Disease relevance of ELF3

• Differentially expressed genes were also found in a comparison of the expression profiles of the biphasic and monophasic histological subgroups of synovial sarcoma, notably several keratin genes, and ELF3, an epithelial-specific transcription factor gene [1].
• Finally, we show that ELF3 expression is increased in a lung carcinoma and adenocarcinoma, as compared to normal tissue [2].
• ELF3 is also expressed in cell lines derived from lung cancers [2].
• Partially unspliced and fully spliced ELF3 mRNA, including a new Alu element in human breast cancer [3].
• The human gastric cancer cell lines, which show undetectable level of TGF-beta RII mRNA, do not express ERT mRNA [4].

Psychiatry related information on ELF3

• In this study, we tested the hypothesis that response to estrogen-hormone replacement therapy (ERT/HRT) is also related to individual differences in estrogen metabolism [5].
• Estrogen replacement therapy either with (HRT) or without (ERT) accompanying progesterone is routinely offered to well women at the time of menopause, in order to relieve vasomotor symptoms, (hot flashes), reduce urogenital atrophy and reduce the risks of cardiovascular disease, osteoporosis and perhaps colon cancer and Alzheimer's disease [6].
• Studies in experimental animal models provide a convincing rationale for a role for ERT in the treatment and prevention of dementia [7].
• OBJECTIVES: To determine the relationships between tobacco smoking, oestrogen replacement (ERT) and body fat and its distribution in postmenopausal women, independent of genetic factors, physical activity, diet composition and socioeconomic factors [8].
• A provocative alcohol x ERT trend suggests that alcohol consumption should be considered in studies of ERT effects on cognitive ability [9].

High impact information on ELF3

• When ERT is contraindicated, viable alternatives to retard bone loss and/or control vasomotor symptoms include calcium supplementation and progestin therapy [10].
• METHODS: In a 5-year multicenter, double-blind, randomized, placebo-controlled osteoporosis prevention trial, healthy postmenopausal women who had undergone hysterectomy less than 15 years before the study and had no history of breast cancer received placebo, raloxifene (at one of two doses), or conjugated estrogens (ERT) [11].
• Within treatment groups, the mean breast density from baseline to 2 years decreased statistically significantly in women receiving the placebo or either the higher or lower raloxifene dose (P = 0.003, P = 0.002, and P<0.001, respectively) and showed a nonstatistically significant increase in women receiving ERT [11].
• ERT for survivors of endometrial cancer? A new trial will resolve debate [12].
• INTERPRETATION: Current ERT reduced primarily sudden cardiac death and predicted reduced cardiovascular mortality, but did not reduce morbidity [13].

Chemical compound and disease context of ELF3

• These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study [14].
• Unopposed estrogen (previously called ERT, now referred to as ET) increases a patient's risk of endometrial cancer [15].
• The potential adverse effects of tamoxifen are partially similar to those of ERT and includes an increased risk of endometrial cancer, hepatic diseases, thromboembolic alterations and ocular toxicity [16].
• Androgen administration has been shown to induce down-regulation of mammary epithelial proliferation and estrogen receptor expression, suggesting that E/A therapy might reduce the risk of breast cancer associated with ERT [17].

Biological context of ELF3

• ELF3 binds and transactivates ETS sequences and interestingly also shows the ability to bind a GGAT-like purine core, a preferential ETS1/ETS2 type binding site [2].
• To assess the possible ELF3 regulation of the TIMP3 promoter, transient transfection assays were performed [18].
• Partially unspliced ELF3 mRNA contained introns 4-7 without any nucleotide mutation at intron/exon splice junction borders [3].
• ESE-1 binds to specific ETS sites within the Ang-1 promoter that are functionally important for transactivation by ESE-1 [19].
• In order to determine whether ESX can act as a transforming gene, we stably transfected MCF-12A human mammary epithelial cells with the ESX expression vector, pCGN2-HA-ESX [20].

Anatomical context of ELF3

• In order to understand transcriptional regulatory mechanisms mediated by ELF3, we investigated its effect on the human keratin 4 gene promoter based upon the role of keratin 4 in early differentiation of the esophageal squamous epithelium [21].
• Expression of the ETS transcription factor ELF3 in the retinal pigment epithelium [18].
• Moreover, the induction of ESE-1 in response to inflammatory cytokine interleukin-1 is associated with a parallel increase of the expression of p300 in vascular endothelial cells, suggesting that in the setting of inflammation, the transcriptional activity of ESE-1 is positively modulated by interaction with the transcriptional co-activator p300 [22].
• Finally, Ang-1 and ESE-1 exhibit a similar and strong expression pattern in the synovium of patients with rheumatoid arthritis [19].
• ESX induces transformation and functional epithelial to mesenchymal transition in MCF-12A mammary epithelial cells [20].

Associations of ELF3 with chemical compounds

• Infection of this cell line with a retroviral construct expressing ERT induced higher levels of endogenous RII mRNA expression and protein expression relative to cells infected with chloramphenicol acetyltransferase (CATneo) as a control [23].
• ESE-1 is an epithelium-specific ETS transcription factor that contains two distinguishing domains, a serine- and aspartic acid-rich (SAR) domain and an AT hook domain [24].
• ESE-1 is induced in response to inflammatory cytokines and lipopolysaccharide in vascular smooth muscle cells, endothelial cells, and cells of the monocyte-macrophage lineage [25].
• BACKGROUND: We conducted a 3-year, double-blind, randomized, placebo-controlled study to determine whether the positive effects of hormone/estrogen replacement therapy (H/ERT) on postcranial bone density are accompanied by similar positive effects on oral bone mass [26].
• A total of 8 patients were treated with 0.6256 mg Premarin daily for 25 days and 5 mg/day of medroxyprogesterone on days 15-25 (ERT, group 2); 7 were followed without ERT (group 1) [27].

Physical interactions of ELF3

• The newly identified epithelium-specific ets transcription factor ERT/ESX/ESE-1 binds to the TGF-beta RII promoter and induces promoter activity [28].
• Transient transfection experiments confirmed the ability of this TBP-binding transactivation domain in ESX to squelch heterologous promoters independent of any promoter binding as efficiently as the transactivation domain from VP16 [29].

Regulatory relationships of ELF3

• Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter [21].
• CONCLUSIONS: The ELF3 transcription factor is highly expressed in the RPE and can regulate important ocular genes, such as TIMP3, in vitro [18].
• In this study, we investigated whether ERT could regulate endogenous TGF-beta RII expression in Hs578t breast cancer cells [23].
• Interestingly, Ku70 and Ku 86 negatively regulate the transcriptional activity of ESE-1 [22].
• Elf3 upregulated the TIMP3 promoter, with Elf3a and -3b inducing an approximate sixfold increase in activity [18].
• These findings provide novel insights into the mechanism of transformation potential of ESE-1 and discovered that ESE-1 functions are coordinately regulated by Pak1 phosphorylation and beta-TrCP-dependent ubiquitin-proteasome pathways [30].

Other interactions of ELF3

• Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation [1].
• The expression of ELF3, unlike most other ETS family members, is absent in hematopoietic cells and hematopoietic organs in humans and mice [2].
• The specific expression of ELF3 in the RPE may reflect an important role for this transcription factor in retinal function [18].
• Positive and negative modulation of the transcriptional activity of the ETS factor ESE-1 through interaction with p300, CREB-binding protein, and Ku 70/86 [22].
• Interestingly, among a panel of ETS factors tested in a transient transfection assay, only the ETS factor ESE-1 was capable of transactivating the Ang-1 promoter [19].

Analytical, diagnostic and therapeutic context of ELF3

• The Ku proteins inhibit the ability of ESE-1 to bind to oligonucleotide probes in gel mobility shift assays [22].
• Luciferase reporter assays demonstrated that the presence of the Ets-binding site at -150 in the promoter region of the claudin7 gene was critical for the transcriptional activity, and gel shift and chromatin immunoprecipitation assays confirmed the binding of ELF3 to the Ets site at -150 [31].
• ELF3 was confirmed to be more highly expressed in biphasic than monophasic SS by real-time quantitative PCR [32].
• We also examined ELF3, a transcription factor associated with epithelial differentiation in SS in a previous cDNA microarray, by RT-PCR [32].
• This exon 4-encoded 31 amino acid domain in ESX was shown by mutation and deletion analysis to possess a 13 residue acidic transactivation core which, based on modeling and circular dichroism analysis, is predicted to form an amphipathic alpha-helical secondary structure [29].

References