ERG (gene)

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

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

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. 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.

Role in Cancer
This gene can be classified as a is_associated_with::proto-oncogene, which participates in chromosomal translocations (a popular example of this phenomenon is the is_associated_with::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. DNA binding protein ERG fuses with RNA binding proteins EWS and TLS/is_associated_with::FUS in is_associated_with::Ewing's sarcoma and is_associated_with::acute myeloid leukemias respectively and function as transcriptional activators. ERG and its fusion proteins EWS-ERG and TLS/FUS-ERG inhibit apoptosis.

TMPRSS2 gene fusion
ERG can fuse with is_associated_with::TMPRSS2 protein to form an oncogenic is_associated_with::fusion gene that is commonly found in human prostate cancer, especially in is_associated_with::hormone-refractory prostate cancer. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of is_associated_with::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.

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 is_associated_with::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.

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:
 * is_associated_with::C-jun,
 * is_associated_with::ETS2,
 * EWSR1,
 * TLS, and
 * is_associated_with::TMPRSS2.