapp C, Wells C, Che KH, Bannister A, Robson S, Kumar U, Parr N, Lee K, Lugo D, Jeffrey P, Taylor S, Vecellio ML, Bountra C, Brennan PE, O'Mahony A, Velichko S, Müller S, Hay D, Daniels DL, Urh M, La Thangue NB, Kouzarides T, Prinjha R, Schwaller J, Knapp S (December 2015). "Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy". Cancer Research. 75 (23): 5106–5119. doi:10.1158/0008-5472.CAN-15-0236. PMC4948672. PMID26552700.
^Ishitani K, Yoshida T, Kitagawa H, Ohta H, Nozawa S, Kato S (July 2003). "p54nrb acts as a transcriptional coactivator for activation function 1 of the human androgen receptor". Biochemical and Biophysical Research Communications. 306 (3): 660–5. doi:10.1016/S0006-291X(03)01021-0. PMID12810069.
^Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T (August 2003). "P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain". Journal of Bone and Mineral Research. 18 (8): 1419–29. doi:10.1359/jbmr.2003.18.8.1419. PMID12929931. S2CID8125330.
^ Jump up to: abcFan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, Erdos M, Goldberg ID, Webb P, Kushner PJ, Pestell RG, Rosen EM (January 2002). "p300 Modulates the BRCA1 inhibition of estrogen receptor activity". Cancer Research. 62 (1): 141–51. PMID11782371.
^Park YK, Ahn DR, Oh M, Lee T, Yang EG, Son M, Park H (July 2008). "Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation". Molecular Pharmacology. 74 (1): 236–45. doi:10.1124/mol.108.045278. PMID18426857. S2CID31675735.
^Hofmann TG, Möller A, Sirma H, Zentgraf H, Taya Y, Dröge W, Will H, Schmitz ML (January 2002). "Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2". Nature Cell Biology. 4 (1): 1–10. doi:10.1038/ncb715. PMID11740489. S2CID37789883.
^Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, Fukamizu A (December 1997). "Functional association between CBP and HNF4 in trans-activation". Biochemical and Biophysical Research Communications. 241 (3): 664–9. doi:10.1006/bbrc.1997.7871. PMID9434765.
^Hong W, Resnick RJ, Rakowski C, Shalloway D, Taylor SJ, Blobel GA (November 2002). "Physical and functional interaction between the transcriptional cofactor CBP and the KH domain protein Sam68". Molecular Cancer Research. 1 (1): 48–55. PMID12496368.
^Ariza A, Funahashi Y, Kozawa S, Faruk MO, Nagai T, Amano M, Kaibuchi K (2021). "Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK". Journal of Neurochemistry. 157 (6): 1774–1788. doi:10.1111/jnc.15303. PMID33449379. S2CID231613803.
^Naltner A, Wert S, Whitsett JA, Yan C (December 2000). "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung". American Journal of Physiology. Lung Cellular and Molecular Physiology. 279 (6): L1066-74. doi:10.1152/ajplung.2000.279.6.l1066. PMID11076796. S2CID27872061.
^Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M (October 2001). "Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription". Genes to Cells. 6 (10): 857–68. doi:10.1046/j.1365-2443.2001.00469.x. PMID11683914. S2CID22999855.
^Almlöf T, Wallberg AE, Gustafsson JA, Wright AP (June 1998). "Role of important hydrophobic amino acids in the interaction between the glucocorticoid receptor tau 1-core activation domain and target factors". Biochemistry. 37 (26): 9586–94. doi:10.1021/bi973029x. PMID9649342.
^ Jump up to: abMatsuzaki K, Minami T, Tojo M, Honda Y, Saitoh N, Nagahiro S, Saya H, Nakao M (March 2003). "PML-nuclear bodies are involved in cellular serum response". Genes to Cells. 8 (3): 275–86. doi:10.1046/j.1365-2443.2003.00632.x. PMID12622724. S2CID9697837.
^Parry GC, Mackman N (December 1997). "Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-kappaB-mediated transcription". Journal of Immunology. 159 (11): 5450–6. PMID9548485.
^Hirose T, Fujii R, Nakamura H, Aratani S, Fujita H, Nakazawa M, Nakamura K, Nishioka K, Nakajima T (June 2003). "Regulation of CREB-mediated transcription by association of CDK4 binding protein p34SEI-1 with CBP". International Journal of Molecular Medicine. 11 (6): 705–12. doi:10.3892/ijmm.11.6.705. PMID12736710.
^Aizawa H, Hu SC, Bobb K, Balakrishnan K, Ince G, Gurevich I, Cowan M, Ghosh A (January 2004). "Dendrite development regulated by CREST, a calcium-regulated transcriptional activator". Science. 303 (5655): 197–202. Bibcode:2004Sci...303..197A. doi:10.1126/science.1089845. PMID14716005. S2CID20879721.
^Bhattacharya S, Eckner R, Grossman S, Oldread E, Arany Z, D'Andrea A, Livingston DM (September 1996). "Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha". Nature. 383 (6598): 344–7. Bibcode:1996Natur.383..344B. doi:10.1038/383344a0. PMID8848048. S2CID4306588.
Goldman PS, Tran VK, Goodman RH (1997). "The multifunctional role of the co-activator CBP in transcriptional regulation". Recent Progress in Hormone Research. 52: 103–19, discussion 119–20. PMID9238849.
Marcello A, Zoppé M, Giacca M (March 2001). "Multiple modes of transcriptional regulation by the HIV-1 Tat transactivator". IUBMB Life. 51 (3): 175–81. doi:10.1080/152165401753544241. PMID11547919. S2CID10931640.
Matt T (2002). "Transcriptional control of the inflammatory response: a role for the CREB-binding protein (CBP)". Acta Medica Austriaca. 29 (3): 77–9. doi:10.1046/j.1563-2571.2002.02010.x. PMID12168567.
Combes R, Balls M, Bansil L, Barratt M, Bell D, Botham P, Broadhead C, Clothier R, George E, Fentem J, Jackson M, Indans I, Loizu G, Navaratnam V, Pentreath V, Phillips B, Stemplewski H, Stewart J (2002). "An assessment of progress in the use of alternatives in toxicity testing since the publication of the report of the second FRAME Toxicity Committee (1991)". Alternatives to Laboratory Animals. 30 (4): 365–406. doi:10.1177/026119290203000403. PMID12234245. S2CID26326825.
Minghetti L, Visentin S, Patrizio M, Franchini L, Ajmone-Cat MA, Levi G (May 2004). "Multiple actions of the human immunodeficiency virus type-1 Tat protein on microglial cell functions". Neurochemical Research. 29 (5): 965–78. doi:10.1023/B:NERE.0000021241.90133.89. PMID15139295. S2CID25323034.
Greene WC, Chen LF (2004). "Regulation of NF-kappaB action by reversible acetylation". Novartis Foundation Symposium. Novartis Foundation Symposia. 259: 208–17, discussion 218–25. doi:10.1002/0470862637.ch15. ISBN9780470862612. PMID15171256.
Liou LY, Herrmann CH, Rice AP (September 2004). "HIV-1 infection and regulation of Tat function in macrophages". The International Journal of Biochemistry & Cell Biology. 36 (9): 1767–75. doi:10.1016/j.biocel.2004.02.018. PMID15183343.
Pugliese A, Vidotto V, Beltramo T, Petrini S, Torre D (2005). "A review of HIV-1 Tat protein biological effects". Cell Biochemistry and Function. 23 (4): 223–7. doi:10.1002/cbf.1147. PMID15473004. S2CID8408278.
Bannwarth S, Gatignol A (January 2005). "HIV-1 TAR RNA: the target of molecular interactions between the virus and its host". Current HIV Research. 3 (1): 61–71. doi:10.2174/1570162052772924. PMID15638724.
Gibellini D, Vitone F, Schiavone P, Re MC (April 2005). "HIV-1 tat protein and cell proliferation and survival: a brief review". The New Microbiologica. 28 (2): 95–109. PMID16035254.
Hetzer C, Dormeyer W, Schnölzer M, Ott M (October 2005). "Decoding Tat: the biology of HIV Tat posttranslational modifications". Microbes and Infection. 7 (13): 1364–9. doi:10.1016/j.micinf.2005.06.003. PMID16046164.
Peruzzi F (January 2006). "The multiple functions of HIV-1 Tat: proliferation versus apoptosis". Frontiers in Bioscience. 11: 708–17. doi:10.2741/1829. PMID16146763. S2CID12438136.
1f81: SOLUTION STRUCTURE OF THE TAZ2 DOMAIN OF THE TRANSCRIPTIONAL ADAPTOR PROTEIN CBP
1jjs: NMR Structure of IBiD, A Domain of CBP/p300
1jsp: NMR Structure of CBP Bromodomain in complex with p53 peptide
1kbh: Mutual Synergistic Folding in the Interaction Between Nuclear Receptor Coactivators CBP and ACTR
1kdx: KIX DOMAIN OF MOUSE CBP (CREB BINDING PROTEIN) IN COMPLEX WITH PHOSPHORYLATED KINASE INDUCIBLE DOMAIN (PKID) OF RAT CREB (CYCLIC AMP RESPONSE ELEMENT BINDING PROTEIN), NMR 17 STRUCTURES
1l3e: NMR Structures of the HIF-1alpha CTAD/p300 CH1 Complex
1l8c: STRUCTURAL BASIS FOR HIF-1ALPHA/CBP RECOGNITION IN THE CELLULAR HYPOXIC RESPONSE
1liq: Non-native Solution Structure of a fragment of the CH1 domain of CBP
1p4q: Solution structure of the CITED2 transactivation domain in complex with the p300 CH1 domain
1r8u: NMR structure of CBP TAZ1/CITED2 complex
1sb0: Solution structure of the KIX domain of CBP bound to the transactivation domain of c-Myb
1u2n: Structure CBP TAZ1 Domain
1zoq: IRF3-CBP complex
2agh: Structural basis for cooperative transcription factor binding to the CBP coactivator
2c52: STRUCTURAL DIVERSITY IN CBP P160 COMPLEXES
2d82: Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association