ERG (gene)

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V-ets erythroblastosis virus E26 oncogene homolog (avian)
Protein ERG PDB 1fli.png
PDB rendering based on 1fli.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ERG ; erg-3; p55
External IDs OMIM165080 MGI95415 HomoloGene15848 ChEMBL: 1293191 GeneCards: ERG Gene
RNA expression pattern
PBB GE ERG 211626 x at tn.png
PBB GE ERG 213541 s at tn.png
PBB GE ERG 222079 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2078 13876
Ensembl ENSG00000157554 ENSMUSG00000040732
UniProt P11308 P81270
RefSeq (mRNA) NM_001136154 NM_133659
RefSeq (protein) NP_001129626 NP_598420
Location (UCSC) Chr 21:
39.75 – 40.03 Mb
Chr 16:
95.36 – 95.59 Mb
PubMed search [1] [2]

ERG (ETS-related gene) is an oncogene meaning that it encodes for a protein that typically is mutated in cancer.[1][2][3] ERG is a member of the ETS (erythroblast transformation- specific) family of transcription factors.[4] The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.

Function[edit]

Transcriptional regulator ERG is a nuclear protein that binds purine-rich sequences of DNA.[5][6] Transcriptional regulator ERG is required for platelet adhesion to the subendothelium and regulates hematopoiesis. It has a DNA binding domain and a PNT (pointed) domain.[4] ERG is expressed at higher levels in early myelocytes than in mature lymphocytes (types of white blood cells). Therefore ERG may act as a regulator of differentiation of early hematopoietic cells.[7]

The Mld2 mutation generated through an ENU mutagenesis screen, was the first non-functional allele of Erg. Homozygous Mld2 is embryonic lethal at day 13.5. Adult mice heterozygous for the Mld2 mutation have hematopoietic stem cell defects.[8] This means that when the ERG gene was not actively transcribed and the ERG protein produced, a mouse's hematopoietic cells were unable to function properly. Since ERG is important to the ability of the hematopoietic cells to function and self-renew, there may be applications in using blood stem cells for tissue repair, transplantation and other therapeutic applications.[9]

Role in Cancer[edit]

This gene can be classified as a proto-oncogene, which participates in chromosomal translocations (a popular example of this phenomenon is the Philadelphia chromosome). Essentially during cell division ERG can accidentally get stuck onto a different chromosome than where it belongs. This results in fusion gene products, which can have bad consequences for cells. Examples of these fusion gene products would be TMPRSS2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing’s Sarcoma, and FUS-ERG in acute myeloid leukemia.[10] DNA binding protein ERG fuses with RNA binding proteins EWS and TLS/FUS in Ewing's sarcoma and acute myeloid leukemias respectively and function as transcriptional activators.[11][12] ERG and its fusion proteins EWS-ERG and TLS/FUS-ERG inhibit apoptosis.[13]

TMPRSS2 gene fusion[edit]

ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in human prostate cancer, especially in hormone-refractory prostate cancer. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling.[14] The fusion gene is critical to the progression of cancer because it inhibits the androgen receptor expression and it binds and inhibits androgen receptors already present in the cell. Essentially TMPRSS2-ERG fusion disrupts the ability of the cells to differentiate into proper prostate cells creating unregulated and unorganized tissue.[14] In 90% of prostate cancers overexpressing ERG, they also possess a fusion TMPRSS2-ERG protein, suggesting that this fusion is the predominant subtype in prostate cancer.[15]

EWS gene fusion[edit]

Ewing's sarcoma is associated with chromosomal translocations, which typically results in fusion genes with transcriptional regulators. This means that the protein transcribes for with the gene could be produced in excess or under- produced resulting in unnatural activity in cells. Typically this is the first step in a cell's progression to malignancy. In about 10% of Ewing's Sarcoma cases have an EWS1-ERG fusion.[4]

Fusion with TLS/FUS[edit]

In Acute Myeloid Leukemia the t(16;21) translocation in myeloid leukemia fuses TLS/FUS to ERG which disrupts the natural TLS/FUS RNA binding domain, and instead inserting the ERG DNA binding domain.[16]

Location[edit]

ERG is located on chromosome 21.[2] The ERG protein is expressed at a similar level throughout the body.[4]

Interactions[edit]

ERG has been shown to interact with:

References[edit]

  1. ^ Reddy ES, Rao VN, Papas TS (September 1987). "The erg gene: a human gene related to the ets oncogene". Proc. Natl. Acad. Sci. U.S.A. 84 (17): 6131–5. doi:10.1073/pnas.84.17.6131. PMC 299022. PMID 3476934. 
  2. ^ a b Rao VN, Papas TS, Reddy ES (1987). "erg, a human ets-related gene on chromosome 21: alternative splicing, polyadenylation, and translation". Science 237 (4815): 635–9. doi:10.1126/science.3299708. PMID 3299708. 
  3. ^ Rao VN, Modi WS, Drabkin HD, Patterson D, O'Brien SJ, Papas TS, Reddy ES (November 1988). "The human erg gene maps to chromosome 21, band q22: relationship to the 8; 21 translocation of acute myelogenous leukemia". Oncogene 3 (5): 497–500. PMID 3274086. 
  4. ^ a b c d http://www.ncbi.nlm.nih.gov/gene/2078
  5. ^ Reddy ES, Rao VN (December 1991). "erg, an ets-related gene, codes for sequence-specific transcriptional activators". Oncogene 6 (12): 2285–9. PMID 1766675. 
  6. ^ Siddique HR, Rao VN, Lee L, Reddy ES (July 1993). "Characterization of the DNA binding and transcriptional activation domains of the erg protein". Oncogene 8 (7): 1751–5. PMID 8510921. 
  7. ^ Murakami K, Mavrothalassitis G, Bhat NK, Fisher RJ, Papas TS (June 1993). "Human ERG-2 protein is a phosphorylated DNA-binding protein--a distinct member of the ets family". Oncogene 8 (6): 1559–66. PMID 8502479. 
  8. ^ Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA, Henley KJ, Ellis S, Voss AK, Metcalf D, Hilton DJ, Alexander WS, Kile BT (July 2008). "The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells". Nat. Immunol. 9 (7): 810–9. doi:10.1038/ni.1617. PMID 18500345. 
  9. ^ 1.S. Taoudi, T. Bee, A. Hilton, K. Knezevic, J. Scott, T. A. Willson, C. Collin, T. Thomas, A. K. Voss, B. T. Kile, W. S. Alexander, J. E. Pimanda, D. J. Hilton (Feb 2011). "ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification". Genes & Development 825 (3): 251–262. doi:10.1101/gad.2009211. PMC 3034900. PMID 21245161. 
  10. ^ "Gene Cards". 
  11. ^ a b Ohno T, Ouchida M, Lee L, Gatalica Z, Rao, VN and Reddy, ES (Oct 1994). "The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains". Oncogene 9 (10): 3087–97. PMID 8084618. 
  12. ^ a b Prasad, DDK, Ouchida, M, Lee, L, Rao, VN and Reddy, ES (Dec 1994). "TLS/FUS fusion domain of TLS/FUS‑erg chimeric protein resulting from the t(16;21) chromosome translocation in human myeloid leukemia functions as a transcriptional activation domain". Oncogene 9 (12): 3717–29. PMID 7970732. 
  13. ^ Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES (March 1997). "Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias". Oncogene 14 (11): 1259–68. doi:10.1038/sj.onc.1201099. PMID 9178886. 
  14. ^ a b c Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM (May 2010). "An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression". Cancer Cell 17 (5): 443–54. doi:10.1016/j.ccr.2010.03.018. PMC 2874722. PMID 20478527. 
  15. ^ Tomlins, Scott A.; Bharathi Laxman, Sooryanarayana Varambally, Xuhong Cao, Jindan Yu, Beth E Helgeson, Qi Cao, John R Prensner, Mark A Rubin, Rajal B Shah, Rohit Mehra, and Arul M Chinnaiyan (2008). "Role of the TMPRSS2-ERG Gene Fusion in Prostate Cancer". Neoplasia: 177–188. 
  16. ^ Ichikawa, H; Shimizu K; Hayashi Y; Ohki M. (Jun 1, 2004). "An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation.". Cancer Research 54 (11): 2865–8. PMID 8187069. 
  17. ^ Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, Stéhelin D, Duterque-Coquillaud M (May 2001). "Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation". J. Biol. Chem. 276 (20): 17181–9. doi:10.1074/jbc.M010208200. PMID 11278640. 
  18. ^ Basuyaux JP, Ferreira E, Stéhelin D, Butticè G (October 1997). "The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner". J. Biol. Chem. 272 (42): 26188–95. doi:10.1074/jbc.272.42.26188. PMID 9334186. 

Further reading[edit]

  • Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES (March 1997). "Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias". Oncogene 14 (11): 1259–68. doi:10.1038/sj.onc.1201099. PMID 9178886. 
  • Rao VN, Papas TS, Reddy ES (1987). "erg, a human ets-related gene on chromosome 21: alternative splicing, polyadenylation, and translation". Science 237 (4815): 635–9. doi:10.1126/science.3299708. PMID 3299708. 
  • Giovannini M, Biegel JA, Serra M, Wang JY, Wei YH, Nycum L, Emanuel BS, Evans GA (August 1994). "EWS-erg and EWS-Fli1 fusion transcripts in Ewing's sarcoma and primitive neuroectodermal tumors with variant translocations". J. Clin. Invest. 94 (2): 489–96. doi:10.1172/JCI117360. PMC 295111. PMID 8040301. 
  • Dunn T, Praissman L, Hagag N, Viola MV (1994). "ERG gene is translocated in an Ewing's sarcoma cell line". Cancer Genet. Cytogenet. 76 (1): 19–22. doi:10.1016/0165-4608(94)90063-9. PMID 8076344. 
  • Ichikawa H, Shimizu K, Hayashi Y, Ohki M (1994). "An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation". Cancer Res. 54 (11): 2865–8. PMID 8187069. 
  • Prasad DD, Rao VN, Lee L, Reddy ES (1994). "Differentially spliced erg-3 product functions as a transcriptional activator". Oncogene 9 (2): 669–73. PMID 8290279. 
  • Duterque-Coquillaud M, Niel C, Plaza S, Stehelin D (1993). "New human erg isoforms generated by alternative splicing are transcriptional activators". Oncogene 8 (7): 1865–73. PMID 8510931. 
  • Basuyaux JP, Ferreira E, Stéhelin D, Butticè G (1997). "The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner". J. Biol. Chem. 272 (42): 26188–95. doi:10.1074/jbc.272.42.26188. PMID 9334186. 
  • Carrère S, Verger A, Flourens A, Stehelin D, Duterque-Coquillaud M (June 1998). "Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains". Oncogene 16 (25): 3261–8. doi:10.1038/sj.onc.1201868. PMID 9681824. 
  • McLaughlin F, Ludbrook VJ, Kola I, Campbell CJ, Randi AM (December 1999). "Characterisation of the tumour necrosis factor (TNF)-(alpha) response elements in the human ICAM-2 promoter". J. Cell. Sci. 112 (24): 4695–703. PMID 10574717. 
  • Mastrangelo T, Modena P, Tornielli S, Bullrich F, Testi MA, Mezzelani A, Radice P, Azzarelli A, Pilotti S, Croce CM, Pierotti MA, Sozzi G (August 2000). "A novel zinc finger gene is fused to EWS in small round cell tumor". Oncogene 19 (33): 3799–804. doi:10.1038/sj.onc.1203762. PMID 10949935. 
  • Hartley JL, Temple GF, Brasch MA (2001). "DNA Cloning Using In Vitro Site-Specific Recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. 
  • Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, Stéhelin D, Duterque-Coquillaud M (May 2001). "Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation". J. Biol. Chem. 276 (20): 17181–9. doi:10.1074/jbc.M010208200. PMID 11278640. 
  • Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (January 2002). "Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor". Oncogene 21 (1): 148–52. doi:10.1038/sj.onc.1204998. PMID 11791185. 
  • Mackereth CD, Schärpf M, Gentile LN, McIntosh LP (2003). "Chemical shift and secondary structure conservation of the PNT/SAM domains from the ets family of transcription factors". J. Biomol. NMR 24 (1): 71–2. doi:10.1023/A:1020617426325. PMID 12449421. 
  • Matsui Y, Chansky HA, Barahmand-Pour F, Zielinska-Kwiatkowska A, Tsumaki N, Myoui A, Yoshikawa H, Yang L, Eyre DR (March 2003). "COL11A2 collagen gene transcription is differentially regulated by EWS/ERG sarcoma fusion protein and wild-type ERG". J. Biol. Chem. 278 (13): 11369–75. doi:10.1074/jbc.M300164200. PMID 12554743. 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.