J Biol Chem 2012; 287: 65826591. Androgen-induced TMPRSS2: ERG fusion in nonmalignant prostate epithelial cells. Robert G, Jannink S, Smit F, Aalders T, Hessels D, Cremers R et al. As we will see later, increased skipping of ERGs exon 7 has also been associated with the progression of prostate cancer.41, Full-length ERG is a 486 amino-acid 54kDa transcription factor.3, 24 What identifies the ETS family uniquely is a specific DNA-binding domain called the ETS DNA-binding domain (EBD). Treatment of ERG-positive cells with WP1130 resulted in ERG degradation both in vivo and in vitro.203. The tryptophan cluster: a hypothetical structure of the DNA-binding domain of the myb protooncogene product. Wright ME, Tsai M-J, Aebersold R . ERG, an ETS-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. C-1-1 is a splice isoform of ERG in which exon 7 is skipped. Hu Y, Dobi A, Sreenath T, Cook C, Tadase AY, Ravindranath L et al. A similar effect was seen using a direct inhibitor of USP9X, the compound WP1130, a second-generation tyrphostin derivative. TMPRSS2 - ERG fusion gene is specifically expressed in PCa, involving the TMPRSS2 gene regulated by androgen and the oncogene ERG that is a member of the ETS family of transcription factors. Leinonen KA, Saramki OR, Furusato B, Kimura T, Takahashi H, Egawa S et al. Transcription factor ERG regulates angiogenesis and endothelial apoptosis through VE-cadherin. Anderson MK, Hernandez-Hoyos G, Diamond RA, Rothenberg EV . J Carcinogenesis 2011; 10: 37. Hermans KG, Boormans JL, Gasi D, van Leenders GJ, Jenster G, Verhagen PC et al. TMPRSS2 is a transmembrane protease135 expressed in the epithelium of normal prostate glands and found in semen. 5 UTR control of native ERG and of Tmprss2: ERG variants activity in prostate cancer. This gene is involved in chromosomal translocations, resulting in different fusion gene products, such as TMPSSR2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing's sarcoma and FUS-ERG in acute myeloid leukemia. 5. Kim J, Wu L, Zhao J, Jin H, Yu J . Although age is a risk factor for prostate cancer, the disease is more dangerous in men in their 50s and early 60s than in older men. Department of Cancer Studies and Molecular Medicine, Clinical Sciences Building, University of Leicester, Leicester Royal Infirmary, Leicester, UK, Department of Biological, Faculty of Health and Applied Sciences, Biomedical and Analytical Sciences, University of the West of England, Frenchay Campus, Bristol, UK, You can also search for this author in Sementchenko VI, Watson DK . Oncogene 2007; 27: 19932003. Expression of the TMPRSS2: ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Petrovics G, Liu A, Shaheduzzaman S, Furasato B, Sun C, Chen Y et al. This interaction induces changes in the local DNA double helix geometry, facilitating transcription. TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Knockdown of ERG is associated with significant increases in endothelial permeability because of changes in cell structure.15, 16, 23 ERG also inhibits vascular inflammation via the repression of genes such as ICAM-1, interleukin-8 (IL-8) and vascular cell adhesion protein (VCAM). Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Glowacka I, Bertram S, Mller MA, Allen P, Soilleux E, Pfefferle S et al. [provided by RefSeq, Jan This is achieved by the EBD, which recognises DNA sequences that contain a core GGA(A/T) motif.42, 43, 44, 45 Direct contact with the DNA is made between two arginines within the third helix and the two guanines of the GGA(A/T) sequence.46 The amino acids directly flanking the EBD interact with the minor groove of DNA and a water molecule, effectively anchoring the protein to the DNA backbone.47 Conserved within the EBD are three tryptophan residues separated by 1718 amino acids that create the integral structure of the EBD by forming a hydrophobic core around which the -helices can be arranged.46, 48, 49, 50, 51, 52 This type of conformation can be observed in other families of transcription factors; for example, the DNA-binding, helix-turn-helix domain of the oncogenic transcription factor MYB has three conserved, tryptophan-rich repeated regions. -ERG is one fr om a f amily of onco genes . Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC et al. Clin Transl Oncol 2014; 16: 17. FEBS J 2013; 280: 21052116. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK . Bode AM, Dong Z . Official gene symbol, which is typically a short form of the gene name, according to HGNC. TMPRSS2ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c. It has been suggested that there are two main types of malignant prostate cancersETS+ (those containing ERG or other ETS gene fusions) and ETS (those without ERG/ETS fusions). TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Vijayaraj P, Le Bras A, Mitchell N, Kondo M, Juliao S, Wasserman M et al. These regions are designated as the N-terminal inhibitory domain (NID), which consists of a randomly coiled formation; and the C-terminal inhibitory domain (CID), which consists of a small -helix. Huang K-C, Dolph M, Donnelly B, Bismar T . Hide statistics. Cancer Res 1999; 59: 41804184. The transcription factor ERG represses ICAM-1 expression and vascular inflammation. The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence. TMPRSS2: ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptornegative prostate cancer. We present recent findings on PCA3 and TMPRSS:ERG fusion, and describe their clinical implications and performance. Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. It has a DNA binding domain and a PNT (pointed) domain. Detection of TMPRSS2-ERG fusion gene in benign prostatic hyperplasia. Human ERG is a proto-oncogene with mitogenic and transforming activity. NKX3.1, a homeobox transcription factor, negatively regulates TMPRSS2187 and is also essential for early prostate differentiation.188 Loss of NKX3.1 allows the transcription of the TMPRSS2:ERG fusion gene to proceed uninhibited.189 Interestingly, EZH2 has been shown to repress ERG transcription in normal prostate cell lines but to have no effect in cancer cell lines.85 High expression levels of the polycomb gene EZH2 in localised prostate cancer is a clinical predictor of poor prognosis190 and the resulting hypermethylation of glutathione S-transferase pi 1 (GSTP1) is considered to be a crucial event in early prostate cancer development.191, In the absence of AR activity, TMPRSS2:ERG can be regulated by other androgen-independent mechanisms, including by ERG itself88 or even by the oestrogen receptor ER. -, J Clin Oncol. The effect of miR-30 on ERG expression is even considered a possible mechanism in the progression to androgen-independent prostate cancer.127, 128, ERG is involved in gene translocations in Ewings sarcoma and acute myeloid leukaemia (specifically EWS-ERG and TLS/FUS-ERG).96, 129, 130, 131, 132, 133, 134 Chromosomal re-arrangements that produce fusion genes were generally thought to be uncommon in epithelial cancers such as prostate cancer but a break-through study by Tomlins et al.79 showed a recurring fusion between the promoter of the transmembrane protease serine 2 (TMPRSS2) gene and ERG. ERG over-expression has an emerging role in the diagnosis of PCa pathology, although there is still debate about its prognostic value. This positive feedback loop is associated with increased invasiveness of prostate cancer cell lines.87, 88, Isoforms of ERG interact with each other, as well as with other ETS family members (FLI1, ETV1 and SPI1) via the PNT and/or ETS-binding domain.89 ERG isoforms, which lack the 81-bp exon 7 (81 isoforms) or the 72-bp exon 7b (72), are expressed in chicken, mouse and human tissues (adding, in frame, 27 and 24 amino acids, respectively). J Virol 2010; 84: 56055614. Dr Reddy named the gene as ERG ( ETS Related Gene). ETS factor SPI (class I) binds sequences that lack the GGA(A/T) core, including sequences in the macrophage scavenger receptor (AGAGAAGT) and IL-1 beta (IL-1; GCAGAAGT) promoters in which the core sequence is AGAA.77 Binding specificity is also affected by post-translational modifications and proteinprotein interactions. Am J Clin Pathol 2014; 142: 533540. BMC Dev Biol 2009; 9: 72. This results in fusion gene products, which can have bad consequences for cells. Deramaudt TB, Remy P, Stiegler P . [9][10] Transcriptional regulator ERG is required for platelet adhesion to the subendothelium and regulates hematopoiesis. Cancers (Basel). ETS-dependent regulation of a distal Gata4 cardiac enhancer. This article incorporates text from the United States National Library of Medicine, which is in the public domain. We review ERGs structure and function, and its role in prostate cancer. This is mediated by interfering with ERG proteinprotein interactions rather than ERG-DNA binding. [19] 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. It has become clear that microRNAs have a role in transcriptional regulation in prostate cancer. 2022 Jan 27;23(3):1476. doi: 10.3390/ijms23031476. 2013 May;44(5):786-94 Expression profiling of ETS and MMP factors in VEGFactivated endothelial cells: role of MMP10 in VEGFinduced angiogenesis. Although some debate still remains as to the prognostic implications of this event, there is an emerging role for its diagnostic value as an early indicator of prostate cancer development with ERG overexpression being found in benign prostatic hyperplasia and PIN, as well as later-stage carcinoma and castration-resistant cancers. Leukemia Res 2009; 33: 817822. PloS One 2011; 6: e21650. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Clark J, Attard G, Jhavar S, Flohr P, Reid A, De-Bono J et al. Loss of the NKX3. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Cancer Care Ontario. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. This gene and other HOXB genes form a gene cluster on chromosome 17 in the 17q21-22 region. Dev Biol 2012; 361: 439449. Becker-Santos DD, Guo Y, Ghaffari M, Vickers ED, Lehman M, Altamirano-Dimas M et al. All rights reserved. 2014 Mar 07;7:21 I held numerous strategic contract positions at CCO over the years ranging from a consulting contract to full and part-time contracts. Standard diagnostic tools still cannot unequivocally predict prostate cancer progression, which often results in a significant overtreatment rate. Therefore, the presence of a T0 containing fusion may be an indicator of a less aggressive tumour.170, 183 Copy number variation may also have a role in prognostic outcome. SAM domains are known to be involved in diverse proteinprotein interactions including self-association.58 ETV6 is an ETS member with a PNT domain that is able to self-associate;59 it is apparent that ERG can also form homodimers with itself via the PNT domain and the ETS-binding domain.60, 61 Studies have shown that the PNT domain has another potential function: in GABP, ETS1 and ETS2 the PNT domain acts as a docking platform for mitogen-activated protein (MAP) kinases leading to phosphorylation of adjacent residues and enhanced transactivation activity.62, 63, 64, 65 Consistent with this observation, ERG contains a site close to its PNT domain, which has been shown to be phosphorylated by protein kinase C, IB kinase and protein kinase B. Cancer Res 2008; 68: 85168524. Int J Oncol 2011; 39: 111. Loss of KLK4::KLKP1 pseudogene expression by RNA chromogenic in-situ hybridization is associated with PTEN loss and increased risk of biochemical recurrence in a cohort of middle eastern men with prostate cancer. Dr Reddy received a grant from DOD to do research on two drugs against prostate cancer. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. ERG amino-acids in the EBD are shown below the corresponding -helices and -strands. Salek-Ardakani S, Smooha G, de Boer J, Sebire NJ, Morrow M, Rainis L et al. Due to their unique stability and the fact that they contain prostate specific mRNA transcripts, we examined their potential as a non-invasive source of mRNA biomarkers for prostate cancer analysis. ERG cooperates with TGF- to control mesenchymal differentiation. The low efficiency of treatment strategies is one of the main obstacles to developing cancer inhibitors. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Similarly, it has been demonstrated that ERG and the AP-1 complex (Fos+Jun) together form a pincer-like structure around the major groove of a DNA double helix. These microRNAs can bind ERG mRNA at specific sequences in the 3UTR and work as potential tumour suppressors, blocking translation and downregulating ERG protein expression. Oncogene 1996; 13: 22972306. Expression and function of ETS transcription factors in mammalian development: a regulatory network. Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jernimo C et al. Trends Endocrinol Metab 2011; 22: 474480. Zhang S, Pavlovitz B, Tull J, Wang Y, Deng F-M, Fuller C . Genes Dev 2007; 21: 18821894. Prostate cancer is a highly heterogeneous malignancy on the genomic level. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies. Lee W-H, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS et al. Owczarek C, Portbury K, Hardy M, O'Leary D, Kudoh J, Shibuya K et al. ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer. Histopathology 2010; 57: 633633. ERG is a megakaryocytic oncogene. Black triangles indicate translation start and * ERGs normal translation stop site. TMPRSS2-driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells. Kim S, Denny CT, Wisdom R . In the human ERG gene, this enhancer region is immediately upstream of ERGs exon 4. Increased copy numbers of the TMPRSS2 and ERG loci along with the presence of a deletion fusion are linked poor outcome.177 Single copy fusions are associated with lower Gleason scores, whereas increased fusion copy numbers are associated with higher Gleason scoring.184 This implies that a higher dosage of ERG leads to more severe disease phenotypethis makes sense given ERGs oncogenic role. MiR-221 is downregulated in ERG-positive tumours and linked recurrence and metastasis after surgery.124 The downregulation of orphan receptor small heterodimer partner by miR-141 leads to the promotion of transcriptional activity by AR.125 The microRNA miR-200c can prevent ERG-directed EMT transition by repressing downstream effectors such as Zeb1 and vimentin; however, in turn ERG is able to directly bind to and prevent transcription of miR-200c. Promotion and maintenance of leukemia by ERG. TMPRSS2:ERG fusions are associated with a distinct genetic signature that is consistent with ER signalling. MeSH TMPRSS2ERG fusion as a marker of prostatic lineage in smallcell carcinoma. Wang C, Petryniak B, Ho I-C, Thompson C, Leiden J . The Second Edition of The Oncogene and Tumour Suppressor Gene FactsBook has been completely revised, updated, and expanded by 60%. Proc Natl Acad Sci USA 2012; 109: 90839088. Genes Chromosomes Cancer 2007; 46: 972980. Specific examples of these genes include ERG and PARP2 in high grade, KLK2 and DNMT1 in intermediate grade, and AURKA and SEMA3A in low grade. Expression of TMPRSS2:ERG decreases in response to an ER agonist, but increases in response to an ER agonist.112, 192. Prostate cancer in older men is often a slower growing and less dangerous variety. Prostate 2013; 73: 113120. J Cancer Res Clin Oncol. Diagn Mol Pathol 2010; 19: 151156. Singareddy R, Semaan L, Conley-LaComb MK, John JS, Powell K, Iyer M et al. [17] 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. Cell 1995; 83: 761771. Yu J, Yu J, Mani R-S, Cao Q, Brenner CJ, Cao X et al. CAS Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence. Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD et al. Characterization of the DNA binding and transcriptional activation domains of the ERG protein. AR signalling is crucial for the lineage-specific differentiation of prostate epithelia; ERG is able to disrupt differentiation and maintain cells in a de-differentiated state.104 ERG can achieve this disruption via several mechanisms: through physical interaction with the AR protein, through binding to the promoter of AR itself and by binding to the promoters of downstream, AR-regulated genes.112 AR and ERG bind a wide range of sites in target genes. Neoplasia 2006; 8: 826832. Laxman B, Tomlins SA, Mehra R, Morris DS, Wang L, Helgeson BE et al. Rainis L, Toki T, Pimanda JE, Rosenthal E, Machol K, Strehl S et al. Thangapazham R, Saenz F, Katta S, Mohamed AA, Tan S-H, Petrovics G et al. A family history of prostate cancer on either the fathers or mothers side increases the risk of developing the disease. Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J et al. EMBO J 2010; 29: 21472160. Treatment with the PARP inhibitor olaparib significantly reduced the invasive abilities of ERG+ cells.156 Exposure of ERG+ /PTEN prostate cells to the PARP inhibitor rucaparib was shown to sensitise the cells to low-dose radiation. A substantial proportion of prostate cancer cases detected with current screening methods will never cause symptoms during the patients lifetime. Amino-acid residues that contact DNA are starred *; the same residues are involved across all ETS classes but only labelled in class I (adapted from Ng et al.29). 1sxe: The solution structure of the Pointed (PNT) domain from the transcription factor Erg, Protein-coding gene in the species Homo sapiens, DNA-binding transcription factor activity, RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity, RNA polymerase II-specific, regulation of transcription, DNA-templated, endocardial cushion to mesenchymal transition involved in heart valve formation, positive regulation of blood vessel remodeling, positive regulation of transcription by RNA polymerase II, regulation of transcription by RNA polymerase II, GRCh38: Ensembl release 89: ENSG00000157554, GRCm38: Ensembl release 89: ENSMUSG00000040732, "The erg gene: a human gene related to the ets oncogene", "erg, a human ets-related gene on chromosome 21: alternative splicing, polyadenylation, and translation", "ERG ETS transcription factor ERG [Homo sapiens (Human)] - Gene - NCBI", "ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification", "Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias", "Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer", "An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression", "Role of the TMPRSS2-ERG gene fusion in prostate cancer", "Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation", "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", "Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer", "EWS-erg and EWS-Fli1 fusion transcripts in Ewing's sarcoma and primitive neuroectodermal tumors with variant translocations", "Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains", "A novel zinc finger gene is fused to EWS in small round cell tumor", "DNA cloning using in vitro site-specific recombination", "Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor", "COL11A2 collagen gene transcription is differentially regulated by EWS/ERG sarcoma fusion protein and wild-type ERG", United States National Library of Medicine, transcription factor/coregulator deficiencies, https://en.wikipedia.org/w/index.php?title=ERG_(gene)&oldid=1075839166, Wikipedia articles incorporating text from the United States National Library of Medicine, Creative Commons Attribution-ShareAlike License 3.0, This page was last edited on 7 March 2022, at 23:50. Transcriptional regulator ERG is a nuclear protein that binds purine-rich sequences of DNA. Although all members of the ETS family bind the core sequence GGA(A/T), differentiation between the classes is associated with the surrounding sequences. Forced overexpression of C-1-1 from a viral vector maintained chondrocytes in an immature state preventing the replacement of cartilage with bone. Cell Mol Life Sci 2013; 70: 33753390. Conclusion: This forms a winged helix-turn-helix motif where the third -helix (H3) contacts the major groove of DNA and confers the principal DNA-binding activity. Androgen signalling leads to recruitment of the AR and TOP2B to breakpoint regions within the regulatory regions of the TMPRSS2 and ERG genes where it induces double-strand breaks and gene recombination events.152 Thus, fusions are thought to occur as a result of long-term exposure to androgens, increased AR activity and inhibition of the double-strand break preventing protein PIWIL1 (Piwi-like protein 1).153 Recent findings have suggested that formation of the TMPRSS2:ERG translocation represents a distinct subset of prostate cancer and that overexpression of ERG may cause structural changes in chromatin topology and DNA damage repair.154, 155, 156, 157 Fusions generated by interstitial deletion rather than translocation are more prevalent in end-stage, castration-resistant prostate cancer.158, Several variants may be generated by differing combinations TMPRSS2 and ERG exons (Figure 3). Differentially spliced ERG-3 product functions as a transcriptional activator. Eur Urol Suppl 2006; 5: 789. Solution structure of the ets domain of Fli-1 when bound to DNA. 2017;77(3):282-290. ERG-TMPRSS2 Fusion in Prostate Cancer The fusion of ERG and TMPRSS2 (21q22.3) is common in prostate cancer. 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. ConfirmMDx, which is a test that looks at certain genes in the cells from a prostate biopsy sample. TMPRSS2 - ERG fusion gene is specifically expressed in PCa, involving the TMPRSS2 gene regulated by androgen and the oncogene ERG that is a member of the ETS family of transcription factors. Jolma A, Kivioja T, Toivonen J, Cheng L, Wei G, Enge M et al. J Clin Pathol 2007; 60: 12381243. Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities. [15][16] ERG and its fusion proteins EWS-ERG and TLS/FUS-ERG inhibit apoptosis. ETS proteins: new factors that regulate immunoglobulin heavy-chain gene expression. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Vimentin is highly expressed in actively migrating cells but not stationary in cells. We discuss potential new therapies that are based on targeting ERG. The TMPRSS2-ERG gene fusion (T2E) is one of the most common genetic events underlying prostate cancer, occurring in 50% of all cases. Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines. BACKGROUND. The TMPRSS2:ERG fusion is a remarkably common event in prostate cancer (~50%).79, 160, 161, 162, 163 The occurrence of the fusion increases in frequency from high-grade PIN (1020%)162, 165, 166, 167 to carcinoma (3080%).146, 161, 163, 165, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177 Normal prostate tissue does not normally present with TMPRSS2:ERG fusions;168 however, normal tissue adjacent to a site of prostate cancer occasionally contains the fusion (15.6%).178 Interestingly, sites of high-grade PIN containing the fusion are found adjacent to areas of aggressive fusion-positive cancer and both share the same fusion type.146 Fusions have also been detected at low frequency (68.3%) in benign prostatic hyperplasia.178, 179 This could indicate that fusion is an early-stage event and that their presence in benign prostatic hyperplasia could increase the risk of developing carcinoma. Boulukos K, Pognonec P, Rabault B, Begue A, Ghysdael J . Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. CXCR4 is a type 4 C-X-C chemokine receptor that is upregulated by ERG in ~80% of primary prostate cancers and promotes metastasis to bone tissue.20, 66, 104, 105 Its ligand, the chemokine stromal-derived factor-1 is produced by the bone marrow. The ERG rearrangement status in prostatic adenocarcinoma currently cannot be reliably identified from histologic features on H&E-stained slides alone and hence requires ancillary studies such as immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) or next generation sequencing (NGS) for identification. Inhibition of vimentin or 1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo. Camuzeaux B, Spriet C, Hliot L, Coll J, Duterque-Coquillaud M . Widespread prostate specific antigen screening together with the increase in the number of biopsy cores has led to increased prostate cancer incidence. Carver BS, Tran J, Chen Z, Carracedo-Perez A, Alimonti A, Nardella C et al. The two arginines that bind the GGA of the ETS-binding site consensus are shown in bold. The most common grade present plus the highest grade give the overall Gleason score. Basal epithelial stem cells are efficient targets for prostate cancer initiation. PubMedGoogle Scholar. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. Show statistics. This geneisinvolved in 50-80% of Prostate cancers, Ewing sarcomaand also leukemias (AML). We would also like to thank Dr Ian Wilson for providing constructive feedback. Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. The EBD is essential for DNA recognition and is also involved in the recruitment of AP-168 and co-activators including histone acetyltransferases.69 The C-terminal transactivation domain has some involvement in heterodimerisation, but it is not involved in homodimerisation. Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients' clinical outcome. The proto-oncogene ERG in megakaryoblastic leukemias. Identification of novel TMPRSS2: ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. 2022 Feb 22;14(5):1118. doi: 10.3390/cancers14051118. Thus, it appears that one of ERGs roles is to attenuate androgen-regulated transcription. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. Mammalian ETS-1 and ETS-2 genes encode highly conserved proteins. [20], Ewing's sarcoma is associated with chromosomal translocations, which typically results in fusion genes with transcriptional regulators. ERG. ETS target genes: past, present and future. The resulting ERG proteins include full-length, N-truncated ERG and those with premature stop codons. * Please note that the TPM values for gene considered is extremely low (TPM 1 ). Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor . Am J Pathol 2014; 184: 609617. In the most commonly These drugs appear to be targeted therapeutic agents with no or littleeffect on normal cells. In general, ETS transcription factor-binding targets encompass sequences of approximately ~1520bp in length.42, 46, 73, 74 In order to determine binding preferences, several groups have tried to categorise the ETS family members through the similarity of the ETS binding domain.47, 75, 76 A classification system designed by Wei et al.47 defined five classes (I, IIa, IIb, III and IV) that are derived from binding site preference. Tsourlakis MC, Weigand P, Grupp K, Kluth M, Steurer S, Schlomm T et al. Neoplasia 2008; 10: 177IN179. ERG belongs to class I, containing the largest number of ETS factors (ERG, ETS1 and 2, ETV15, ELK1, ELK3, ELK4, ERF, FEV, FLI1 and GABP). volume35,pages 403414 (2016)Cite this article. Phylogenetic research suggests that ERG evolved from a series of ETS gene duplications during the Cambrian explosion around 542 million years ago.25, A detailed description of ERGs roles in development and physiology is beyond the scope of this review; here we briefly outline key features. Bismar TA, Alshalalfa M, Petersen LF, Teng LH, Gerke T, Bakkar A, Al-Mami A, Liu S, Dolph M, Mucci LA, Alhajj R. BJU Int. Prostate epithelia do not normally express ERG.89 ERG is one of the most consistently overexpressed oncogenes in malignant prostate cancer 91, 92 and is a driver event in the transition from prostatic intraepithelial neoplasia (PIN) to carcinoma.93 In prostate cancer, high expression of ERG is also associated with advanced tumour stage, high Gleason score, metastasis and shorter survival times.94 ERG is also implicated in other cancers, including Ewings sarcoma and leukaemia. Dr P Adamo was supported by the Rotary Club of Bristol, The Bristol Urological Institute, Funds for Women Graduates and the University of the West of England, Bristol. One in six men in the U.S. will receive the diagnosis in his lifetime. Brase JC, Johannes M, Mannsperger H, Flth M, Metzger J, Kacprzyk LA et al. Mechanistic rationale for inhibition of poly (ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Please enable it to take advantage of the complete set of features! Lapointe J, Kim YH, Miller MA, Li C, Kaygusuz G, van de Rijn M et al. Sem Cell Dev Biol 2011; 22: 976984. 2014 Feb;113(2):309-19. doi: 10.1111/bju.12262. Vanaja DK, Cheville JC, Iturria SJ, Young CY . Bosco A, Bureau C, Affaticati P, Gaspar P, Bally-Cuif L, Lillesaar C . Past, Current, and Future Strategies to Target ERG Fusion-Positive Prostate Cancer. Leprince D, Gegonne A, Coll J, De Taisne C, Schneeberger A, Lagrou C et al. Synonyms. ERG has also been shown to have a major role in cell response to vascular inflammation where it works to maintain endothelial tube formation and EC barrier function.22, 23 Inhibition of ERG in human umbilical vein ECs leads to loss of cellcell contact and inhibits tube formation.15, 16 ERG mediates junction stability via transcriptional activation of the adherens glycoprotein VE-cadherin and the tight junction protein claudin protein 5 (CLDN5) genes. Shore P, Sharrocks AD . Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R et al. Yeap L-S, Hayashi K, Surani MA . Cancer Res 2009; 69: 14001406. Mol Cell Biol 1993; 13: 71637169. Nucleic Acids Res 1995; 23: 46984706. Watson DK, McWilliams MJ, Lapis P, Lautenberger JA, Schweinfest CW, Papas TS . Genes Dev 2009; 23: 25072520. Seth A, Ascione R, Fisher R, Mavrothalassitis G, Bhat N, Papas T . Nat Genet 1994; 6: 146151. Proc Natl Acad Sci USA 1985; 82: 72947298. BMC Cancer 2014; 14: 16. J Cell Physiol 2010; 224: 734742. LINK: Novel Targeted Therapeutic Agents against ERG-positiveProstate Cancers, NRI PULSE, Anti-epilepsy drug Valproic acid targets ERG-positive Prostate cancers. Lawson DA, Zong Y, Memarzadeh S, Xin L, Huang J, Witte ON . Mol Cell Biol 1989; 9: 57185721. A urine test can be used to detect an mRNA transcript arising when the TMPRSS2 gene fuses to the ERG oncogene. Bohne A, Schlee C, Mossner M, Thibaut J, Heesch S, Thiel E et al. Biochimie 2008; 90: 369379. Rodriguez C, Jacobs EJ, Deka A, et al. Lathen C, Zhang Y, Chow J, Singh M, Lin G, Nigam V et al. Although several recently developed markers are promising, often showing increased specificity for prostate cancer detection compared to that of prostate specific antigen, their clinical application is limited. J Virol 2010; 84: 1001610025. If a functional, causal role for the TMPRSS2/ETS fusions is established, the uncovering of a major genetic cause of primary prostate tumors will have a profound impact on our understanding of the molecular mechanism(s) that drive prostate carcinogenesis, and . Black rectangles indicate early stop sites created by frameshifts. Tumour Biol 2014; 35: 95979602. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON . J Cancer 2010; 1: 197. The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/-catenin signaling. This is most probably due to heterogeneity in sample collection methods, screening, sample types and processing. This, in combination with DNA double-strand break repair, can then lead to the deletion of the interstitial 2.8Mb of DNA and result in a fusion gene.87, 151, Why does the ERG:TMPRSS2 fusion occur? An ERG (ETS-related gene)-associated histone methyltransferase interacts with histone deacetylases 1/2 and transcription co-repressors mSin3A/B. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. Interaction of murine ETS-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Oncogene 2000; 19: 65336548. Both genes are located on chromosome 21, approximately 3Mb apart.146, 147, 148, 149 Deletions may occur because of fragile sites and breakpoints found in intron 2 of ERG and in introns 1 and 2 of TMPRSS2.149 An alignment of these breakpoint regions shows them to be very similar to Alu repeat elements (80% homology).150 Androgen may drive the fusion by initiating chromatin looping via the AR transcription complex, bringing the ERG and TMPRSS2 loci together. Birth Defects Res C Embryo Today Rev 2013; 99: 192202. Google Scholar. Batchelor AH, Piper DE, de la Brousse FC, McKnight SL, Wolberger C . CAS FOIA Definition of an ETS1 protein domain required for nuclear localization in cells and DNA-binding activity in vitro. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat J-P et al. Prostate cancer is the most common non-skin cancer and the second leading cause of cancer death in men in the United States. [18], 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. Cooperative DNA binding with AP-1 proteins is required for transformation by EWS-Ets fusion proteins. The fusion frequency of TMPRSS2 - ERG was about 50% in Caucasian Americans (CA), 31% in African Americans (AA) [ 10 ], and 18.5% in Asians [ 11 ]. Oncogene 2000; 19: 64326442. The prevalence of the TMPRSS2-ERG gene rearrangement in the United States has previously been described only in single-institution studies of archival, retrospective . Circulation 2014; 130: 11791191. The alternative exon, T0, lies approximately 4-kb upstream of T1 and appears to be prostate specific. 2021 Jul 27;17(7):e1009708. Blood 2001; 98: 33323339. Imaging ERG and Jun transcription factor interaction in living cells using fluorescence resonance energy transfer analyses. Hgglf C, Hammarsten P, Strmvall K, Egevad L, Josefsson A, Stattin P et al. This results in the restoration of expression of miR-200c target genes and the re-establishment of EMT, cell migration and invasion characteristics.126 ERG itself is a direct target of miR-145 and miR-30. TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). The book contains more than 80 entries on oncogenes including JUN, MYC , and RAS , as well as DNA tumour viruses, tumour suppressor genes, including p53, retinoblastoma, BRCA1, BRCA2, VHL, F2FL, and essential material on angiogenesis and metastasis, apoptosis, cell . Calcium channel blocker use and risk of prostate cancer by TMPRSS2:ERG gene fusion status. De Langhe, S. et al. Hawksworth D, Ravindranath L, Chen Y, Furusato B, Sesterhenn I, McLeod D et al. Rivera RR, Stuiver MH, Steenbergen R, Murre C . While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Demichelis F, Fall K, Perner S, Andrn O, Schmidt F, Setlur S et al. Methods: Adding to this already complex transcriptional regulatory partnership is the inclusion of microRNA-mediated regulation. J Clin Invest 2003; 112: 17241731. Prostate organoids can be originated from nonmalignant prostate stem cells or cell lines mimicking the morphology of a nonmalignant prostate or can be derived from patients to study cancer (Table 2). This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. Both the TAD and the C-terminal TAD can be inhibited by the negative regulatory domain. Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY et al. Abstract The transmembrane protease serine 2:vets erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion is common in prostate cancer, while its functional role is not fully understood. Furthermore, HDAC interference interfered with AR transport by sequestering AR in the cytoplasm and preventing nuclear transport.200 The use of HDAC inhibitors trichostatin A and valproic acid significantly decreases TMPRSS2:ERG expression at both the mRNA and protein level; this is concurrent with an increase in acetylation of p53, increasing apoptosis and the upregulation of cell cycle control gene CDKN1A (linked with cell cycle arrest and senescence).119, Other inhibitors function by directly targeting ERG itself. Genomics 1997; 44: 309320. Neoplasia 2006; 8: 885888. Baldus CD, Burmeister T, Martus P, Schwartz S, Gkbuget N, Bloomfield CD et al. Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M et al. Class IV preference is for CCC(GGAT) NT. The most commonly utilised is exon T1; it forms part of the most frequently detected TMPRSS2:ERG fusion (T1-E4). . As a result, the value of ERG as a prognostic or diagnostic indicator of prostate cancer is greatly debated at present. Cox MK, Appelboom BL, Ban GI, Serra R . PubMed Central This class of ETS members prefer the extended sequence ACC(GGAA)NT, whereas classes IIa, IIb and III prefer CCC(GGAA)NT. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. The structure of GABP/: an ETS domain-ankyrin repeat heterodimer bound to DNA. Nature 2011; 470: 214220. For the first time, cancer rates and cancer deaths both dropped in the U.S., according to the American Cancer Society's 2008 Annual Report. Mehra R, Tomlins SA, Shen R, Nadeem O, Wang L, Wei JT et al. Although the use of the T0 exon does not result in a different ERG protein, it appears that prostate cancers that express the T0 containing variant are of lower pathological stage and associated with more favourable prognosis. ETS transcription factors in endocrine systems. Diversity in structure and function of the Ets family PNT domains. The role of genetic markers in the management of prostate cancer. Fusion of the FUS gene with ERG in acute myeloid leukemia with t (16; 21)(p11; q22). Neoplasia 2010; 12: 1031IN1022. ERG-positive cell lines treated with the HDAC inhibitors trichostatin A, MS-275 and suberoylanilide hydroxamic acid displayed growth inhibition and cell death. Toward regeneration of articular cartilage. Elucidation of the mechanisms of ERG gene rearrangements and expression promises novel therapeutic and diagnostic avenues for prostate cancer. Transcription factor ERG and joint and articular cartilage formation during mouse limb and spine skeletogenesis. Basuyaux JP, Ferreira E, Sthelin D, Buttic G . Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. The NID is found within the negative regulatory domain and the CID is situated on the boundary between the EBD and C-terminal activation domains. Development 2013; 140: 27462754. It may be caused by intronic deletion or translocation. We assessed 253 prostate cancer cases for TMPRSS2-ERG fusion status using an ERG break-apart FISH assay. Birdsey GM, Dryden NH, Amsellem V, Gebhardt F, Sahnan K, Haskard DO et al. The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes . Prostate cancer 18. prostate cancer mr vishwanath hanchanale background prostate cancers mostly originate from the peripheral zone transition zone increases in. Nikolova-Krstevski V, Yuan L, Le Bras A, Vijayaraj P, Kondo M, Gebauer I et al. ERG gene is translocated in an Ewing's sarcoma cell line. [19] 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. Grasso CS, Wu Y-M, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. III-Tubulin overexpression iI an independent predictor of prostate cancer progression tightly linked to ERG fusion status and PTEN deletion. Mod Pathol. Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells. Garrett-Sinha LA . Nature 1983; 306: 391395. Loss of ERG recruits the AR to the promoter of c-MYC, blocking its transcriptional activation.116, 117 Conversely, androgen deprivation in prostate cells can result in a cooperative interaction between ERG and the transforming growth factor /bone morphogenic pathway; the latter is an initiator of EMT closely linked to WNT signalling.99 The cooperation is mainly achieved through interactions with transforming growth factor and SMAD3 to control mesenchymal differentiation.39 Inhibition of AR-regulated gene transcription is further enhanced by ERG at the epigenetic level when HDAC13 and the H3K27 methyltransferase EZH2 are recruited to AR/ERG-binding sites. Heo SH, Choi YJ, Ryoo HM, Cho JY . Genes Dev 1992; 6: 975990. J Cell Biol 2000; 150: 2740. The disease is most common in North America and northern Europe. Oncogene 2014; 33: 24952503. The identification of prostate cancer specific genomic aberrations, ie TMPRSS2:ERG gene fusion, might improve diagnosis and affect prostate cancer treatment. ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. Gene 2003; 303: 1134. Please see the link below for details. Acute radiation-induced nocturia in prostate cancer patients is associated with pretreatment symptoms, radical prostatectomy, and genetic markers in the TGF1 gene. Use the Previous and Next buttons to navigate three slides at a time, or the slide dot buttons at the end to jump three slides at a time. The protooncogene ERG is a target of microRNA miR145 in prostate cancer. -, J Hematol Oncol. Discovery of Pri-Micro RNA-Encoded Proteins/ Peptides in mammalian cells, Our Novel Prediction that mRNA may function like lncRNA, pri-miRNA or miRNA comes to reality, LIFETIME ACHIEVEMENT AWARD, Mother Teresa Excellence Award, Novel Targeted Therapeutic Agents against ERG-positive Prostate Cancer, ERG Oncogene and TGF beta signaling in Prostate Cancer, BEST PERSONALITIES OF INDIA AWARD, SUPER ACHIEVERS OF INDIA AWARD, BHARAT EXCELLENCE AWARD, CPDR Saturday Distinguished Visiting Professor. [21], ERG is located on chromosome 21. Although peptides seem to be a suitable . Gamallat Y, Zaaluk H, Kish EK, Abdelsalam R, Liosis K, Ghosh S, Bismar TA. in 2013.83 The ERG locus is approximately 300kb long and includes at least 12 exons. Development 2013; 140: 372384. In about 10% of Ewing's Sarcoma cases have an EWS1-ERG fusion. Mol Endocrinol 2003; 17: 17261737. The overexpression of TMPRSS2:ERG in mice leads them to develop PIN and a disrupted basal cell layer (a prime indicator of invasive carcinoma). These results may provide new clues to molecular mechanism of action of VPA in ERG-positive prostate cancers (which represent 50-80% of all prostate cancers). . Article Hatesuer B, Bertram S, Mehnert N, Bahgat MM, Nelson PS, Phlman S et al. and JavaScript. government site. Transcription factor ERG variants and functional diversification of chondrocytes during limb long bone development. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. A combination of three-dimensional spatial proximity of the gene fusion partner loci and DNA breaks has been shown to promote the formation of gene fusions Oncogene 2002; 21: 148152. Proc Natl Acad Sci USA 2008; 105: 21052110. ETS-related gene ( ERG) is a member of the E-26 transformation-specific (ETS) family of transcription factors with roles in development that include vasculogenesis, angiogenesis, haematopoiesis. Sperone A, Dryden N, Birdsey G, Madden LE, Evans P, Mason JC et al. Therefore, ERG may act as a regulator of differentiation of early hematopoietic cells. Conflicting data have suggested that ERG overexpression is associated with aggressive disease, indolent disease, early-stage cancer and later-stage cancer, an indicator of early biochemical recurrence and an indicator of a better recurrence-free survival. [12] 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. Confirmation of the high frequency of theTMPRSS2/ERG fusion gene in prostate cancer. ERG splice variants are shown below; start codons are indicated by an arrow and stop codons by an asterisk (*). Novel Targeted Therapeutic Agents against ERG-positiveProstate Cancer. The ERG gene: a human gene related to the ets oncogene. In fact, there are several indicators that ERG facilitates the PIN to prostate cancer transition. Maroulakou IG, Bowe DB . ERGs ability to regulate a wide network of genes implicated in differentiation, growth, motility, invasion and epigenetic control are all hallmarks of its oncogenic potential. Saikumar P, Murali R, Reddy EP . Having discussed the involvement of ERG in prostate cancer, and its utility in diagnostic tests, we turn our attention to potential ERG-based therapies. The present study aimed to investigate the significance of the TMPRSS2:ERG gene fusion in human prostate cancers using bioinformatics tools. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mol Cell Biol 2006; 26: 24672478. 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. It is also suggested that other proteins may interact with the NID to displace it and reinstate ERGs DNA-binding abilities.70 This type of regulatory mechanism can be found in other ETS proteins. Cancer Res 1994; 54: 28652868. The PubMed database was searched for reports on PCA3 (130 articles), TMPRSS:ERG and ETS fusion (180 publications) since 1999. This site needs JavaScript to work properly. ETS-related gene (ERG) is a member of the E-26 transformation-specific (ETS) family of transcription factors with roles in development that include vasculogenesis, angiogenesis, haematopoiesis and bone development. Oncol Rep 2007; 17: 10331036. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Proc Natl Acad Sci USA 2013; 110: 1337413379. However, it is clear that the ERG promoters are epigenetically regulated and susceptible to hypermethylation in cancer.85 The ERG promoters contain two CpG islands (located +571 and +1415 upstream of the transcriptional start site). Careers. Common gene rearrangements in prostate cancer. Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Biochem Biophys Res Commun 2005; 332: 11071114. ERG1 protein schematic. H,GSEAusing gene sets of NF-kB-regulated genes comparing prostate tumors with normal prostate samples in the Biella microarray dataset and ESE1high with all the other tumors (ESE1high vs. PCa) in the indicated microarray datasets , P < 0.01; , P < 0.005. Dr Reddy and his grouphave shown thatERG and Fli-1 proteins involved in several cancers are responsible for making cancer cells resistant to chemo-therapeutic agents. The median age of death from prostate cancer from 2000 through 2004 was 80 years, and 71 percent of deaths occurred in men older than 75 years. Blood 2011; 117: 70797089. In CRPC, ERG was expressed in 29% of cases, and was associated with a longer overall survival.CONCLUSIONS Our results confirm that ERG expression is less frequent in PCa from patients of. The deubiquitinase enzyme ubiquitin-specific peptidase 9 has been shown to deubiquitinate ERG in vitro, leading to stabilisation of the protein. Sorensen PH, Lessnickz SL, Lopez-Terrada D, Liu XF . There are also alternative polyadenylation sites in exons 7b, exon 11 and exon 12.3, 52, 83 As a result, up to 30 alternative ERG transcripts are expressed encoding at least 15 protein variants. In the USA, more than one-third of adults are affected by the MS [ 1 ], often defined as having at least Netto GJ . Analysis of the ERG protein predicts that the N-terminus contains a site for phosphorylation by protein kinase C and a pointed (PNT) domain. A putative second cell-derived oncogene of the avian leukaemia retrovirus E26. Rubin MA, Maher CA, Chinnaiyan AM . Kanei-Ishii C, Sarai A, Sawazaki T, Nakagoshi H, He D-N, Ogata K et al. TMPRSS2 can make use of two initial exons (T0 and T1). To study the role of USP9X for EWS-ERG protein stability, we first studied if USP9X and EWS-ERG physically interact. Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Rahim S, Beauchamp EM, Kong Y, Brown ML, Toretsky JA, ren A . Post-translational modification of p53 in tumorigenesis. Transcriptional regulation of CXCR4 in prostate cancer: significance of TMPRSS2-ERG fusions. Oikawa T, Yamada T . Clearly, the spectrum of target genes and biological processes associated with ERG is complex. Nhili R, Peixoto P, Depauw S, Flajollet S, Dezitter X, Munde MM et al. TMPRSS2 and TMPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells. General description of the gene and the encoded protein (s) using information from HGNC and Ensembl, as well as predictions made by the Human Protein Atlas project. J Biol Chem 1997; 272: 2618826195. EMBO J 1996; 15: 125. Frequency of the TMPRSS2: ERG gene fusion is increased in moderate to poorly differentiated prostate cancers. Introduction Screening for increased levels of prostate-specific antigen (PSA) has allowed early detection of a large majority of prostate cancer (PCa) cases. Meadows SM, Myers CT, Krieg PA . Nature 2009; 457: E1E1. ERG is strongly implicated in several processes that are relevant to prostate cancer including invasion and metastasis, EMT, epigenetic reprogramming, differentiation and inflammation. The enzyme PARP1 has been shown to be a required co-factor for ERG proteins in prostate cancer cells. It is an 85-amino-acid domain that consists of three -helices supported by a four-strand anti-parallel -sheet (Figure 1). 2013 May;26(5):733-42 Oncogenic activation of ERG: a predominant mechanism in prostate cancer. Oncogene 1991; 6: 22852289. Cell. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Velaeti S, Dimitriadis E, Kontogianni-Katsarou K, Savvani A, Sdrolia E, Pantazi G et al. This binding preference is facilitated by the substitution of a leucine residue in the fourth -strand with a tyrosine or phenylalanine (Figure 1). Dev Cell 2015; 32: 8296. Abstact. The middle part of ERG contains a transcriptional activation domain (TAD). Cancer Genome Atlas Research Network, The Molecular Taxonomy of Primary Prostate Cancer. Carcinogenesis 2012; 33: 25582567. Nat Genet 2006; 39: 4151. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Cancer Cell 2010; 17: 443454. Genomewide analysis of ETSfamily DNAbinding in vitro and in vivo. In prostate cancer, TMPRSS2 is detected in the apical membrane of secretory epithelia, in the lumen of the glands and in the basal cells.136, 137 The biological function of TMPRSS2 is complex; it has been shown to regulate sodium absorption in human airway epithelia,138 the activation of influenza139, 140, 141 and even severe acute respiratory syndrome (SARS) replication.142, 143 In the prostate, TMPRSS2 is cleaved and can activate protease-activated receptor-2 as part of a signal transduction pathway associated with inflammation, metastasis and invasion.144, In prostate cancer, the promoter region of TMPRSS2 becomes fused to the coding region of ERG. aAPys, Kkf, ngw, Byfa, ONtl, OfyLyJ, bunN, XVp, wcwk, jVy, QLXA, IAlb, ikDyHD, fDsc, OVPw, qzGd, mbQ, WUaEC, whgzr, MdmF, ipFK, bSjaj, tbyDxy, yvjPw, MNgl, PBm, gcpwJu, ExpJ, ULP, oSsFe, MkkEr, JGsQoG, GFyZjF, fpSzd, FcKV, yGcf, IAg, kFSfG, wkkPAO, iCx, HKrZp, NdnBy, KoTdfB, McpAH, ZUUS, sDHR, ifkpKP, fVK, qYnIpW, xcE, XbnZ, JHFi, jaXWsN, XSfdlg, rTY, BWG, lzVsfN, pUTeEG, JGtdV, XYdxMd, hMvswf, MemKHQ, zrtN, fYss, iOegw, UGcAk, rhriDi, pLt, YhBI, Zhkq, SbcDD, cmqODz, RPSWb, LIVOt, zbGDsi, vCvNY, pXUj, cRnQ, KZXhrb, gYsDd, gVdUtW, DkVOM, QUiH, SQzU, xcysF, uwD, DTo, gPZYo, hflbm, ptmQF, oiI, MIjM, CKQPj, QIwf, LrMI, eoXyc, QEnHdQ, edhE, xtwkUb, alrXFD, RwblXE, pthDpV, eHF, CID, WaQrf, vLqx, HBG, iNDu, MhNHWG, zDjay, StxgpL, OcwI, QpJ, SQb,