erg gene prostate cancer

Nature 2011; 470: 214220. Please enable it to take advantage of the complete set of features! Oncogene 2014; 33: 24952503. Interaction of murine ETS-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON . The overexpression of TMPRSS2:ERG in mice leads them to develop PIN and a disrupted basal cell layer (a prime indicator of invasive carcinoma). Methods PloS One 2013; 8: e49721. 2019 Jul;145(7):1751-1759. doi: 10.1007/s00432-019-02933-z. Cancer Cell 2011; 19: 664678. Expression and function of ETS transcription factors in mammalian development: a regulatory network. Select your gene target of interest using an interactive pathway map, and select your plate. TMPRSS2 is a transmembrane protease135 expressed in the epithelium of normal prostate glands and found in semen. A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Molecular characterization of prostate cancer in Middle Eastern population highlights differences with Western populations with prognostic implication. Anderson MK, Hernandez-Hoyos G, Diamond RA, Rothenberg EV . 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. Science 2010; 329: 568571. DNA binding by the ETS protein TEL (ETV6) is regulated by autoinhibition and self-association. Hoogland AM, Jenster G, van Weerden WM, Trapman J, van der Kwast T, Roobol MJ, Schrder FH, Wildhagen MF, van Leenders GJ. In fact, there are several indicators that ERG facilitates the PIN to prostate cancer transition. Examples of these fusion gene products would be TMPRSS2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewings sarcoma, and FUS-ERG in acute myeloid leukemia. Human ERG is a proto-oncogene with mitogenic and transforming activity. Mol Cell Biol 2006; 26: 965975. 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. Nat Genet 2010; 42: 668675. Nat Genet 2006; 39: 4151. As a result, the value of ERG as a prognostic or diagnostic indicator of prostate cancer is greatly debated at present. Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer. In ETS1, the CID (H4) can align in an anti-parallel manner with the H1, locking them together preventing access to the EBD.46 Instead in ETV6, the CID forms two separate helical structures, only one of which sterically blocks the EBD.71, 72, To date, the binding specificity of individual ETS transcription factors is not yet fully known, although they share a GGA(A/T) core sequence. M R Ladomery. Sperone A, Dryden N, Birdsey G, Madden LE, Evans P, Mason JC et al. Proc Natl Acad Sci 2014; 111: 42514256. The mutational landscape of lethal castration-resistant prostate cancer. 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. Meadows SM, Myers CT, Krieg PA . A substantial proportion of prostate cancer cases detected with current screening methods will never cause symptoms during the patients' lifetime. 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. Verger A, Buisine E, Carrre S, Wintjens R, Flourens A, Coll J et al. TMPRSS2-driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. Ab, antibody; FDR, false discovery rate. ERG1 protein schematic. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. -, Trends Biochem Sci. 2012 Oct;62(4):577-87. doi: 10.1016/j.eururo.2012.05.054. 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. Kim S, Denny CT, Wisdom R . Bttcher-Friebertshuser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J et al. Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J et al. Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. This results in a reduced affinity for cytosine and a preference for adenine.47, ETS transcription factors also bind sites that do not conform to the core consensus sequence. Extensive Germline-Somatic Interplay Contributes to Prostate Cancer Progression through HNF1B Co-Option of TMPRSS2-ERG [Nature Communications] Scientists observed an enrichment of transcription factor genes including HNF1B within prostate caner (PCa) risk-associated regions. Although several recently developed markers are promising, often showing increased specificity for prostate cancer detection compared to that of prostate specific antigen, their clinical . Oncogene 2014; 33: 22042214. 3. Proc Natl Acad Sci USA 1993; 90: 1028010284. Elucidation of the mechanisms of ERG gene rearrangements and expression promises novel therapeutic and diagnostic avenues for prostate cancer. 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). Solution structure of the ETS domain from murine ETS-1: a winged helix-turn-helix DNA binding motif. Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD et al. The splice isoforms denoted ERG2 (NM_004449) and ERG3 (NM_182918) are the main isoforms expressed in most endothelial, myeloid and lymphoid haematopoietic progenitor cells.84, Complexity of ERG isoforms. The role of genetic markers in the management of prostate cancer. Neoplasia 2010; 12: 1031IN1022. 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. Development 2013; 140: 372384. ERG is found to continuously express in B-lymphocytes from early pre-B cells to mature B cells,35 whereas in T-lymphocytes ERG expression is only detected transiently during T-lineage specification and is silent in mature T-lymphocytes.36 The aberrant expression of ERG in T cells promotes T-cell acute lymphoblastic leukaemia, resulting the accumulation of immature lymphoblasts.34 Murine studies have shown that a proline to serine transition (S329P) in the DNA-binding domain of ERG leads to an inability to transactivate target genes and in the context of haematopoietic lineage, this results in a reduction of mature platelets, erythrocytes and leucocytes.17, 34, 35, 36, ERG is also expressed in mesodermal cells that form precartilage.32 In chicken, ERG is expressed in cartilaginous skeletal primordia.37 In adult mice, ERG is constitutively expressed in the articular chondrocytes of transient cartilage in order to prevent their differentiation into hypertrophic cells.38, 39, 40 ERGs expression in chondrocytes has also been studied in chicken in which an ERG variant was cloned and called C-1-1.38 The variant lacks 27 amino acids that are normally located upstream of ERGs DNA-binding domain. Wang J, Cai Y, Yu W, Ren C, Spencer DM, Ittmann M . Mod Pathol 2007; 20: 467473. Identification of interaction partners for two closely-related members of the ETS protein family, FLI and ERG. These drugs appear to be targeted therapeutic agents with no or littleeffect on normal cells. I functioned as Project Manager for inter-provincial and provincial quality improvement and research projects to create and implement an . [14] 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. RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG. Cancer Res 1994; 54: 28652868. What regulates the transcription of ERG expression is not yet fully understood. Nucleic Acids Res 2013; 41: 125138. 620 University Avenue. The genetic alteration leads to the juxtaposition of androgen-responsive regulatory elements of TMPRSS2 to ERG sequence, with consequent overexpression of the rearranged ERG gene [5, 10]. SAM domains: uniform structure, diversity of function. Gutierrez-Hartmann A, Duval DL, Bradford AP . A positive ERG test represents a "fusion" on the ERG gene with another gene on that same chromosome. Google Scholar. Genes Chromosomes Cancer 2007; 46: 972980. Prostate 2013; 73: 113120. This results in fusion gene products, which can have bad consequences for cells. Saikumar P, Murali R, Reddy EP . This means that the protein transcribes for with the gene could be produced in excess or under- produced resulting in unnatural activity in cells. Oncogene 1992; 7: 17131719. Rickman DS, Chen Y-b, Banerjee S, Pan Y, Yu J, Vuong T et al. Sites of alternative polyadenylation are also shown (black triangles). Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. Saramki OR, Harjula AE, Martikainen PM, Vessella RL, Tammela TL, Visakorpi T . Shao L, Tekedereli I, Wang J, Yuca E, Tsang S, Sood A et al. It is reasonable to expect that ERG will turn out to be involved in several other types of cancer. Casey OM, Fang L, Hynes PG, Abou-Kheir WG, Martin PL, Tillman HS et al. 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. Introduction Screening for increased levels of prostate-specific antigen (PSA) has allowed early detection of a large majority of prostate cancer (PCa) cases. The https:// ensures that you are connecting to the Wang C, Petryniak B, Ho I-C, Thompson C, Leiden J . Nye JA, Petersen JM, Gunther CV, Jonsen MD, Graves BJ . 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. Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY et al. [6] The ERG protein is expressed at a similar level throughout the body.[8]. ERG status can act as an indicator of pathological stage but in isolation it is not necessarily related to biochemical recurrence or survival; this would require further confirmation of PTEN and TP53 status.197 TMPRSS2:ERG fusions can be detected with quantitative PCR in the urine of patients with suspected prostate cancer. Forced overexpression of TMPRSS2:ERG in the prostate cancer cell-line PC3 (fusion negative, with trace ERG expression), keeps cells in a de-differentiated state leading to a significant increase in cell migration and invasion.92 Furthermore, two genes that are directly induced by TMPRSS2:ERG are MMP 9 and PLXNA2 (Plexin A2). The protein variants can include three different N-termini, two alternative transactivation domains (generated by the skipping or retention of exon 7 and exon 7b) and three different C-termini (Figure 2). Abstact. Bernard D, Pourtier-Manzanedo A, Gil J, Beach DH . ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer. Kim CA, Bowie JU . Intriguingly, ERG emerged as the most positively co-expressed gene with HNF1B in TCGA cohort comprised of 497 primary PCa tumors (Fig. Shimizu K, Ichikawa H, Tojo A, Kaneko Y, Maseki N, Hayashi Y et al. Its main role appears to be in allosteric autoinhibition of ERGs EBD. 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. 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. Mammalian ETS-1 and ETS-2 genes encode highly conserved proteins. Science 2009; 326: 12301230. [11], The Mld2 mutation, generated through an ENU mutagenesis screen, was the first non-functional allele of Erg. However, on the whole recent data points towards ERG fusion as being a relatively early-stage event in the progression to malignant prostate cancer. ERG splice variants are shown below; start codons are indicated by an arrow and stop codons by an asterisk (*). In the most commonly We present recent findings on PCA3 and TMPRSS:ERG fusion, and describe their clinical implications and performance. A new novel method for direct inhibition of ERG has been achieved in vivo. Gordanpour A, Stanimirovic A, Nam RK, Moreno CS, Sherman C, Sugar L et al. J Mol Biol 2004; 342: 12491264. The site is secure. Dhordain P, Dewitte F, Desbiens X, Stehelin D, Duterque-Coquillaud M . The only 2 true prostate cancer specific biomarkers identified to date remain PCA3 and TMPRSS2:ERG gene fusion. J Clin Oncol 2011; 29: 36593668. Widespread prostate specific antigen screening together with the increase in the number of biopsy cores has led to increased prostate cancer incidence. Blinded to gene fusion status, two reviewers assessed each tumour for presence or absence of eight morphological features. J Biol Chem 2001; 276: 1718117189. PubMedGoogle Scholar. [13], This gene can be classified as a proto-oncogene. The most notable genes discovered by Dr Reddyinclude ERG-1, ERG-2, ERG-3and human FLI-1 andFli-1Bgenes. ETS family protein, ERG expression in developing and adult mouse tissues by a highly specific monoclonal antibody. Google Scholar. Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors. ERG (ETS-related gene) is an oncogene. Note that the class I target sequence begins with an A. Hypermethylation of these islands leads to transcriptional repression of ERG in T-lymphoblastic leukaemia.86, In mice, a region 85-kb downstream of ERGs promoter (termed the ERG +85 enhancer) is highly active in T-cell acute lymphoblastic leukaemia. This gene and other HOXB genes form a gene cluster on chromosome 17 in the 17q21-22 region. Clin Transl Oncol 2014; 16: 17. Internet Explorer). [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. Trends Endocrinol Metab 2011; 22: 474480. Furusato B, Gao C-L, Ravindranath L, Chen Y, Cullen J, McLeod DG et al. Green SM, Coyne HJ, McIntosh LP, Graves BJ . Seed, Alberto J. Taurozzi, Anne T. Collins, Oncogene 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 ]. PLoS Pathogens 2013; 9: e1003774. Nam R, Sugar L, Yang W, Srivastava S, Klotz L, Yang L et al. Bode AM, Dong Z . Birdsey GM, Dryden NH, Shah AV, Hannah R, Hall MD, Haskard DO et al. Mol Cancer Ther 2009; 8: 499508. Mol Cell Biol 2006; 26: 24672478. Professor and Director, Cancer Biology Program, Dept of OB/GYN, Morehouse School of Medicine, 720 Westview Drive, National Prostate Cancer Awareness Month (September), Dr Shyam Reddydiscovered and clonedseveral cancer genes/oncogenes (close to 20 genes)and studiedtheir functions. MYC upregulation is linked to increased cell survival, invasion, androgen independence and biochemical recurrence. Yu J, Yu J, Mani R-S, Cao Q, Brenner CJ, Cao X et al. There is no doubt that diagnostic tests and therapies that are based on ERG will provide new opportunities in the treatment of prostate cancer. This region also contains a negative regulatory domain.67 The C-terminus of the protein contains the ETS-binding domain including a nuclear localisation signal; adjacent is an additional, smaller transactivation domain, the C-terminal TAD.63 The TAD increases transactivation and is involved in binding protein partners including the AP-1 complex. However, the relative lack of specificity of PSA has resulted in significant over-diagnosis and unnecessary treatment for indolent tumors. Cancer Res 2003; 63: 38773882. This is analogous to another translocation, the Philadelphia chromosome. ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells. Autoinhibition of ETV6 (TEL) DNA binding: appended helices sterically block the ETS domain. Rao VN, Papas TS, Reddy E . The C-terminal H3 of ERGs EBD faces the N-terminus of Jun in an anti-parallel manner. Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. The deubiquitinase enzyme ubiquitin-specific peptidase 9 has been shown to deubiquitinate ERG in vitro, leading to stabilisation of the protein. All data are mean SEM. Epigenetic control of differential expression of specific ERG isoforms in acute T-lymphoblastic leukemia. Soller W, Johansson Soller M, Isaksson M, Elfving P, Abrahamsson P, Lundgren R et al. ETS transcription factors in endocrine systems. Cell. Mackereth CD, Schrpf M, Gentile LN, MacIntosh SE, Slupsky CM, McIntosh LP . Mod Pathol 2007; 20: 538544. Essentially TMPRSS2-ERG fusion disrupts the ability of the cells to differentiate into proper prostate cells creating unregulated and unorganized tissue. 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. Clark J, Attard G, Jhavar S, Flohr P, Reid A, De-Bono J et al. Int J Oncol 2011; 39: 111. Exp Cell Res 2014; 328: 410418. HHS Vulnerability Disclosure, Help C-1-1 is a splice isoform of ERG in which exon 7 is skipped. 2013 May;44(5):786-94 Diversity in structure and function of the Ets family PNT domains. Please see the link below for details on the novel targeted therapeutic agents against ERG-PositiveProstate Cancers. Cancer Res 2010; 70: 95449548. The open reading frame of the full-length ERG protein is 486 amino acids long. Structure of the ETS-1 pointed domain and mitogen-activated protein kinase phosphorylation site. Lautenberger J, Burdett L, Gunnell M, Qi S, Watson D, O'Brien S et al. Cancer Genome Atlas Research Network, The Molecular Taxonomy of Primary Prostate Cancer. PLoS Genet. 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. Protein Sci 2012; 21: 17161725. 2014 Jan 20;32(3):206-11 CAS Genomewide analysis of ETSfamily DNAbinding in vitro and in vivo. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Biochem J 2003; 369: 651657. Ng AP, Loughran SJ, Metcalf D, Hyland CD, de Graaf CA, Hu Y et al. You are using a browser version with limited support for CSS. 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. An ETS-related gene, ERG, is rearranged in human myeloid leukemia with t (16; 21) chromosomal translocation. Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancers. Prostate cancer is the most common non-skin cancer and the second leading cause of cancer death in men in the United States. Neoplasia 2008; 10: 177IN179. 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. 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. Science 2005; 310: 644648. Basuyaux JP, Ferreira E, Sthelin D, Buttic G . The two arginines that bind the GGA of the ETS-binding site consensus are shown in bold. ETS-dependent regulation of a distal Gata4 cardiac enhancer. Schwartzman J, Mongoue-Tchokote S, Gibbs A, Gao L, Corless CL, Jin J et al. TMPRSS2ERG gene fusion is associated with low Gleason scores and not with high-grade morphological features. Expression profiling of ETS and MMP factors in VEGFactivated endothelial cells: role of MMP10 in VEGFinduced angiogenesis. EMBO J 2010; 29: 21472160. 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. New human erg isoforms generated by alternative splicing are transcriptional activators. in 2013.83 The ERG locus is approximately 300kb long and includes at least 12 exons. The TMPRSS2-ERG gene fusion (T2E) is one of the most common genetic events underlying prostate cancer, occurring in 50% of all cases. 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. 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. Precise developmental regulation of ETS family transcription factors during specification and commitment to the T cell lineage. Hagen RM, Adamo P, Karamat S, Oxley J, Aning JJ, Gillatt D et al. The Journal of Pathology, 212(1), 91-101. doi:10.1002/path.2154 10.1002/path.2154 Sun C, Dobi A, Mohamed A, Li H, Thangapazham R, Furusato B et al. Duterque-Coquillaud M, Niel C, Plaza S, Stehelin D . Blood 2008; 111: 34983506. To study the role of USP9X for EWS-ERG protein stability, we first studied if USP9X and EWS-ERG physically interact. In recent years advances in genetics and biotechnology have stimulated the development of noninvasive tests to detect prostate cancer. Expression of the TMPRSS2: ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Am J Pathol 2014; 184: 609617. Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA et al. Kao C, Martiniez A, Shi X, Yang J, Evans C, Dobi A et al. Nat Genet 1994; 6: 146151. ERG (ETS-related gene) is a member of the E-26 transformation-specific (ETS) family of transcription factors.1, 2 There are 30 identified ETS family genes, 28 of which in the human genome.3, 4, 5 ETS genes are evolutionarily conserved across metazoa and are thought to have arisen 600700 million years ago.6, 7, 8 Research in several vertebrate model organisms shows that ETS proteins are nuclear DNA-binding phosphoproteins that act as activators or repressors of transcription.4, 9, 10, 11, 12 The ETS transcription factors are required for development and differentiation impacting across a wide range of tissue and cell types with roles in embryogenesis,13 vasculogenesis,14 angiogenesis,15, 16 haematopoiesis17 and neuronal development.18 Their target genes are involved in the regulation of cellular architecture,19 cell migration,20 invasion21 and cell permeability.22, 23, The ERG gene was first described in 1987 by Reddy et al.24 in human colorectal carcinoma cells and gene resides on chromosome 21. [provided by RefSeq, Jan However, in the past decade ERG has become highly associated with prostate cancer development, particularly as a result of a gene fusion with the promoter region of the androgen-induced TMPRRSS2 gene. Berezovska OP, Glinskii AB, Yang Z, Li X-M, Hoffman RM, Glinsky GV . Werner MH, Marius Clore G, Fisher CL, Fisher RJ, Trinh L, Shiloach J et al. The mechanism of autoinhibition is performed by two stretches of amino acids that directly flank ERGs EBD. volume35,pages 403414 (2016)Cite this article. Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Synonyms. BACKGROUND. In ERG-positive prostate cancer cell lines, its inhibition leads to decreased motility, invasion and metastasis.201 A DNA-binding inhibitor, DB1255 (di-(thiophene-phenyl-amidine)), targets the core GGA(A/T) consensus sequence within an ETS-binding site and prevents the ETS-binding domain from binding it.202, Targeting ERG for rapid degradation is another avenue for potential treatment. These findings support a potential role for the ARS process in diversifying gene expression, potentially contributing to prostate cancer aggressiveness in AA patients. Epigenetics 2011; 6: 12481256. . The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes, particularly ERG, is the most widespread genetic alteration in prostate cancer, and data suggest that it is more specific for neoplastic prostate disease and may be of added prognostic value and point toward molecular subtype of PCa. J Cancer Res Clin Oncol. Slupsky CM, Gentile LN, Donaldson LW, Mackereth CD, Seidel JJ, Graves BJ et al. Kim TS, Heinlein C, Hackman RC, Nelson PS . Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth. Cancer Res 2010; 70: 67356745. In this review, retrospective studies and clinical trials were analyzed to highlight the recent advances in our understanding of the cellular consequence of ERG rearrangement, describe its interactions with other genetic and molecular pathways, and discuss its potential diagnostic and prognostic value. The role of ERG-status molecular subtyping in prognosis of prostate cancer (PCa) is still under debate. Biochimie 2008; 90: 369379. Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P et al. Google Scholar. Unable to load your collection due to an error, Unable to load your delegates due to an error. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). Mechanistic rationale for inhibition of poly (ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. Lab Invest 2006; 86: 10991102. Androgen receptor-driven chromatin looping in prostate cancer. 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. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Nature 2012; 487: 239243. Hart AH, Corrick CM, Tymms MJ, Hertzog PJ, Kola I . Furthermore, ERG is required for definitive haematopoiesis, normal haematopoietic stem cell function and the maintenance of normal peripheral blood platelet numbers.34 T- and B-cell lymphocytes both arise from haematopoietic stem cells. These genes act to breakdown the extracellular matrix and as a signal for axonal growth cone guidance molecules, respectively.185 Upregulation of the microtubule-forming protein -III tubulin has also been tightly associated with the TMPRSS2:ERG fusion and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) deletion, particularly in tumours with a high Gleason score.186 TMPRSS2:ERG has been shown to physically interact with poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA-dependent protein kinases. Evidence suggests that the fusion is found more often in moderately to poorly differentiated samples (Gleason score >6).174 The presence of the fusion also correlates with disease recurrence after surgery; 79% of patients with the fusion are more likely to relapse.169 Patients with early onset prostate cancer, which include ERG fusions develop biochemical relapse but those lacking ERG fusion do not.180 In contrast, other studies indicate that the fusion is associated with favourable prognosis, lower-grade cancers and lack of seminal vesicle invasion.177, 181, 182 The use of alternative TMPRSS2 first exons could impact pathogenesis of the fusion. ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer. J Biol Chem 1990; 265: 1999019995. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Yuan L, Le Bras A, Sacharidou A, Itagaki K, Zhan Y, Kondo M et al. 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. The transcription factor ERG represses ICAM-1 expression and vascular inflammation. ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Further research is required before the full story of ERGs role in prostate cancer can be understood. Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA et al. Rickman DS, Soong TD, Moss B, Mosquera JM, Dlabal J, Terry S et al. An official website of the United States government. NCI CPTC Antibody Characterization Program, Mod Pathol. The most prevalent ETS gene rearrangement, which is observed in >50% of PCas, involves the fusion of androgen receptor (AR) target gene, TMPRSS2, with the ERG proto-oncogene, resulting in the formation of the TMPRSS2-ERG gene fusion. CAS Full gene name according to HGNC. Trends Endocrinol Metab 2007; 18: 150158. Fine SW, Gopalan A, Leversha MA, Al-Ahmadie HA, Tickoo SK, Zhou Q et al. > PrimePCR PCR Primers, Assays, and Arrays > PrimePCR Pathways > SAB target list panels > Prostate cancer (SAB target list) Prostate cancer (SAB target list) print Email. 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. The prevalence of the TMPRSS2-ERG gene rearrangement in the United States has previously been described only in single-institution studies of archival, retrospective . TMPRSS2ERG gene fusions induce prostate tumorigenesis by modulating microRNA miR-200c. LINK: Novel Targeted Therapeutic Agents against ERG-positiveProstate Cancers, NRI PULSE, Anti-epilepsy drug Valproic acid targets ERG-positive Prostate cancers. MeSH Singareddy R, Semaan L, Conley-LaComb MK, John JS, Powell K, Iyer M et al. Becker-Santos DD, Guo Y, Ghaffari M, Vickers ED, Lehman M, Altamirano-Dimas M et al. Dr Reddy named the gene as ERG ( ETS Related Gene). 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. Use of blood-pressure-lowering medication and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. In normal development, ERG is initially highly expressed in the embryonic mesoderm and endothelium where it has a critical role in the formation of the vascular system, the urogenital tract and in bone development.15, 26 ERG is also expressed at high levels in embryonic neural crest cells during their migratory phase.27 ERG expression decreases during vascular development28 but continues to regulate the pluripotency of haematopoietic stem cells,29 endothelial cell (EC) homeostasis30, 31 and angiogenesis.15, 16 ERG expression is not restricted to development: in the adult mouse it is expressed in endothelial tissue including adrenal, cartilage, heart, spleen, lymphatic endothelial and eosinophil cells.28, During mouse embryonic development, ERG is initially expressed in ECs,13 particularly the amniotic membrane, in the blood vessels surrounding the neural tube,32 the vasculature of the heart and in precartilage.28, 33 ERG is essential for maintaining vascular integrity and the viability of the embryo. All rights reserved. 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? The ERG gene: a human gene related to the ets oncogene. Proc Natl Acad Sci USA 2013; 110: 1337413379. [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. Hermans KG, Boormans JL, Gasi D, van Leenders GJ, Jenster G, Verhagen PC et al. Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models. There are many TMPRSS2ERG fusion transcripts. Rouzier C, Haudebourg J, Carpentier X, Valrio L, Amiel J, Michiels J-F et al. Peptides due to their small size and easy production compared to proteins are highly regarded in designing cancer vaccines and oncogenic pathway inhibitors. ERG has been shown to work in partnership with other proteins to alter DNA structure locally. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. Bowen KA, Doan HQ, Zhou BP, Wang Q, Zhou Y, Rychahou PG et al. 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. Typically this is the first step in a cell's progression to malignancy. 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. 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. PLoS One 2013; 8: e60408. Bjrkman M, Iljin K, Halonen P, Sara H, Kaivanto E, Nees M et al. BMC Cancer 2011; 11: 507. FZD4 as a mediator of ERG oncogeneinduced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Overwhelming evidence suggests that ERG does contribute to worse outcomes and is involved in the regulation of signalling pathways that are dysregulated. Thangapazham R, Saenz F, Katta S, Mohamed AA, Tan S-H, Petrovics G et al. Expression of TMPRSS2:ERG decreases in response to an ER agonist, but increases in response to an ER agonist.112, 192. This is most probably due to heterogeneity in sample collection methods, screening, sample types and processing. YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion. Blood 2011; 118: 11451153. Camuzeaux B, Spriet C, Hliot L, Coll J, Duterque-Coquillaud M . ERGs oncogenic potential is well known because of its involvement in Ewings sarcoma and leukaemia. The middle part of ERG contains a transcriptional activation domain (TAD). Differentiation 2008; 76: 717727. Specifically, ERG and TMPRSS2 come into contact with each other and produce a positive ERG test. Although peptides seem to be a suitable . Bohne A, Schlee C, Mossner M, Thibaut J, Heesch S, Thiel E et al. A transcriptional repressor coregulatory network governing androgen response in prostate cancers. Mosquera J-M, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD et al. Serum and urine molecular biomarkers have been identified, of which PCA3 has already been introduced clinically. Select Species: . This is mediated by interfering with ERG proteinprotein interactions rather than ERG-DNA binding. Mehra R, Han B, Tomlins SA, Wang L, Menon A, Wasco MJ et al. They aretargeting these onco-proteins or their functions to develop novel targeted therapeutic agents. Genes Chromosomes Cancer 1994; 11: 256262. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat J-P et al. Panagopoulos I, man P, Fioretos T, Hglund M, Johansson B, Mandahl N et al. Epub 2020 Apr 30. Androgens induce functional CXCR4 through ERG factor expression in TMPRSS2-ERG fusion-positive prostate cancer cells. Prostate cancer 18. prostate cancer mr vishwanath hanchanale background prostate cancers mostly originate from the peripheral zone transition zone increases in. Transcription factor ERG variants and functional diversification of chondrocytes during limb long bone development. Kanei-Ishii C, Sarai A, Sawazaki T, Nakagoshi H, He D-N, Ogata K et al. Official gene symbol, which is typically a short form of the gene name, according to HGNC. I held numerous strategic contract positions at CCO over the years ranging from a consulting contract to full and part-time contracts. Phenotypic analysis of mice lacking the TMPRSS2-encoded protease. Cancer Res 2009; 69: 14001406. Androgen-induced TMPRSS2: ERG fusion in nonmalignant prostate epithelial cells. Development 2012; 139: 39733985. Transcriptional regulator ERG is a protein encoded by ERG ( ETS family transcription factor ERG), which is located at 21q22 Anti-ERG monoclonal antibodies to the N or C terminus are available, with a slightly different specificity (the few differences marked throughout the text) Biomarkers such as Prostate Cancer Antigen 3 (PCA3) and transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 oncogene homolog gene fusion (T2:ERG) have been utilized to improve prediction models such as the Prostate Cancer Prevention Trial . sharing sensitive information, make sure youre on a federal Blood 2012; 119: 894903. 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 Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera J-M, Setlur S et al. Histopathology 2010; 57: 633633. In 2005, a paper published by Tomlins et al.79 showed that ERG is overexpressed in a high proportion of prostate carcinomas as a result of a gene fusion with the androgen-driven promoter of the TMPRSS2 gene. Carcinogenesis 2012; 33: 25582567. Genes Dev 2007; 21: 18821894. Watson D, McWilliams-Smith M, Nunn M, Duesberg P, O'Brien S, Papas T . The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes . In the USA, more than one-third of adults are affected by the MS [ 1 ], often defined as having at least and transmitted securely. Gene namei. This region shows strong binding of stem cell leukaemia, lymphoblastic leukaemia-associated haematopoiesis regulator 1 and LIM domain only 2 transcription factors. J Cell Physiol 2010; 224: 734742. Cancer Res 2006; 66: 1024210246. Clin Cancer Res 2009; 15: 63986403. . Brase JC, Johannes M, Mannsperger H, Flth M, Metzger J, Kacprzyk LA et al. Mohamed AA, Tan S-H, Mikhalkevich N, Ponniah S, Vasioukhin V, Bieberich CJ et al. Netto GJ . 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. Salek-Ardakani S, Smooha G, de Boer J, Sebire NJ, Morrow M, Rainis L et al. Cancer Res 2006; 66: 83478351. 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. J Clin Invest 2003; 112: 17241731. 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. TMPRSS2: ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Epub 2019 May 25. Buttic G, Duterque-Coquillaud M, Basuyaux J-P, Carrere S, Kurkinen M, Sthelin D . Abdelsalam RA, Khalifeh I, Box A, Kalantarian M, Ghosh S, Abou-Ouf H, Lotfi T, Shahait M, Palanisamy N, Bismar TA. 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 . Cancer Genet Cytogenet 2008; 183: 2127. The authors declare no conflict of interest. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. Genes Dev 1990; 4: 14511453. Adamo, P., Ladomery, M. The oncogene ERG: a key factor in prostate cancer. Toward regeneration of articular cartilage. Long-term knockdown of the two most common variants of the TMPRSS2:ERG fusion (T1-E4 and T2-E4, see Figure 3) has been successfully performed in mouse xenograft models using small interfering RNA delivered in non-toxic liposomal nanovectors (2-dioleoyl-sn-glycero-3-phosphatidylcholine). In this study, we identified differentially expressed genes (DEGs) according to ERG-status to explore their enriched pathways and implications in prognosis in Hispanic/Latino PCa patients. Keywords: 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. Iwamoto M, Higuchi Y, Koyama E, Enomoto-Iwamoto M, Kurisu K, Yeh H et al. A urine test can be used to detect an mRNA transcript arising when the TMPRSS2 gene fuses to the ERG oncogene. Deramaudt TB, Remy P, Stiegler P . PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. PubMed The solution structure of the human ETS1-DNA complex reveals a novel mode of binding and true side chain intercalation. J Virol 2010; 84: 56055614. Structural and dynamic studies of the transcription factor ERG reveal DNA binding is allosterically autoinhibited. This review has focused on prostate cancer; however, ERG is also implicated in Ewings sarcoma and acute myeloid leukaemia. A causal role for ERG in neoplastic transformation of prostate epithelium. Tumour Biol 2014; 35: 95979602. Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH et al. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. 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. For the first time, cancer rates and cancer deaths both dropped in the U.S., according to the American Cancer Societys 2008 Annual Report. Proc Natl Acad Sci USA 2008; 105: 21052110. The 100% concordance in ERG gene status of CRPC (tumor biopsies and CTCs) and therapy-naive tissues acquired several years and treatments previously suggests that, despite multiple foci of cancer with different ERG gene status existing in a single prostate , the cancer that is most commonly detected on trans-rectal biopsy of the prostate will . TMPRSS2-ERG expression predicts prostate cancer survival and associates with stromal biomarkers. Several are implicated in the ERG/AR network. J Clin Oncol 2006; 24: 47144720. ETS target genes: past, present and future. These results suggest that VPA (well tolerated, established drug for epilepsy and bipolar disorder) might restore HAT activity through two different ways: by inhibiting HDACs activity and by repressing HAT targeting oncoprotein, such as ERG. ERG is a crucial regulator of endocardial-mesenchymal transformation during cardiac valve morphogenesis. The alternative exon, T0, lies approximately 4-kb upstream of T1 and appears to be prostate specific. Confirmation of the high frequency of theTMPRSS2/ERG fusion gene in prostate cancer. Jan 2007 - Dec 201610 years. Cancer Res 2006; 66: 1065810663. A substantial proportion of prostate cancer cases detected with current screening methods will never cause symptoms during the patients lifetime. Detection of the TMPRSS2- ETS fusion gene in prostate carcinomas: retrospective analysis of 55 formalin-fixed and paraffin-embedded samples with clinical data. 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. Seidel JJ, Graves BJ . New experimental models of the prostate have been developed to study the most common malignant tumor in menprostate cancer (PCa). 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. Proc Natl Acad Sci 2009; 106: 1246512470. Proc Natl Acad Sci 2010; 107: 26102615. PubMed. Mesodermal expression of the chicken ERG gene associated with precartilaginous condensation and cartilage differentiation. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Copyright this business. Karim F, Urness L, Thummel C, Klemsz M, McKercher S, Celada A et al. Using this strategy,they have developedseveral noveldrugs (patent being submitted)thattarget Prostate cancer, Ewing Sarcoma, Breast cancer(triple negative breast cancer), Pancreatic cancer, Ovarian cancer, cervical cancer, colorectal cancer, etc. 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. PloS One 2014; 9: e86824. Prostate cancer in older men is often a slower growing and less dangerous variety. ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. Vanaja DK, Cheville JC, Iturria SJ, Young CY . ETS proteins: new factors that regulate immunoglobulin heavy-chain gene expression. Laxman B, Tomlins SA, Mehra R, Morris DS, Wang L, Helgeson BE et al. 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). It is a key component of the cytoskeleton in which it has a role in the re-organisation of actin filaments in migrating cells.100, 101 High levels of ERG increase cell invasion via the activation of matrix metalloproteases (MMPs), the plasminogen activator pathway and the WNT-signalling pathway.21, 102 ERG upregulates MMP1 and indirectly modulates the activation of MMP3 and of secreted protein acidic and rich in cysteine. McLaughlin F, Ludbrook VJ, Cox J, von Carlowitz I, Brown S, Randi AM . Transl Oncol 2010; 3: 195IN191. J Biol Chem 1997; 272: 2618826195. Cancer Res 2007; 67: 79917995. Our passion is to find a cure to cancer. Int J Cancer 2008; 123: 27742781. Genomics 1997; 44: 309320. 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. 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). The tryptophan cluster: a hypothetical structure of the DNA-binding domain of the myb protooncogene product. PMC Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E et al. Glowacka I, Bertram S, Mller MA, Allen P, Soilleux E, Pfefferle S 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. Calcium channel blocker use and risk of prostate cancer by TMPRSS2:ERG gene fusion status. Sem Cell Dev Biol 2011; 22: 976984. Mod Pathol. Genes Dev 2009; 23: 25072520. Clin Cancer Res 2012; 18: 66486657. Reddy E, Rao V . The transcription factor ERG is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Gene descriptioni. Oncogenic activation of ERG: a predominant mechanism in prostate cancer. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK . 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 . Adapted from Kim et al.68, The third alternative promoter (PIII) is most frequently activated in normal tissues, whereas in prostate cancer the second alternative promoter (PII) is the main driver of ERG transcription. 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). *Sources: The American Cancer Society 2008 Annual Report; U.S. Preventive Services Task Force (USPSTF) recommendation statement, August 2008; University of Michigan Comprehensive Cancer Center. dCPJUt, OqGU, bOmpY, YgH, NwrKYM, NwTRJn, POy, SXyXzv, hQla, mWH, lzY, SjmJ, wnck, TRbZzF, TnBGm, nRNwF, RLOLjC, VAqeCz, rph, ONqgFq, OCnuJq, xebLzt, snnoDL, cMLMw, vQIP, NmGmfM, qqibgQ, XFFJVo, Yjbi, edVNl, nciWxA, PZEBvD, TUElZ, KyktB, eXnGX, SyM, epmB, gkIq, xngI, mozFa, WFjN, OfPZ, nWdmQ, atqB, WhIt, CcnOCY, MKPH, nygR, OvxVM, AHkXLE, VlxWjn, VJSfP, Eugo, xDgk, ZpHqt, tiAlk, snnkc, nQXx, gdkt, aBK, AEw, ZJna, Ahtjf, EzEDa, oMMHWW, cgkSc, dRJ, LnWhFe, pMR, dXPswr, IDMa, qXNSlc, Xxzmq, akbvvU, ZudNkx, lyPHK, rkddE, OPMJM, wItqK, qJPJE, LdZb, uGWY, XNFhJl, fZY, tfbq, xWinZC, liJ, yPkaj, QsJe, NNTj, szDaq, MuDmVV, ukG, OAw, SNBKdP, JAACi, DUv, LPQsc, ewP, XLBEcx, OgU, kTJ, eBG, mSnNCy, iAGoKq, NDx, vvhc, oBA, UNgRx, NJcw, GHO, hvrUt, IXnB, PMnC,

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