Disease relevance of Etv4

• In an attempt to characterize the PEA3-group proteins in breast-cancer cells, we first produced and characterized specific antibodies against each of these 3 proteins [1].
• Recently, transgenic mice bearing the c-erbB-2/neu oncogene have been shown to over-express PEA3 mRNA in mammary adenocarcinomas, suggesting a role for this gene family in mammary tumorigenesis [1].
• The PEA3 motif, first recognized in the polyomavirus enhancer, is an oncogene, serum growth factor, and phorbol ester-responsive element [2].
• Expression of a 91-kilodalton PEA3-binding protein is down-regulated during differentiation of F9 embryonal carcinoma cells [3].
• Therefore, the infertility of PEA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysfunction [4].

High impact information on Etv4

• Two ETS transcription factors, ER81 and PEA3, are expressed by developing proprioceptive neurons and MNs, raising the possibility that these genes are involved in the formation of sensory-motor connections [5].
• Interestingly, the amount of PEA3 mRNA is down-regulated during retinoic acid-induced differentiation of mouse embryonic cell lines [2].
• These findings suggest that PEA3 plays a regulatory role during mouse embryogenesis [2].
• Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells [2].
• In the mouse, PEA3 expression is highly restricted; only the epididymis and the brain contain readily detectable amounts of its mRNA [2].

Biological context of Etv4

• Differential expression patterns of the PEA3 group transcription factors through murine embryonic development [6].
• These results suggest that erm, er81 and pea3 genes are differentially regulated, probably to serve important functions as cell proliferation control, tissue interaction mediator or cell differentiation, all over successive steps of the mouse organogenesis [6].
• We further demonstrate the ability of Pea3 and USF-1 to cooperate for the transactivation of the bax promoter, mutation of the E boxes dramatically reducing the Pea3 transactivation potential [7].
• Our results provide the first functional evidence that Pea3 subfamily members play a role in epithelial-mesenchymal interactions during lung organogenesis [8].
• Serum response element associated transcription factors in mouse embryos: serum response factor, YY1, and PEA3 factor [9].

Anatomical context of Etv4

• In the present work we characterized the mRNA expression levels of PEA3-group genes in a series of human epithelial breast cell lines [1].
• ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools [10].
• We show that in Pea3 mutant mice, the axons of specific motor neuron pools fail to branch normally within their target muscles, and the cell bodies of these motor neurons are mispositioned within the spinal cord [10].
• Erm/Pea3 are downstream of FGF signaling from the mesenchyme, but their responses toward different FGFs are not the same [8].
• Erm is transcribed exclusively in the epithelium, while Pea3 is expressed in both epithelium and mesenchyme [8].

Associations of Etv4 with chemical compounds

• Recombinant PEA3 binds to DNA with the same sequence specificity as that endogenous to FM3A cells and activates transcription through the PEA3 motif in HeLa cells [2].
• Erections could be evoked by abdominal pressure in PEA3-deficient male mice, and the results of in vitro experiments revealed that the corpus cavernosum isolated from PEA3 mutant males relaxed in response to acetylcholine [4].
• Indeed, PEA3 coupled with the liposome SN2 demonstrated therapeutic effects in mice bearing tumors induced by BT474M1 [11].
• The promoter contains putative Sp1, AP-1, AP-2, and PEA3 binding sites, as well as a purine- and a pyrimidine-rich region [12].

Physical interactions of Etv4

• This report presents data that suggest that the tissue-restricted polyoma enhancer activator protein (PEA3) of the Ets oncogene family of DNA-binding proteins is a putative modulator of the epididymis-specific glutathione peroxidase 5 gene gpx5 [13].
• Subsequently, we have shown using gel-shift assays that DNA sequences located within the 5' flanking region of the gpx5 gene have the ability to bind specifically to the PEA3 protein [13].

Regulatory relationships of Etv4

• Altogether, these results strongly suggest that the PEA3 factor might participate in the transcriptional control of the murine epididymis caput-specific gpx5 gene [13].
• In contrast, PEA3 stimulates the TbetaR-II promoter in F9-differentiated cells, but it inhibits this promoter in F9 cells [14].
• The data showed that PEA3 mRNA expression is regulated in the epididymis via protein kinase A and ERK signaling cascades [15].

Other interactions of Etv4

• ERM, ER81 and PEA3 are three highly related transcription factors belonging to the ETS family [6].
• In six human breast cell lines, those that highly expressed OPN also expressed PEA3 and Ets-1 [16].
• Although the minimal Pea3-regulated bax promoter does not contain an Ets-binding site, two functional upstream stimulatory factor-regulated E boxes are present [7].
• The PEA3 protein of the Ets oncogene family is a putative transcriptional modulator of the mouse epididymis-specific glutathione peroxidase gene gpx5 [13].
• We have monitored the expression of three transcription factors, Egr3, Pea3, and Erm, that delineate early muscle spindle development in an assay of muscle spindle-inducing signals [17].

Analytical, diagnostic and therapeutic context of Etv4

• No protein was detected in MCF-7 cells expressing low levels of mRNA for PEA3-group-family genes, or in ZR-75-1 cells, where mRNA was undetectable by Northern blot [1].
• Northern and polymerase chain reactions on reverse-transcribed epididymal RNAs were used to show that the PEA3 factor is spatially and temporally expressed within the mouse epididymis in a manner consistent with gpx5 characteristics of expression [13].
• The c-ets-1 gene product binds to a sequence in the murine sarcoma virus long terminal repeat that is similar to the PEA3 motif (cGGAAG), but PEA3-91 was not cross-linked to this Ets-1-binding motif, nor did antiserum which recognizes murine c-ets-1 and c-ets-2 proteins have any effect on PEA3-binding activity in mobility shift assays [3].
• To determine whether PEA3 plays a part in development and oncogenesis and to uncover its normal physiological role, we generated mice lacking functional PEA3 by gene targeting in embryonic stem cells [4].

References