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ERG (gene)

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ERG (gene)

V-ets avian erythroblastosis virus E26 oncogene homolog

PDB rendering based on 1fli.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; erg-3; p55
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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

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

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

ERG can fuse with [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

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

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

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

Interactions

ERG has been shown to interact with:

References

  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  
  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.  

Further reading

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