Disease relevance of ETV4

• The ETV4 protein was localised to nuclei of spermatogonia and revealed an intense staining in seminoma cells [1].
• In the present study, we determined the genomic breakpoint and characterized the chimeric transcript of the EWSR1-ETV4 fusion gene in two t(17;22) Ewing sarcomas [2].
• E1AF expression was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumor-node-metastasis stage and recurrence [3].
• E1AF mRNA was detected in 43 (47.8%) of the 90 colorectal tumors [4].
• E1AF mRNA expression was detected in 64% of the 100 gastric cancer tissues, but was undetectable or only faintly detected in adjacent non-tumor tissues [3].

High impact information on ETV4

• Target-Induced Transcriptional Control of Dendritic Patterning and Connectivity in Motor Neurons by the ETS Gene Pea3 [5].
• In this issue, find that this retrograde GDNF-Pea3 signal controls dendrite patterning and assembly of a sensory-motor reflex circuit [6].
• Glial-derived neurotrophic factor (GDNF), secreted by skeletal muscle, triggers expression of the ETS transcription factor Pea3 in a subset of motor neurons in the spinal cord [6].
• We have identified that the DNA-binding protein PEA3, which is encoded by a previously isolated gene of the ets family, specifically targeted a DNA sequence on the HER-2/neu promoter and downregulated the promoter activity [7].
• Expression of PEA3 resulted in preferential inhibition of cell growth and tumor development of HER-2/neu-overexpressing cancer cells [7].

Chemical compound and disease context of ETV4

• Recently, a unique fusion between the prostate-specific, androgen-regulated TMPRSS2 gene and the ETS genes ERG, ETV1, or ETV4 has been described in clinical prostate cancer [8].
• Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells [9].
• We showed that the PEA3 transcriptional factor interacted with LKB1, a serine/threonine kinase, which is somatically mutated in lung cancer [10].
• Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene [11].
• They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma [12].

Biological context of ETV4

• These observations suggest a mechanism of EWSR1-ETV4 gene fusion [2].
• In this study, we used real-time reverse transcription (RT)-polymerase chain reaction (PCR) to measure the levels of E1A-F, COX-2, and MMP-7 in matched normal mucosa, adenomas, and/or carcinomas from 128 patients [13].
• In this study, we identified a new chimera gene between the transactivation domain of EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein [14].
• Our results do not support recent findings suggesting that PEA3 could be a tumor-suppressor gene that can act therapeutically in ERBB2 over-expressed tumors [15].
• Nucleotide sequence analysis of about 1 kb of the 5'-flanking region of the collagenase-3 gene revealed the presence of a TATA box, an AP-1 motif, a PEA-3 consensus sequence, an osteoblast specific element (OSE-2), and a TGF-beta inhibitory element [16].

Anatomical context of ETV4

• Transcription factors TEA domain family member 4 and ETS variant gene 4 (ETV4), weakly expressed in normal testis, were strongly augmented during tumourigenesis [1].
• The PEA3/E1AF/ETV4 gene encodes an Ets-related transcription factor that is expressed in the epithelial cells of the mammary gland [15].
• Results using PEA3, ETS and AP-1 artificial promoters showed that EGF enhanced PEA3 transcription factor activity by up to 70% in comparison to non-treated cell lines [17].
• ETV4 protein was localized to principal cell nuclei and displayed the highest expression in the most proximal region of the initial segment [18].
• One cDNA clone produced recombinant E1A-F protein with the same DNA binding specificity as that endogenous to HeLa cells [19].

Associations of ETV4 with chemical compounds

• A PEA3 site (-75/-72) was identified juxtaposed to the cyclic AMP-response element [20].
• We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells [9].
• Indeed, malonyl-CoA on its own dramatically decreases HER2 promoter activity, while OA or malonyl-CoA similarly up-regulates PEA3 gene promoter activity [21].
• In addition, ETV4 protein levels were diminished after loss of testicular luminal fluid factors [18].
• The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase [22].

Physical interactions of ETV4

• Using EMSA analysis we also observed that the EGF stimulated increase in PEA3 transcription factors led to increased binding to specific ETS sites within the MMP-7 promoter [17].
• Interestingly, a significant accumulation of the DNA-binding protein PEA3, a member of the Ets transcription factor family that specifically targets a PEA3-binding motif present on the Her2/neu gene promoter and down-regulates its activity, was observed in orlistat-treated SK-Br3 cells [11].
• Here, we have identified the LIM domain protein LPP as a novel coregulatory binding partner for PEA3 [23].
• Basic calcium phosphate crystals induce matrix metalloproteinase-1 through the Ras/mitogen-activated protein kinase/c-Fos/AP-1/metalloproteinase 1 pathway. Involvement of transcription factor binding sites AP-1 and PEA-3 [24].
• Of the oligonucleotides tested, EMSA revealed that TGF-beta treated OA chondrocyte proteins bound only to the AP-1 and PEA-3 [25].

Enzymatic interactions of ETV4

• LKB1 phosphorylated PEA3 and promoted its degradation through a proteasome-mediated mechanism [10].
• HER2/neu promoter activity was decreased by deleting PEA3 binding site, and was downregulated when the PEA3 binding site was mutated [26].

Regulatory relationships of ETV4

• Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation [27].
• Since E1A-F is known to activate matrix metalloproteinase genes, the chimera gene may possibly be involved in tumor progression and could be a novel tumor marker for Ewing's sarcoma/PNET [14].
• Western blot analysis of nuclear extracts from EGF stimulated cells demonstrated that there was an increase in PEA3 protein when compared to non-treated cells [17].
• BACKGROUND: Recently, PEA3 has been reported to suppress HER-2/neu overexpression by promoter activity and thereby inhibit tumorigenesis of breast cancer both in vitro and in vivo [28].
• On the other hand, E1AF upregulates p21waf1/cip1 to induce cell cycle arrest when cells are exposed to stress [29].

Other interactions of ETV4

• Among the MMPs analyzed, expression of matrilysin (MMP-7) was significantly correlated with E1AF expression [3].
• A novel chimera gene between EWS and E1A-F, encoding the adenovirus E1A enhancer-binding protein, in extraosseous Ewing's sarcoma [14].
• The correlation of E1AF expression with COX-2 and iNOS expression was also demonstrated by immunohistochemistry [4].
• For ETV4 expression, a significant correlation with the increased expression of matrix metalloproteinase 2 and a disintegrin and metalloproteinase domain 15 was determined [1].
• This study clarifies the function of CIC and its role in tumorigenesis, as well as the importance of the PEA3 subclass of ETS family proteins in the development of EFTs arising through mechanisms different from those involving EWS-ETS chimeras [27].

Analytical, diagnostic and therapeutic context of ETV4

• Long PCR and sequence analysis of genomic DNA revealed that either exon 8 or intron 7 of EWSR1 is fused to the same intron of ETV4 in both tumors [2].
• E1AF expression retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors (P = 0.0082 and P = 0.0096, respectively) [3].
• Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we analyzed 100 gastric cancer tissues for E1AF mRNA expression [3].
• We investigated mechanisms of expression of four ETS genes, ERG, ETV1, ETV4, and FLI1, in 11 xenografts representing different stages of prostate cancer [8].
• It was identified that E1AF could bind to and activate the GalT I promoter by electrophoretic mobility shift assay in PGLH7 cells and COS1 cells [30].

References