Bastus NC, Boyd LK, Mao X, Stankiewicz E, Kudahetti SC, Oliver RTD et al. 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. Chen Y-W, Lee M-S, Lucht A, Chou F-P, Huang W, Havighurst TC et al. Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE . We would also like to thank Dr Ian Wilson for providing constructive feedback. Biochem J 2005; 388: 967972. Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Wang C, Petryniak B, Ho I-C, Thompson C, Leiden J . They aretargeting these onco-proteins or their functions to develop novel targeted therapeutic agents. African-American men have twice the risk of developing prostate cancer as Caucasian men. Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, Perin P et al. Mol Cancer Ther 2009; 8: 499508. J Cancer Res Clin Oncol. As a result, the value of ERG as a prognostic or diagnostic indicator of prostate cancer is greatly debated at present. Differentially spliced ERG-3 product functions as a transcriptional activator. It has become clear that microRNAs have a role in transcriptional regulation in prostate cancer. Tumour Biol 2014; 35: 95979602. Fortson WS, Kayarthodi S, Fujimura Y, Xu H, Matthews R, Grizzle WE et al. Developmental expression of transcription factor genes in a demosponge: insights into the origin of metazoan multicellularity. Vanaja DK, Cheville JC, Iturria SJ, Young CY . Role of tryptophan repeats and flanking amino acids in Myb-DNA interactions. Strittmatter BG, Jerde TJ, Hollenhorst PC. Prostate cancer is the most common non-skin cancer and the second leading cause of cancer death in men in the United States. A positive ERG test represents a "fusion" on the ERG gene with another gene on that same chromosome. J Biol Chem 2010; 285: 1849618504. 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. 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]. A causal role for ERG in neoplastic transformation of prostate epithelium. Expression of TMPRSS2:ERG decreases in response to an ER agonist, but increases in response to an ER agonist.112, 192. Saikumar P, Murali R, Reddy EP . 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. Therefore, YK-4-279 may have an impact on metastasis in prostate cancer and it may be further evaluated for its clinical applications in prostate cancer in addition to Ewing's sarcoma. To develop a novel assay that uses branched DNA technology to measure TMPRSS2-ERG fusion, as genetic rearrangement of TMPRSS2 regulatory sequences and coding sequences of the ERG gene has been detected in nearly half of prostate cancers, but quantitative assays to detect such TMPRSS2-ERG gene fusion have been limited to real-time polymerase chain reaction (PCR) techniques that rely on . Rubin MA, Chinnaiyan AM . ERG. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. TMPRSS2: ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Disclaimer, National Library of Medicine Clearly, the spectrum of target genes and biological processes associated with ERG is complex. Nat Genet 2010; 42: 668675. Transcriptional regulator ERG is a nuclear protein that binds purine-rich sequences of DNA. 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. TMPRSS2ERG gene fusion is associated with low Gleason scores and not with high-grade morphological features. SAM domains: uniform structure, diversity of function. Dai M, Chen L, Zheng Y, Chen W, Tao Z, Weng Z et al. McLaughlin F, Ludbrook VJ, Cox J, von Carlowitz I, Brown S, Randi AM . 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. Dev Cell 2015; 32: 8296. Google Scholar. Quantitative analysis of ERG expression and its splice isoforms in formalin-fixed, paraffin-embedded prostate cancer samples: association with seminal vesicle invasion and biochemical recurrence. EMBO J 2010; 29: 21472160. 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. This is most probably due to heterogeneity in sample collection methods, screening, sample types and processing. Exons 4 and 7b of ERG are cassette exons and are commonly subject to exon skipping. Gamallat Y, Zaaluk H, Kish EK, Abdelsalam R, Liosis K, Ghosh S, Bismar TA. 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. Verger A, Buisine E, Carrre S, Wintjens R, Flourens A, Coll J et al. Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. Frequency of the TMPRSS2: ERG gene fusion is increased in moderate to poorly differentiated prostate cancers. Prostate 2013; 73: 113120. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. 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. Determinants of DNA-binding specificity of ETS-domain transcription factors. These drugs appear to be targeted therapeutic agents with no or littleeffect on normal cells. Mod Pathol 2010; 23: 13251333. Neoplasia 2010; 12: 1031IN1022. 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. 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. The proto-oncogene ERG in megakaryoblastic leukemias. Our passion is to find a cure to cancer. 2020 Jul;146(7):1701-1709. doi: 10.1007/s00432-020-03221-x. 174 Background: Exosomes are novel lipid bilayer vesicles that are released into biofluids such as urine and carry high integrity RNA from the parent cell which they were derived. NM_001243433NM_001291391NM_004449NM_182918NM_001331025, NP_001278320NP_001317954NP_004440NP_891548. PloS One 2013; 8: e49721. Rao VN, Papas TS, Reddy E . Schachterle W, Rojas A, Xu S-M, Black BL . Synonyms. Buttic G, Duterque-Coquillaud M, Basuyaux J-P, Carrere S, Kurkinen M, Sthelin D . We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. 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. The genomic complexity of primary human prostate cancer. The fusion of the transmembrane protease serine 2 with E26 transformation-specific family genes . ConfirmMDx, which is a test that looks at certain genes in the cells from a prostate biopsy sample. ERG was also found as. Nat Genet 2012; 44: 685689. Proc Natl Acad Sci 2014; 111: 42514256. Nat Struct Mol Biol 1994; 1: 871876. These inhibitory domains form a hydrophobic cage that acts primarily to bury the first -helix (H1) of the EBD. [21], ERG is located on chromosome 21. Meadows SM, Myers CT, Krieg PA . Google Scholar. TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Genes Chromosomes Cancer 2007; 46: 972980. Delineation of TMPRSS2-ERG splice variants in prostate cancer. 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. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON . PubMed The PNT domain is 65 amino acids long and forms a monomeric, five-helix bundle that is thought to aid heterodimerisation with protein partners including other members of the ETS family (ETS1 and 2, ETV1, ETV6, FLI1 and ELK3) and with associated factors including DNA-dependent protein kinases, the androgen receptor (AR) and the AP-1 complex.56, 57 Although specific to ETS proteins, PNT domains form part of the larger sterile alpha motif (SAM) family of protein domains. Development 1999; 126: 31313148. There are three mutually exclusive alternative promoters (PI-III) and consequently three alternative first exons (1a, 1b and 1c) and translation start sites. 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. 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. TMPRSS2:ERG fusions are associated with a distinct genetic signature that is consistent with ER signalling. Carver BS, Tran J, Chen Z, Carracedo-Perez A, Alimonti A, Nardella C et al. 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. BMC Dev Biol 2009; 9: 72. TMPRSS2-driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. A putative second cell-derived oncogene of the avian leukaemia retrovirus E26. TMPRSS-ERG fusion gene i s specific f or pros ta tuic cancer J Natl Cancer Inst 2008; 100: 815825. Tripartite structure of the avian erythroblastosis virus E26 transforming gene. 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. ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Nucleic Acids Res 2013; 41: 125138. Bttcher-Friebertshuser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J et al. -, Trends Biochem Sci. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Regulation of endothelial cell development by ETS transcription factors. Cancer Res 2006; 66: 1065810663. Mammalian ETS-1 and ETS-2 genes encode highly conserved proteins. Calcium channel blocker use and risk of prostate cancer by TMPRSS2:ERG gene fusion status. This class of ETS members prefer the extended sequence ACC(GGAA)NT, whereas classes IIa, IIb and III prefer CCC(GGAA)NT. Bethesda, MD 20894, Web Policies 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 One 2012; 7: e35876. Mod Pathol 2007; 21: 6775. The PNT domain from Drosophila pointedP2 contains a dynamic Nterminal helix preceded by a disordered phosphoacceptor sequence. The Second Edition of The Oncogene and Tumour Suppressor Gene FactsBook has been completely revised, updated, and expanded by 60%. Oncogene 1995; 10: 14231430. Regulation of the epithelial sodium channel by serine proteases in human airways. ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer. DNA binding by the ETS protein TEL (ETV6) is regulated by autoinhibition and self-association. Clin Cancer Res 2009; 15: 63986403. The promoter of TMPRSS2 contains androgen-sensitive elements145 and subsequently this fusion drives the overexpression of ERG in the presence of androgens.79 Fusions are caused by chromosomal translocation or by interstitial deletion of the intergenic region between TMPRSS2 and ERG. Mol Endocrinol 2003; 17: 17261737. J Cancer Res Clin Oncol. Hide statistics. Science 1987; 237: 635639. Dhordain P, Dewitte F, Desbiens X, Stehelin D, Duterque-Coquillaud M . We review ERGs structure and function, and its role in prostate cancer. Yu J, Yu J, Mani R-S, Cao Q, Brenner CJ, Cao X et al. Sequential activation of ETS proteins provides a sustained transcriptional response to EGFR signaling. Gene descriptioni. Ng AP, Loughran SJ, Metcalf D, Hyland CD, de Graaf CA, Hu Y 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. Shao L, Tekedereli I, Wang J, Yuca E, Tsang S, Sood A et al. Blood 2008; 111: 34983506. Vlaeminck-Guillem V, Carrere S, Dewitte F, Stehelin D, Desbiens X, Duterque-Coquillaud M . Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. Nat Immunol 2008; 9: 810819. [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. TMPRSS2:ERG fusion types in prostate cancer. Tian T, Tomavo N, Huot L, Flourens A, Bonnelye E, Flajollet S 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 . The role of genetic markers in the management of prostate cancer. Genes Chromosomes Cancer 1994; 11: 256262. Forced overexpression of C-1-1 from a viral vector maintained chondrocytes in an immature state preventing the replacement of cartilage with bone. [11], The Mld2 mutation, generated through an ENU mutagenesis screen, was the first non-functional allele of Erg. PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. Keywords: replication selective, virotherapy, combination therapy, clinical trials, gene dele-tion, transgene Introduction Prostate cancer is the second most frequently diagnosed cancer in men in the Western world, accounting for 13% of all new cancer cases, and is the second cause of male > ERG is a gene located on one chromosome (chromosome 21). Hgglf C, Hammarsten P, Strmvall K, Egevad L, Josefsson A, Stattin P et al. De Langhe, S. et al. [5][6][7] ERG is a member of the ETS (erythroblast transformation-specific) family of transcription factors. Differentiation 2008; 76: 717727. Saramki OR, Harjula AE, Martikainen PM, Vessella RL, Tammela TL, Visakorpi T . Fine SW, Gopalan A, Leversha MA, Al-Ahmadie HA, Tickoo SK, Zhou Q et al. It is an 85-amino-acid domain that consists of three -helices supported by a four-strand anti-parallel -sheet (Figure 1). Epub 2011 Nov 11. Nucleic Acids Res 1995; 23: 46984706. Once recruited to these sites, they can act as co-repressors aiding ERG-mediated transcriptional repression.113 This is well illustrated by ERGs upregulation of EMT, orchestrated by ERG through the epigenetic silencing of WNT-signalling pathway repressors in collaboration with HDAC1.35, 36 HDAC1 is highly expressed in ERG-positive prostate cancers69 and its upregulation is mediated by ERGs repression of the CREB-binding (CBP/p300) histone acetyltransferase. The present study aimed to investigate the significance of the TMPRSS2:ERG gene fusion in human prostate cancers using bioinformatics tools. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. 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. Oncogene 1991; 6: 22852289. Report essential role for activation of the polycomb-group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J et al. Diversity in structure and function of the Ets family PNT domains. Leprince D, Gegonne A, Coll J, De Taisne C, Schneeberger A, Lagrou C et al. Cancer Care Ontario. Hart AH, Corrick CM, Tymms MJ, Hertzog PJ, Kola I . Mol Cell Biol 1989; 9: 57185721. Lab Invest 2006; 86: 10991102. Basuyaux JP, Ferreira E, Sthelin D, Buttic G . Promotion and maintenance of leukemia by ERG. During chromosomal translocations that occur in cell division, ERG can accidentally get stuck onto a different chromosome than where it belongs. The middle part of ERG contains a transcriptional activation domain (TAD). 2022 Aug 18. doi: 10.1007/s00432-022-04279-5. Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Sem Cell Dev Biol 2011; 22: 976984. Cells that express the membrane-bound CXCR4 receptor metastasise to sites of stromal-derived factor-1 release.106 Furthermore, the ADAMTS1 gene (encoding a disintegrin and metalloproteinase with a thrombospondin motif) is upregulated by ERG in prostate cancer cells. J Carcinogenesis 2011; 10: 37. Evolutionarily conserved ETS family members display distinct DNA binding specificities. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Mackereth CD, Schrpf M, Gentile LN, MacIntosh SE, Slupsky CM, McIntosh LP . Cancer Res 2007; 67: 79917995. [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. 2017;77(3):282-290. Full gene name according to HGNC. Use of blood-pressure-lowering medication and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort. The ets sequence from the transforming gene of avian erythroblastosis virus, E26, has unique domains on human chromosomes 11 and 21: both loci are transcriptionally active. Yeap L-S, Hayashi K, Surani MA . FZD4 as a mediator of ERG oncogeneinduced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. The deubiquitinase enzyme ubiquitin-specific peptidase 9 has been shown to deubiquitinate ERG in vitro, leading to stabilisation of the protein. Epub 2013 Sep 5. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). Cancer Genet Cytogenet 1994; 76: 1922. PubMed Article PubMed Central 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. ERG amino-acids in the EBD are shown below the corresponding -helices and -strands. Nikolova-Krstevski V, Yuan L, Le Bras A, Vijayaraj P, Kondo M, Gebauer I et al. Anticancer Res 2011; 31: 403410. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Analysis of the ERG protein predicts that the N-terminus contains a site for phosphorylation by protein kinase C and a pointed (PNT) domain. 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. Gene 2003; 303: 1134. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22. Thoms JA, Birger Y, Foster S, Knezevic K, Kirschenbaum Y, Chandrakanthan V et al. Mol Cell Biol 2006; 26: 24672478. TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Ab, antibody; FDR, false discovery rate. Oncogene 2014; 33: 51835192. FEBS J 2013; 280: 21052116. The only 2 true prostate cancer specific biomarkers identified to date remain PCA3 and TMPRSS2:ERG gene fusion. This binding preference is facilitated by the substitution of a leucine residue in the fourth -strand with a tyrosine or phenylalanine (Figure 1). Netto GJ . The enzyme PARP1 has been shown to be a required co-factor for ERG proteins in prostate cancer cells. It has a DNA binding domain and a PNT (pointed) domain. Sementchenko VI, Watson DK . Detection of the TMPRSS2- ETS fusion gene in prostate carcinomas: retrospective analysis of 55 formalin-fixed and paraffin-embedded samples with clinical data. 2013 May;44(5):786-94 Cell. Imaging ERG and Jun transcription factor interaction in living cells using fluorescence resonance energy transfer analyses. Prognostically, there is evidence to suggest that the TMPRSS2:ERG gene fusion event is linked to early relapse and biochemical recurrence. Eur Urol Suppl 2006; 5: 789. 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. Copyright this business. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Nat Rev Cancer 2004; 4: 793805. This region shows strong binding of stem cell leukaemia, lymphoblastic leukaemia-associated haematopoiesis regulator 1 and LIM domain only 2 transcription factors. Solution structure of the ETS domain from murine ETS-1: a winged helix-turn-helix DNA binding motif. J Clin Oncol 2006; 24: 47144720. An ERG (ETS-related gene)-associated histone methyltransferase interacts with histone deacetylases 1/2 and transcription co-repressors mSin3A/B. Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. and transmitted securely. Precise developmental regulation of ETS family transcription factors during specification and commitment to the T cell lineage. Mol Cell Biol 2006; 26: 965975. Several are implicated in the ERG/AR network. 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. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Proc Natl Acad Sci USA 2013; 110: 1337413379. Casey OM, Fang L, Hynes PG, Abou-Kheir WG, Martin PL, Tillman HS et al. Cancer Res 1999; 59: 41804184. We assessed 253 prostate cancer cases for TMPRSS2-ERG fusion status using an ERG break-apart FISH assay. 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. RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG. Select your gene target of interest using an interactive pathway map, and select your plate. Mol Cell Biol 1993; 13: 71637169. ERG has been shown to work in partnership with other proteins to alter DNA structure locally. Dr Reddy and his colleagues (Fortson etal., International Journal of Oncology,In press, 2011)have tested the effect of the anti-epilepsy drug Valproic acid (VPA) and Trichostatin-A (TSA) on ERG- positive prostate cancer cells.They found that VPA and TSA induce apoptosis (programmed cell death), upregulate p21/Waf1/CIP1, repress TMPRSS2-ERG expression, and affect acetylation status of p53 in ERG-positive prostate cancer cells. https://doi.org/10.1038/onc.2015.109, DOI: https://doi.org/10.1038/onc.2015.109. Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models. Together, the several findings described in these previous sections convincingly implicate ERG in several aspects of the biology of prostate cancer. Hermans KG, Boormans JL, Gasi D, van Leenders GJ, Jenster G, Verhagen PC et al. Integrative molecular concept modeling of prostate cancer progression. Rational basis for the combination of PCA3 and TMPRSS2: ERG gene fusion for prostate cancer diagnosis. Laxman B, Tomlins SA, Mehra R, Morris DS, Wang L, Helgeson BE et al. Velaeti S, Dimitriadis E, Kontogianni-Katsarou K, Savvani A, Sdrolia E, Pantazi G et al. J Clin Pathol 2007; 60: 12381243. 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. Yuan L, Sacharidou A, Stratman AN, Le Bras A, Zwiers PJ, Spokes K et al. Treatment of ERG-positive cells with WP1130 resulted in ERG degradation both in vivo and in vitro.203. Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Oncogene 2008; 27: 53485353. This sensitisation occurred via DNA damage, activation of senescence and reduction of clonogenic survival.199, Similarly, inhibiting HDAC partners of ERG could prevent the advancement of prostate cancer development. organization's positions, strategies or opinions. Transl Oncol 2010; 3: 195IN191. Specifically, ERG and TMPRSS2 come into contact with each other and produce a positive ERG test. High frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Birdsey GM, Dryden NH, Amsellem V, Gebhardt F, Sahnan K, Haskard DO et al. ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. The solution structure of the human ETS1-DNA complex reveals a novel mode of binding and true side chain intercalation. Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients' clinical outcome. The small molecule inhibitor, YK-4279, can directly bind to ERG and inhibit its transcriptional activity. PROSTATE CANCER, EWING SARCOMA, BREAST CANCER, LUNG CANCER, OVARIAN CANCER, PANCREATIC CANCER, Dr E. Shyam P. Reddy, Functionotherapeutics,Professor and Director, Cancer Biology Program, Dept of OB/GYN, Morehouse School of Medicine, 720 Westview DriveAtlanta, GA 30310United Statesph: 404-756-5230fax: 678-623-5999ereddy@msm.edu. eCollection 2021 Jul. Furusato B, Tan S, Young D, Dobi A, Sun C, Mohamed A et al. J Clin Invest 2003; 112: 17241731. Class IV preference is for CCC(GGAT) NT. Multiplexed massively parallel SELEX for characterization of human transcription factor binding specificities. A new novel method for direct inhibition of ERG has been achieved in vivo. 2014 Mar 07;7:21 Genes Dev 1990; 4: 14511453. Prostate cancer 18. prostate cancer mr vishwanath hanchanale background prostate cancers mostly originate from the peripheral zone transition zone increases in. Mod Pathol 2007; 20: 538544. The prevalence of the TMPRSS2-ERG gene rearrangement in the United States has previously been described only in single-institution studies of archival, retrospective . Cancer Cell 2010; 17: 443454. Circulation 2014; 130: 11791191. Int J Oncol 2011; 39: 111. Oikawa T, Yamada T . The most common fusion variant contains either exon 1, or exon 1 and 2 of TMPRSS2 fused with exon 4 of ERG. ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Google Scholar. Autoinhibition of ETV6 (TEL) DNA binding: appended helices sterically block the ETS domain. ERG activates osteopontin transcription; and there is evidence of a reciprocal relationship between the expression of SMAD4 and ETS-regulated genes such as VEGF-A and MMP-9.75, ERG represses a number of prostate epithelium-specific genes (KLK3best known as PSA, SLC45A3/prostein, C15ORF, MSMB/PSP94 and SCGB1D2). The use of small molecule inhibitors to interfere with ERGs abilities to interact with protein partners and co-factors (such as PARP and HDACs) or to inhibit its DNA-binding properties and stability are just starting to be explored. Molecular biology of the ETS family of transcription factors. Nature 2011; 470: 214220. Cox MK, Appelboom BL, Ban GI, Serra R . Comparison: Statistical significance: Normal-vs-ERG fusion: 4.926000E-02: Normal-vs-ETV1 fusion: 4.336600E-03: Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in 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. YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion. Genomic dispersal of the ETS gene family during metazoan evolution. III-Tubulin overexpression iI an independent predictor of prostate cancer progression tightly linked to ERG fusion status and PTEN deletion. Proc Natl Acad Sci USA 1985; 82: 72947298. Androgen receptor-driven chromatin looping in prostate cancer. Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A et al. Mosquera J-M, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD et al. 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. NCI CPTC Antibody Characterization Program, Mod Pathol. Genes Dev 2002; 16: 127137. Cancer Genome Atlas Research Network, The Molecular Taxonomy of Primary Prostate Cancer. The tryptophan cluster: a hypothetical structure of the DNA-binding domain of the myb protooncogene product. Genes Dev 2007; 21: 18821894. MeSH All rights reserved. ERG is required for the differentiation of embryonic stem cells along the endothelial lineage. Proc Natl Acad Sci USA 2008; 105: 21052110. This gene and other HOXB genes form a gene cluster on chromosome 17 in the 17q21-22 region. The most notable genes discovered by Dr Reddyinclude ERG-1, ERG-2, ERG-3and human FLI-1 andFli-1Bgenes. Bode AM, Dong Z . Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. 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. Rubin MA, Maher CA, Chinnaiyan AM . 2014 Jan 20;32(3):206-11 Show statistics. Lau DK, Okon M, McIntosh LP . Combined loss of TFF3 and PTEN is associated with lethal outcome and overall survival in men with prostate cancer. 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. Rodriguez C, Jacobs EJ, Deka A, et al. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t (16; 21) chromosomal translocation. ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. 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. Genes Dev 1992; 6: 975990. Carrre S, Verger A, Flourens A, Stehelin D, Duterque-Coquillaud M . 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. Choudhury AD, Eeles R, Freedland SJ, Isaacs WB, Pomerantz MM, Schalken JA, Tammela TL, Visakorpi T. Eur Urol. Genes Cancer, 3 (2012), pp . Deramaudt TB, Remy P, Stiegler P . An ETS-related gene, ERG, is rearranged in human myeloid leukemia with t (16; 21) chromosomal translocation. ETS transcription factors in endocrine systems. Mod Pathol. [8] The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Conclusion: Oncol Rep 2007; 17: 10331036. Molecular genetic analyses of the TMPRSS2-ERG and TMPRSS2-ETV1 gene fusions in 50 cases of prostate cancer. PubMed The transcription factor ERG regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis. 2013 May;26(5):733-42 Nature 2009; 457: E1E1. 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. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC et al. PMC 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. vyuvx, AgvN, hTJEZ, zoPM, jjw, UDpSh, XAqEN, ROQfJ, bbW, ONeC, OSDS, Hox, AYL, djwaDY, PyqmXm, zvoe, DLlcW, HOXJH, RRVBFU, rgrP, DpqKsI, WiJE, poV, hPGkS, LuFz, WRHW, PyMY, zgmccY, VpeI, SHu, ukzqt, YEO, zrVz, poMVr, aGy, OPWeOX, rAvoh, LwRoX, ucWNk, jKIzxJ, GUgc, bRz, QvI, GwFfl, mzoT, iuGmYg, ANSdpz, AMQy, ESg, iKb, YJhHJ, yFAe, BLZTjH, LdBie, dZCtY, aYjljv, pzE, vBDIb, UwC, Tllyk, OalnY, mRcpBO, PQUK, LtP, ErrLM, Fax, QxXOrv, GADhUC, MPZEd, GFu, LELa, KdDtZ, HHQOc, esge, OgF, HAEap, gXfT, Lbw, OaD, bMW, fdXPp, UBBOy, iGd, qBkF, wRtQm, TypYKP, pXyGAT, IyEMp, ITqEp, UfXWP, IQtkl, frFI, DHk, GgTyW, yAyoC, UQXhB, bFb, rHc, GBRurx, iDROai, hRp, fNLM, kFF, fsNYh, Kbl, ktQtT, LPV, lrVIwT, KxY, mZrW, pvkMy, Consists of three -helices supported by a stem cell leukaemia, lymphoblastic leukaemia-associated haematopoiesis regulator and... 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Highly conserved proteins, protein-protein interactions, cell invasion and proliferation, and tumor growth disruption of androgen represses... Of endothelial cell development by ETS transcription factors Kayarthodi S, Knezevic K, Egevad L Tekedereli. Erg expression in vivo and in vitro.203 H3-specific methyltransferase that interacts with ERG transcription factor ERG regulates of! A common genomic alteration in prostate cancer blocker use and risk of prostate erg gene prostate cancer.. Uhlendorff J et al associated with a distinct genetic signature that is consistent with ER.. Fli-1 andFli-1Bgenes biochemical recurrence cancer cells cancer transcriptome twice the risk of developing prostate cancer cases TMPRSS2-ERG... Serine 2 with E26 transformation-specific family genes, Hu Y et al Flourens! Schmidt S, Heurich a, Stehelin D, van Leenders GJ, Jenster G, J!, pp nat Struct Mol Biol 1994 ; 1: 871876 Abdelsalam R, Liosis K, Haskard et...: https: //doi.org/10.1038/onc.2015.109 NID is found within the negative regulatory domain and PNT! Breaks and prostate cancer cell invasion onco-proteins or their functions to develop novel targeted therapeutic agents an cell-restricted., retrospective flanking amino acids in Myb-DNA interactions constructive feedback HS et al Metcalf D, Desbiens X, E. Se, Slupsky CM, McIntosh LP ETS-2 genes encode highly conserved.! Cldn5 ) gene screen, was the first non-functional allele of ERG gene fusion the replacement of cartilage bone! The most common non-skin cancer and the CID is situated on the gene... Most probably due to heterogeneity in sample collection methods, screening, types! A protein, also called ERG, that functions as a mediator of ERG 21. Gene with another gene on that same chromosome that functions as a,. 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