Transcriptional/epigenetic Regulator CBP/p300 in Tumorigenesis: Structural and Functional Versatility in Target Recognition

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2013 Jan 12

PMID 23307074

Citations 149

Authors

Feng Wang

Christopher B Marshall

Mitsuhiko Ikura

Affiliations

Soon will be listed here.

Abstract

In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four separate transactivation domains (TADs) that interact with the TADs of a number of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiological and pathological processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is associated with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.

Citing Articles

Diverse RNA methylation patterns in neutrophils: key drivers in hepatocellular carcinoma.

Xu G, Jiang Y, Tu Z, Li Y, Xu X, Tong R Clin Transl Oncol. 2024; .

PMID: 39621240 DOI: 10.1007/s12094-024-03756-2.

P300 Modulates Endothelial Mechanotransduction of Fluid Shear Stress.

Whitworth C, Aw W, Doherty E, Handler C, Ambekar Y, Sawhney A Cell Mol Bioeng. 2024; 17(5):507-523.

PMID: 39513009 PMC: 11538229. DOI: 10.1007/s12195-024-00805-2.

Genetic dysregulation of EP300 in cancers in light of cancer epigenome control - targeting of p300-proficient and -deficient cancers.

Gronkowska K, Robaszkiewicz A Mol Ther Oncol. 2024; 32(4):200871.

PMID: 39351073 PMC: 11440307. DOI: 10.1016/j.omton.2024.200871.

CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer.

Yuan X, Hao X, Chan H, Zhao N, Pedroza D, Liu F JCI Insight. 2024; 9(20).

PMID: 39287984 PMC: 11533985. DOI: 10.1172/jci.insight.182621.

Chemical Synthesis of Human Proteoforms and Application in Biomedicine.

Ai H, Pan M, Liu L ACS Cent Sci. 2024; 10(8):1442-1459.

PMID: 39220697 PMC: 11363345. DOI: 10.1021/acscentsci.4c00642.

References

Renault V, Thekkat P, Hoang K, White J, Brady C, Broz D . The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor. Oncogene. 2011; 30(29):3207-21. PMC: 3136551. DOI: 10.1038/onc.2011.35. View

Mujtaba S, He Y, Zeng L, Yan S, Plotnikova O, Sachchidanand . Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol Cell. 2004; 13(2):251-63. DOI: 10.1016/s1097-2765(03)00528-8. View

Satake N, Ishida Y, Otoh Y, Hinohara S, Kobayashi H, Sakashita A . Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16)(q23;p13) chromosome translocation. Genes Chromosomes Cancer. 1997; 20(1):60-3. View

Hosoda H, Kato K, Asano H, Ito M, Kato H, Iwamoto T . CBP/p300 is a cell type-specific modulator of CLOCK/BMAL1-mediated transcription. Mol Brain. 2009; 2:34. PMC: 2785803. DOI: 10.1186/1756-6606-2-34. View

Scolnick D, Chehab N, Stavridi E, LIEN M, Caruso L, Moran E . CREB-binding protein and p300/CBP-associated factor are transcriptional coactivators of the p53 tumor suppressor protein. Cancer Res. 1997; 57(17):3693-6. View

Patel D, Huang S, Baglia L, McCance D . The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300. EMBO J. 1999; 18(18):5061-72. PMC: 1171577. DOI: 10.1093/emboj/18.18.5061. View

Ferreon J, Martinez-Yamout M, Dyson H, Wright P . Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein. Proc Natl Acad Sci U S A. 2009; 106(32):13260-5. PMC: 2726373. DOI: 10.1073/pnas.0906770106. View

Cook P, Polakowski N, Lemasson I . HTLV-1 HBZ protein deregulates interactions between cellular factors and the KIX domain of p300/CBP. J Mol Biol. 2011; 409(3):384-98. PMC: 3139367. DOI: 10.1016/j.jmb.2011.04.003. View

Sartorelli V, Huang J, Hamamori Y, Kedes L . Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C. Mol Cell Biol. 1997; 17(2):1010-26. PMC: 231826. DOI: 10.1128/MCB.17.2.1010. View

10.

Felzien L, Farrell S, Betts J, Mosavin R, Nabel G . Specificity of cyclin E-Cdk2, TFIIB, and E1A interactions with a common domain of the p300 coactivator. Mol Cell Biol. 1999; 19(6):4241-6. PMC: 104383. DOI: 10.1128/MCB.19.6.4241. View

11.

Kee B, Arias J, Montminy M . Adaptor-mediated recruitment of RNA polymerase II to a signal-dependent activator. J Biol Chem. 1996; 271(5):2373-5. DOI: 10.1074/jbc.271.5.2373. View

12.

Bakker W, Harris I, Mak T . FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell. 2007; 28(6):941-53. DOI: 10.1016/j.molcel.2007.10.035. View

13.

Kim Y, Bjorklund S, Li Y, Sayre M, Kornberg R . A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell. 1994; 77(4):599-608. DOI: 10.1016/0092-8674(94)90221-6. View

14.

Ramirez J, Nyborg J . Molecular characterization of HTLV-1 Tax interaction with the KIX domain of CBP/p300. J Mol Biol. 2007; 372(4):958-969. PMC: 2039700. DOI: 10.1016/j.jmb.2007.06.062. View

15.

Lin C, Hare B, Wagner G, Harrison S, Maniatis T, FRAENKEL E . A small domain of CBP/p300 binds diverse proteins: solution structure and functional studies. Mol Cell. 2001; 8(3):581-90. DOI: 10.1016/s1097-2765(01)00333-1. View

16.

Petrij F, Dorsman J, Dauwerse H, Giles R, Peeters T, Hennekam R . Rubinstein-Taybi syndrome caused by a De Novo reciprocal translocation t(2;16)(q36.3;p13.3). Am J Med Genet. 2000; 92(1):47-52. DOI: 10.1002/(sici)1096-8628(20000501)92:1<47::aid-ajmg8>3.0.co;2-h. View

17.

Spiegelman B, Heinrich R . Biological control through regulated transcriptional coactivators. Cell. 2004; 119(2):157-67. DOI: 10.1016/j.cell.2004.09.037. View

18.

Youn H, Chatila T, Liu J . Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J. 2000; 19(16):4323-31. PMC: 302027. DOI: 10.1093/emboj/19.16.4323. View

19.

Yin Z, Haynie J, Yang X, Han B, Kiatchoosakun S, Restivo J . The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation. Proc Natl Acad Sci U S A. 2002; 99(16):10488-93. PMC: 124951. DOI: 10.1073/pnas.162371799. View

20.

De Guzman R, Martinez-Yamout M, Dyson H, Wright P . Interaction of the TAZ1 domain of the CREB-binding protein with the activation domain of CITED2: regulation by competition between intrinsically unstructured ligands for non-identical binding sites. J Biol Chem. 2003; 279(4):3042-9. DOI: 10.1074/jbc.M310348200. View