Disease relevance of ETS1

• We previously demonstrated that the breakpoint of t(11;14)(q23;q32) in the RC-K8 B cell lymphoma cell line lies between CD3 and THY1/ETS1 on chromosome 11q23, and we cloned this region and named it the rck locus [1].
• Differential regulation of the response to DNA damage in Ewing's sarcoma cells by ETS1 and EWS/FLI-1 [2].
• Further localization of ETS1 indicates that the chromosomal rearrangement in Ewing sarcoma does not occur at fra(11)(q23) [3].
• Because chromosomal translocations have been associated with different human leukemias, studies addressing the possible association with the ETS1 (11q23) or ETS2 (21q22.3) loci are reviewed [4].
• By using astrocytomas of different grades as a source of astrocytes, we demonstrate the presence of ETS1 and ETS2 messenger RNAs and proteins [5].

High impact information on ETS1

• The substrate specificity of p40 differed from that of p42 and p54 MAP kinases [6].
• Interleukin 1 alpha activates two forms of p54 alpha mitogen-activated protein kinase in rabbit liver [7].
• The p46 and p54 isoforms of c-Jun amino-terminal kinase (JNKs) were identified as HNE targets and were activated by this aldehyde [8].
• In vitro reconstitution of an HIV-1 5' LTR fragment into nucleosome core particles demonstrates that Sp1, NF-kappaB1, LEF-1, ETS-1 and USF can gain access to their binding sites in HIV-1 nucleosomal DNA [9].
• These sites are the target of p54 and p46 stress-activated protein kinases (SAPKs) which bind to, and phosphorylate ATF-2 in vitro [10].

Chemical compound and disease context of ETS1

• The p54 cleaved form of the tyrosine kinase Lyn generated by caspases during BCR-induced cell death in B lymphoma acts as a negative regulator of apoptosis [11].

Biological context of ETS1

• Late after stimulation, ETS1 mRNA is reinduced and maintained at a high level, while ETS2 gene expression decreases to undetectable levels [12].
• We have previously shown that ETS transcription factors, regulate cell growth and differentiation, and ETS1 and ETS2 are able to transcriptionally regulate wt p53 gene expression [13].
• The ETS1 and FLI-1 proteins provide a novel mechanism of activation for GADD153, allowing these two ETS genes to control its expression during cell growth and differentiation, rather than in response to oxidative stress [13].
• Mutation of the core ETS binding site from -GGAA- to -GGAT- prevents the binding of ETS-like factors with the exception of ETS1 [14].
• EAPII negatively modulates ETS1 transcriptional activity and attenuates synergistic transactivation by ETS1 and AP-1 [15].

Anatomical context of ETS1

• Our results show that resting T cells express high levels of ETS1 mRNA and protein, while expression of ETS2 is undetectable [12].
• The antisense oligonucleotides directed against the ETS1 gene thus altered a cellular property of endothelial cells that is correlated with the ability of the cells to migrate through basement membranes [16].
• Vascular endothelial growth factor (VEGF) increased the level of ETS1 mRNA in human umbilical vein endothelial cells (HUVEC) and human lung microvascular endothelial cells (HMVEC-L) over 5-fold [16].
• In vitro studies have linked the up regulation of ERG expression with stromal cell independence in erythroleukemic clones and shown that the ERG related genes ETS1 and ETS2 have a mitogenic and transforming activity when overexpressed in NIH3T3 cells [17].
• ETS1 plays important roles in differentiation, lymphoid cell development, invasiveness and angiogenesis [15].

Associations of ETS1 with chemical compounds

• The expression of the protooncogenes ETS1 and ETS2 has been studied in purified human T cells activated either by cross-linking of the T-cell receptor-CD3 complex on their cell surface or by direct stimulation with phorbol esters and ionomycin [12].
• In AS ETS1 transfectants, IL-2 formation was completely inhibited by cyclosporin A and FK590 [18].
• The ETS1 gene encodes a sequence-specific transcription factor binding to purine-rich DNA sequences (-GGAA-) present in the transcriptional regulatory regions of many cellular and viral promoters/enhancers, including many lymphokine genes [18].
• The IL-2 promoter linked to a chloramphenicol acetyl transferase reporter gene has high activity in AS ETS1 transfectants, indicating that increased IL-2 production seems to be a result of transcriptional induction [18].
• This threonine residue was neither phosphorylated by JNK1, nor by p38 MAP kinases and was required for the induction of transcriptional activity of ETS1 by HGF/SF [19].

Physical interactions of ETS1

• SP100 protein interacts with ETS1 both in vitro and in vivo [20].
• EAPII interacts with ETS1 and modulates its transcriptional function [15].
• Expression of ETS1 DNA binding domain in Jurkat T cells also decreased the production of IL-2 [18].
• The region in EAP1/Daxx which specifically binds to ETS1 is located within its carboxy terminal 173 amino acid region [21].
• In vitro, Sp1 and Ets1 are shown to cooperate to form a ternary complex with the SP1/ERE-A element [22].

Enzymatic interactions of ETS1

• The result of Western blotting analysis confirmed that Ets1 was really phosphorylated when mutant K-ras was activated [23].

Regulatory relationships of ETS1

• The VEGF-induced invasiveness was inhibited by ETS1 antisense oligonucleotides but not by a sense control [16].
• SP100 inhibits ETS1 activity in primary endothelial cells [24].
• Ets1 up-regulated the expression of MMP-1 promoter activity, whereas Fli1 had antagonistic effects on them [25].
• Addition of Ets1 greatly enhanced the Smad3/TGF beta-mediated activation [26].
• Furthermore, ETS-1 mediated activation of IKKalpha is negatively regulated by p53 binding to ETS-1 [27].
• Mechanistic analyses revealed that in endothelial cells EGF/FGF2 signaling induces ETS1 expression, increases HIF-2alpha protein level in absence of hypoxia, and recruits both ETS1 and HIF-2alpha to the VEGFR1 chromatin domain [28].

Other interactions of ETS1

• Finally, functional studies indicate that transcriptional antagonism exists between NURR1 and ETS1 on the MMP-1 promoter [29].
• These data demonstrate that SP100 modulates ETS1-dependent biological processes [20].
• A number of the ETS family of transcription factors are expressed in T cells, including ETS1 and ELF1 [14].
• The CD3D, G, and E genes have been positioned proximal to the 11q23 breakpoint of the 4;11 translocation while the THY1 and ETS1 genes have been mapped distal to this breakpoint [30].
• Several HBx mutant proteins unable to bind DDB1 remained competent for transactivation, indicating that HBx binding to DDB1 is not required for HBx transactivation of the ETS1 promoter [31].

Analytical, diagnostic and therapeutic context of ETS1

• Using immunoglobulin light-chain constant region, ETS1 probes, and the technique of in situ hybridization, we previously were able to show that the constitutional and ES/NE breakpoints are different [32].
• In the second approach, to isolate ETS target promoters directly, we performed ETS1 binding with MboI-cleaved genomic DNA in the presence of a specific mAb followed by whole genome PCR [33].
• By Northern blot analysis, several clones showed differential patterns of mRNA expression in the NIH 3T3-, ETS1-, and ETS2-expressing cell lines [33].
• By using surface plasmon resonance, electrophoretic mobility shift assay, and photo-cross-linking, we showed that full-length human ETS-1 (p51) binds cooperatively to the ETS-binding site palindrome of the human stromelysin-1 promoter, with facilitated binding of the second ETS-1 molecule to form an ETS-1.DNA.ETS-1 ternary complex [34].
• Deletion and mutation analyses as well as chromatin immunoprecipitation and electrophoretic mobility shift assay indicated that ETS-1 binds to the core IKKalpha promoter and strongly induces its activity [27].

References