Biology:EP300

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the EP300 gene.[1] It functions as histone acetyltransferase that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating cell growth and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after birth.

The EP300 gene is located on the long (q) arm of the human chromosome 22 at position 13.2. This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein.

EP300 is closely related to another gene, CREB binding protein, which is found on human chromosome 16.

Function

p300 HAT functions as histone acetyltransferase[2] that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein.

p300 HAT contains a bromodomain which is involved in IL6 signaling.[3]:3.1

This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.[4]

Mechanism

The p300 protein carries out its function of activating transcription by binding to transcription factors, and the transcription machinery. On the basis of this function, p300 is called a transcriptional coactivator. The p300 interaction with transcription factors is managed by one or more of p300 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 last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.[5]

Clinical significance

Mutations in the EP300 gene are responsible for a small percentage of cases of Rubinstein-Taybi syndrome. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of p300 protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development.[citation needed]

Chromosomal rearrangements involving chromosome 22 have rarely been associated with certain types of cancer. These rearrangements, called translocations, disrupt the region of chromosome 22 that contains the EP300 gene. For example, researchers have found a translocation between chromosomes 8 and 22 in several people with a cancer of blood cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer.[citation needed]

Mutations in the EP300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, EP300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form.[citation needed]

Interactions

EP300 has been shown to interact with:


References

  1. ↑ "Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor". Genes Dev. 8 (8): 869–84. April 1994. doi:10.1101/gad.8.8.869. PMID 7523245. 
  2. ↑ "The transcriptional coactivators p300 and CBP are histone acetyltransferases". Cell 87 (5): 953–9. 1996. doi:10.1016/S0092-8674(00)82001-2. PMID 8945521. 
  3. ↑ "Bromodomains: Translating the words of lysine acetylation into myelin injury and repair". Neuroscience Letters 625: 4–10. June 2016. doi:10.1016/j.neulet.2015.10.015. PMID 26472704. 
  4. ↑ "Entrez Gene: EP300". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2033. 
  5. ↑ "Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53". PNAS 104 (17): 7009–7014. April 2007. doi:10.1073/pnas.0702010104. PMID 17438265. Bibcode: 2007PNAS..104.7009T. ; "Nine-amino-acid transactivation domain: establishment and prediction utilities". Genomics 89 (6): 756–68. June 2007. doi:10.1016/j.ygeno.2007.02.003. PMID 17467953. 
  6. ↑ "Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation". J. Biol. Chem. 274 (40): 28491–6. October 1999. doi:10.1074/jbc.274.40.28491. PMID 10497212. 
  7. ↑ 7.0 7.1 "p300 Modulates the BRCA1 inhibition of estrogen receptor activity". Cancer Res. 62 (1): 141–51. January 2002. PMID 11782371. 
  8. ↑ "CBP/p300 interact with and function as transcriptional coactivators of BRCA1". Proc. Natl. Acad. Sci. U.S.A. 97 (3): 1020–5. February 2000. doi:10.1073/pnas.97.3.1020. PMID 10655477. Bibcode: 2000PNAS...97.1020P. 
  9. ↑ 9.0 9.1 "Glucagon gene transcription activation mediated by synergistic interactions of pax-6 and cdx-2 with the p300 co-activator". J. Biol. Chem. 274 (41): 28950–7. October 1999. doi:10.1074/jbc.274.41.28950. PMID 10506141. 
  10. ↑ "Interaction and functional collaboration of p300 and C/EBPbeta". Mol. Cell. Biol. 17 (11): 6609–17. November 1997. doi:10.1128/mcb.17.11.6609. PMID 9343424. 
  11. ↑ "The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors". J. Biol. Chem. 275 (12): 8825–34. March 2000. doi:10.1074/jbc.275.12.8825. PMID 10722728. 
  12. ↑ "Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1". Genes Dev. 13 (1): 64–75. January 1999. doi:10.1101/gad.13.1.64. PMID 9887100. 
  13. ↑ 13.0 13.1 "Physical and functional interactions among AP-2 transcription factors, p300/CREB-binding protein, and CITED2". J. Biol. Chem. 278 (18): 16021–9. May 2003. doi:10.1074/jbc.M208144200. PMID 12586840. 
  14. ↑ "Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2". J. Biol. Chem. 277 (10): 8559–65. March 2002. doi:10.1074/jbc.M110850200. PMID 11744733. 
  15. ↑ "MRG1 binds to the LIM domain of Lhx2 and may function as a coactivator to stimulate glycoprotein hormone alpha-subunit gene expression". J. Biol. Chem. 274 (51): 36159–67. December 1999. doi:10.1074/jbc.274.51.36159. PMID 10593900. 
  16. ↑ "Synergism between p68 RNA helicase and the transcriptional coactivators CBP and p300". Oncogene 22 (1): 151–6. January 2003. doi:10.1038/sj.onc.1206067. PMID 12527917. 
  17. ↑ "Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor". J. Biol. Chem. 276 (48): 45031–40. November 2001. doi:10.1074/jbc.M105245200. PMID 11564735. 
  18. ↑ "Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle". Mol. Cell. Biol. 20 (23): 8889–902. December 2000. doi:10.1128/mcb.20.23.8889-8902.2000. PMID 11073989. 
  19. ↑ "A novel Rb- and p300-binding protein inhibits transactivation by MyoD". Mol. Cell. Biol. 20 (23): 8903–15. December 2000. doi:10.1128/mcb.20.23.8903-8915.2000. PMID 11073990. 
  20. ↑ "MAP kinase phosphorylation-dependent activation of Elk-1 leads to activation of the co-activator p300". EMBO J. 22 (2): 281–91. January 2003. doi:10.1093/emboj/cdg028. PMID 12514134. 
  21. ↑ 21.0 21.1 "The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation". Dev. Cell 3 (6): 903–10. December 2002. doi:10.1016/s1534-5807(02)00360-x. PMID 12479814. 
  22. ↑ "The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro". Proc. Natl. Acad. Sci. U.S.A. 99 (5): 2642–7. March 2002. doi:10.1073/pnas.261715899. PMID 11867769. Bibcode: 2002PNAS...99.2642K. 
  23. ↑ "Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300". Mol. Cell 7 (6): 1221–31. June 2001. doi:10.1016/s1097-2765(01)00272-6. PMID 11430825. 
  24. ↑ "AMF-1/Gps2 binds p300 and enhances its interaction with papillomavirus E2 proteins". J. Virol. 74 (13): 5872–9. July 2000. doi:10.1128/jvi.74.13.5872-5879.2000. PMID 10846067. 
  25. ↑ "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch". Science 295 (5556): 858–61. February 2002. doi:10.1126/science.1068592. PMID 11823643. Bibcode: 2002Sci...295..858L. 
  26. ↑ "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5367–72. April 2002. doi:10.1073/pnas.082117899. PMID 11959990. Bibcode: 2002PNAS...99.5367F. 
  27. ↑ "Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter". Diabetes 51 (5): 1409–18. May 2002. doi:10.2337/diabetes.51.5.1409. PMID 11978637. 
  28. ↑ "Scaffold/matrix attachment region elements interact with a p300-scaffold attachment factor A complex and are bound by acetylated nucleosomes". Mol. Cell. Biol. 22 (8): 2598–606. April 2002. doi:10.1128/mcb.22.8.2598-2606.2002. PMID 11909954. 
  29. ↑ 29.0 29.1 "p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity". Cancer Res. 63 (10): 2373–8. May 2003. PMID 12750254. 
  30. ↑ "Coactivator p300 acetylates the interferon regulatory factor-2 in U937 cells following phorbol ester treatment". J. Biol. Chem. 276 (24): 20973–80. June 2001. doi:10.1074/jbc.M101707200. PMID 11304541. 
  31. ↑ "Identification of a promoter-specific transcriptional activation domain at the C terminus of the Wnt effector protein T-cell factor 4". J. Biol. Chem. 278 (6): 3776–85. February 2003. doi:10.1074/jbc.M210081200. PMID 12446687. 
  32. ↑ 32.0 32.1 "CREB-binding protein/p300 co-activation of crystallin gene expression". J. Biol. Chem. 277 (27): 24081–9. July 2002. doi:10.1074/jbc.M201821200. PMID 11943779. 
  33. ↑ "p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro". Mol. Cell. Biol. 22 (22): 7812–9. November 2002. doi:10.1128/mcb.22.22.7812-7819.2002. PMID 12391150. 
  34. ↑ "Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex". Genes Dev. 16 (11): 1397–411. June 2002. doi:10.1101/gad.991602. PMID 12050117. 
  35. ↑ 35.0 35.1 "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. 17 (2): 1010–26. February 1997. doi:10.1128/mcb.17.2.1010. PMID 9001254. 
  36. ↑ "Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4". J. Biol. Chem. 275 (29): 22563–7. July 2000. doi:10.1074/jbc.C000304200. PMID 10825153. 
  37. ↑ "Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2". Immunity 13 (1): 85–94. July 2000. doi:10.1016/s1074-7613(00)00010-8. PMID 10933397. 
  38. ↑ "Effects of B-Myb on gene transcription: phosphorylation-dependent activity and acetylation by p300". J. Biol. Chem. 277 (6): 4088–97. February 2002. doi:10.1074/jbc.M105112200. PMID 11733503. 
  39. ↑ 39.0 39.1 "p300/MDM2 complexes participate in MDM2-mediated p53 degradation". Mol. Cell 2 (4): 405–15. October 1998. doi:10.1016/s1097-2765(00)80140-9. PMID 9809062. 
  40. ↑ 40.0 40.1 "Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD". Nucleic Acids Res. 27 (2): 411–20. January 1999. doi:10.1093/nar/27.2.411. PMID 9862959. 
  41. ↑ 41.0 41.1 "p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) modulates co-operation between myocyte enhancer factor 2A (MEF2A) and thyroid hormone receptor-retinoid X receptor". Biochem. J. 369 (Pt 3): 477–84. February 2003. doi:10.1042/BJ20020057. PMID 12371907. 
  42. ↑ "Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator". Proc. Natl. Acad. Sci. U.S.A. 97 (11): 6212–7. May 2000. doi:10.1073/pnas.97.11.6212. PMID 10823961. Bibcode: 2000PNAS...97.6212K. 
  43. ↑ "Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein (CBP)". J. Exp. Med. 187 (12): 2031–6. June 1998. doi:10.1084/jem.187.12.2031. PMID 9625762. 
  44. ↑ "Histone acetyltransferase-dependent chromatin remodeling and the vascular clock". J. Biol. Chem. 279 (8): 7091–7. February 2004. doi:10.1074/jbc.M311973200. PMID 14645221. 
  45. ↑ "Recruitment of p300/CBP in p53-dependent signal pathways". Cell 89 (7): 1175–84. 1997. doi:10.1016/s0092-8674(00)80304-9. PMID 9215639. 
  46. ↑ "Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53". Cell 117 (6): 735–48. June 2004. doi:10.1016/j.cell.2004.05.009. PMID 15186775. 
  47. ↑ "Regulation of transcription of the human presenilin-1 gene by ets transcription factors and the p53 protooncogene". J. Biol. Chem. 275 (45): 34938–45. November 2000. doi:10.1074/jbc.M005411200. PMID 10942770. 
  48. ↑ "p53 Transcriptional activity is mediated through the SRC1-interacting domain of CBP/p300". J. Biol. Chem. 277 (11): 9054–61. March 2002. doi:10.1074/jbc.M108870200. PMID 11782467. 
  49. ↑ "Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis". Nature 410 (6826): 387–91. March 2001. doi:10.1038/35066610. PMID 11268218. Bibcode: 2001Natur.410..387H. 
  50. ↑ "Epstein-Barr virus nuclear antigen 3C and prothymosin alpha interact with the p300 transcriptional coactivator at the CH1 and CH3/HAT domains and cooperate in regulation of transcription and histone acetylation". J. Virol. 76 (10): 4699–708. May 2002. doi:10.1128/jvi.76.10.4699-4708.2002. PMID 11967287. 
  51. ↑ "p300 functions as a coactivator for the peroxisome proliferator-activated receptor alpha". J. Biol. Chem. 272 (52): 33435–43. December 1997. doi:10.1074/jbc.272.52.33435. PMID 9407140. 
  52. ↑ "Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein". J. Biol. Chem. 274 (22): 15901–7. May 1999. doi:10.1074/jbc.274.22.15901. PMID 10336495. 
  53. ↑ "Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators". J. Biol. Chem. 275 (43): 33201–4. October 2000. doi:10.1074/jbc.C000517200. PMID 10944516. 
  54. ↑ "Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65". J. Biol. Chem. 278 (4): 2758–66. January 2003. doi:10.1074/jbc.M209572200. PMID 12419806. 
  55. ↑ "CREB-binding protein/p300 are transcriptional coactivators of p65". Proc. Natl. Acad. Sci. U.S.A. 94 (7): 2927–32. April 1997. doi:10.1073/pnas.94.7.2927. PMID 9096323. Bibcode: 1997PNAS...94.2927G. 
  56. ↑ "Activation of Smad1-mediated transcription by p300/CBP". Biochim. Biophys. Acta 1489 (2–3): 354–64. December 1999. doi:10.1016/S0167-4781(99)00166-9. PMID 10673036. 
  57. ↑ 57.0 57.1 "Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300". Science 284 (5413): 479–82. April 1999. doi:10.1126/science.284.5413.479. PMID 10205054. Bibcode: 1999Sci...284..479N. 
  58. ↑ "A Smad transcriptional corepressor". Cell 97 (1): 29–39. April 1999. doi:10.1016/S0092-8674(00)80712-6. PMID 10199400. 
  59. ↑ "c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity". Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6198–203. May 2001. doi:10.1073/pnas.101579798. PMID 11371641. Bibcode: 2001PNAS...98.6198P. 
  60. ↑ "Control of Smad7 stability by competition between acetylation and ubiquitination". Mol. Cell 10 (3): 483–93. September 2002. doi:10.1016/s1097-2765(02)00639-1. PMID 12408818. 
  61. ↑ "A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction". Genes Dev. 14 (13): 1605–16. July 2000. doi:10.1101/gad.14.13.1605. PMID 10887155. 
  62. ↑ "p300 interacts with the nuclear proto-oncoprotein SYT as part of the active control of cell adhesion". Cell 102 (6): 839–48. September 2000. doi:10.1016/s0092-8674(00)00072-6. PMID 11030627. 
  63. ↑ "Cooperation of the transcriptional coactivators CBP and p300 with Stat6". J. Interferon Cytokine Res. 19 (7): 711–22. July 1999. doi:10.1089/107999099313550. PMID 10454341. 
  64. ↑ "p300 functions as a transcriptional coactivator for the TAL1/SCL oncoprotein". Oncogene 18 (35): 4958–67. September 1999. doi:10.1038/sj.onc.1202889. PMID 10490830. 
  65. ↑ "Regulation of E2A activities by histone acetyltransferases in B lymphocyte development". J. Biol. Chem. 278 (4): 2370–6. January 2003. doi:10.1074/jbc.M211464200. PMID 12435739. 
  66. ↑ "Interaction of PIMT with transcriptional coactivators CBP, p300, and PBP differential role in transcriptional regulation". J. Biol. Chem. 277 (22): 20011–9. May 2002. doi:10.1074/jbc.M201739200. PMID 11912212. 
  67. ↑ "A novel zinc finger protein TReP-132 interacts with CBP/p300 to regulate human CYP11A1 gene expression". J. Biol. Chem. 276 (36): 33881–92. September 2001. doi:10.1074/jbc.M100113200. PMID 11349124. 
  68. ↑ "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300". Cancer 86 (4): 689–96. August 1999. doi:10.1002/(sici)1097-0142(19990815)86:4<689::aid-cncr19>3.0.co;2-p. PMID 10440698. 
  69. ↑ "Regulation of histone acetyltransferases p300 and PCAF by the bHLH protein twist and adenoviral oncoprotein E1A". Cell 96 (3): 405–13. February 1999. doi:10.1016/S0092-8674(00)80553-X. PMID 10025406. 
  70. ↑ "Regulation of transcription factor YY1 by acetylation and deacetylation". Mol. Cell. Biol. 21 (17): 5979–91. September 2001. doi:10.1128/mcb.21.17.5979-5991.2001. PMID 11486036. 
  71. ↑ "Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300". Genes Dev. 9 (10): 1188–98. May 1995. doi:10.1101/gad.9.10.1188. PMID 7758944. 
  72. ↑ "cAMP-response-element-binding-protein-binding protein (CBP) and p300 are transcriptional co-activators of early growth response factor-1 (Egr-1)". Biochem. J. 336 (1): 183–9. November 1998. doi:10.1042/bj3360183. PMID 9806899. 

Further reading

External links

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