ERG (gene) explained

ERG (ETS-related gene) is an oncogene.[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. 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]

Cancer

This gene can be classified as a proto-oncogene. During chromosomal translocations that occur in cell division, ERG can accidentally get stuck onto a different chromosome than where it belongs. This is analogous to another translocation, the Philadelphia chromosome. 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] Morpholino splice-switching oligonucleotides have been used to induce exon 4 skipping in prostate cancer cell lines, mouse models and tissue explants, leading to anti-cancer effects, including reduction of proliferation and induction of apoptosis.[14]

TMPRSS2 gene fusion

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. 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. 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.

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. The ERG protein is expressed at a similar level throughout the body.

Interactions

ERG has been shown to interact with:

Further reading

Notes and References

  1. Reddy ES, Rao VN, Papas TS . The erg gene: a human gene related to the ets oncogene . Proceedings of the National Academy of Sciences of the United States of America . 84 . 17 . 6131–5 . Sep 1987 . 3476934 . 299022 . 10.1073/pnas.84.17.6131 . 1987PNAS...84.6131R . free .
  2. Rao VN, Papas TS, Reddy ES . erg, a human ets-related gene on chromosome 21: alternative splicing, polyadenylation, and translation . Science . 237 . 4815 . 635–9 . Aug 1987 . 3299708 . 10.1126/science.3299708 . 1987Sci...237..635R .
  3. Rao VN, Modi WS, Drabkin HD, Patterson D, O'Brien SJ, Papas TS, Reddy ES . 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 . Nov 1988 . 3274086 .
  4. Web site: ERG ETS transcription factor ERG [Homo sapiens (Human)] - Gene - NCBI.
  5. Reddy ES, Rao VN . erg, an ets-related gene, codes for sequence-specific transcriptional activators . Oncogene . 6 . 12 . 2285–9 . Dec 1991 . 1766675 .
  6. Siddique HR, Rao VN, Lee L, Reddy ES . Characterization of the DNA binding and transcriptional activation domains of the erg protein . Oncogene . 8 . 7 . 1751–5 . Jul 1993 . 8510921 .
  7. Murakami K, Mavrothalassitis G, Bhat NK, Fisher RJ, Papas TS . Human ERG-2 protein is a phosphorylated DNA-binding protein--a distinct member of the ets family . Oncogene . 8 . 6 . 1559–66 . Jun 1993 . 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 . The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells . Nature Immunology . 9 . 7 . 810–9 . Jul 2008 . 18500345 . 10.1038/ni.1617 . 205361508 .
  9. Taoudi S, Bee T, Hilton A, Knezevic K, Scott J, Willson TA, Collin C, Thomas T, Voss AK, Kile BT, Alexander WS, Pimanda JE, Hilton DJ . ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification . Genes & Development . 25 . 3 . 251–62 . Feb 2011 . 21245161 . 3034900 . 10.1101/gad.2009211 .
  10. Web site: Gene Cards .
  11. Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES . 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 . Oct 1994 . 8084618 .
  12. Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES . TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain . Oncogene . 9 . 12 . 3717–29 . Dec 1994 . 7970732 .
  13. Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES . Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias . Oncogene . 14 . 11 . 1259–68 . Mar 1997 . 9178886 . 10.1038/sj.onc.1201099 . free .
  14. Li L, Hobson L, Perry L, Clark B, Heavey S, Haider A, Sridhar A, Shaw G, Kelly J, Freeman A, Wilson . 6 . 2020-06-25. Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer . British Journal of Cancer . 123 . 6 . 1024–1032. 10.1038/s41416-020-0951-2 . 32581342 . 7493922 . 220049871 .
  15. Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin MA, Shah RB, Mehra R, Chinnaiyan AM . Role of the TMPRSS2-ERG gene fusion in prostate cancer . Neoplasia . 10 . 2 . 177–88 . 2008 . 18283340 . 2244693 . 10.1593/neo.07822.
  16. Ichikawa H, Shimizu K, Hayashi Y, Ohki M . 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 . Jun 1994 . 8187069 .
  17. Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, Stéhelin D, Duterque-Coquillaud M . Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation . The Journal of Biological Chemistry . 276 . 20 . 17181–9 . May 2001 . 11278640 . 10.1074/jbc.M010208200 . 32288807 . free .
  18. Basuyaux JP, Ferreira E, Stéhelin D, Butticè G . 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 . The Journal of Biological Chemistry . 272 . 42 . 26188–95 . Oct 1997 . 9334186 . 10.1074/jbc.272.42.26188 . free .
  19. 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 . An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression . Cancer Cell . 17 . 5 . 443–54 . May 2010 . 20478527 . 2874722 . 10.1016/j.ccr.2010.03.018 .
  20. Wang S, Kollipara R, Srivastava N, Li R, Ravindranathan P, Hernandez E, Freeman E, Humphries C, Kapur P, Lotan Y, Fazli L, Gleave M, Plymate S, Raj G, Hsieh J, Kittler R . Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer . Proc Natl Acad Sci USA . 111 . 11 . 4251–56 . Mar 2014 . 24591637 . 10.1073/pnas.1322198111 . 3964108 . 2014PNAS..111.4251W . free .

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