Disease relevance of ETS2

• ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiological features of Down syndrome (DS) [1].
• These results indicate that AURKA is a direct target of the MAPK pathway and that its overexpression in pancreatic cancer is induced by hyperactivation of the pathway, at least via ETS2 [2].
• 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 [3].
• The organization of the PEA3 with the AP1-like motif in the ETS2 promoter resembles the oncogene-responsive unit previously identified in the polyoma virus enhancer region [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].

Psychiatry related information on ETS2

• Recently, a microduplication on chromosome 21 including ETS2 locus was described in karyotypically 'normal' Down's syndrome and suspected in Alzheimer's disease; when testing Alzheimer's disease-affected brain cortex sections, no obvious difference was observed with the technique used [5].

High impact information on ETS2

• The induction of p16INK4a by Ets2, which is abundant in young human diploid fibroblasts, is potentiated by signalling through the Ras-Raf-MEK kinase cascade and inhibited by a direct interaction with the helix-loop-helix protein Id1 (ref. 11) [6].
• Ets2 is located on human chromosome 21 (ref. 8) and is overexpressed in Down's syndrome (trisomy 21) [7].
• Expression of Ets2, a proto-oncogene and transcription factor, occurs in a variety of cell types [7].
• Rapid and transient expression of Ets2 in mature macrophages following stimulation with cMGF, LPS, and PKC activators [8].
• Because Ets2 is localized in the nucleus of macrophages and binds to DNA in vitro, the kinetics of its expression suggest a role for Ets2 in the transduction within the nucleus of specific signals received at the cell membrane and involved in securing the survival and/or the development of functional competence of these cells [8].

Biological context of ETS2

• 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 [9].
• Both the N-terminal region, comprising the transactivation domain, and the C-terminal region of ETS2 associated with ERG and, interestingly, the interaction of ERG through the transactivation domain of ETS2 was DNA-independent [10].
• ETS1 and ETS2 in p53 regulation: spatial separation of ETS binding sites (EBS) modulate protein: DNA interaction [11].
• 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 [12].
• The coding regions of all of the ETS2 RNA species are the same length and, thus, should contain the same open reading frame [13].

Anatomical context of ETS2

• ETS2 is involved in protein kinase C-activated expression of granulocyte-macrophage colony-stimulating factor in human non-small lung carcinoma cell line, A549 [14].
• Our results show that resting T cells express high levels of ETS1 mRNA and protein, while expression of ETS2 is undetectable [15].
• Previously, we have shown that the overexpression of ETS1 and ETS2 genes effects transformation of NIH 3T3 cells and specific transformants produce high levels of the ETS proteins [16].
• Indeed we report for the first time that the ETS2 overexpression transgenic mouse develops a smaller thymus and lymphocyte abnormalities similar to that observed in DS [1].
• In an effort to contribute to the construction of a transcriptional map of the DS CHD region we have performed direct cDNA selection using a YAC contig that maps between ETS2 and D21S15 and cDNAs synthesised from fetal heart structures [17].

Associations of ETS2 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 [15].
• The mammalian homologue of the 3' v-ets domain was similarly mapped to human chromosome 21 (ETS2), to mouse chromosome 16 (Ets-2), and to feline chromosome C2 (ETS2) [18].
• PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway [19].
• Early-passage cells which have been induced to become tumorigenic by exposure to the carcinogen nitrosomethylurea also have the localization of the ETS2 at 3qter [20].
• Phosphoamino acid analysis of radiolabeled Ets2 revealed that Ras induced normally absent threonine-specific phosphorylation of the protein [21].

Physical interactions of ETS2

• Our data shows that T/T homozygotes have a lower t/n-TRFLR, but a stronger TA expression, suggesting that the studied Ets2 binding site is a positive regulator of hTERT gene [22].
• The Pointed domain has been implicated in protein-protein interactions and we find that Ets2 requires an intact Pointed domain to bind Cdk10 [23].
• Progressive truncation of reporter constructs indicated that the site of PKA/Ets2 responsiveness lay in a region of the promoter between -126 and -67, which lacks a cAMP response element but contains the functional Ets2-binding site and an activator protein 1 (AP1) site [24].

Regulatory relationships of ETS2

• These data indicate that GM-CSF is up-regulated by ETS2, a target of protein kinase C [14].
• The MEK inhibitor PD590089 abrogates insulin-stimulated phosphorylation of ETS-2 [19].
• Four antibodies are ETS-2 specific and two antibodies cross-react with ETS-1, an ETS family member with the highest amino acid sequence homology to ETS-2 [25].

Other interactions of ETS2

• Results of transient transfection assays with A549 cells indicated that ETS2 had a strong positive effect on GM-CSF promoter activity [14].
• These BACs span the molecular markers D21S55, ERG, ETS2, MX1/2, collagen XVIII and collagen VI A1/A2 [26].
• Overexpression of ETS2 in SKBr3 cells reconstitutes AP1-ETS element-dependent hdm2-P2 promoter activity, resulting in increased levels of hdm2 protein in the cells [27].
• ERF (ETS2 Repressor Factor) is a novel member of the ets family of genes, which was isolated by virtue of its interaction with the ets binding site (EBS) within the ETS2 promoter [28].
• Transcription factors Ets1, Ets2, and Elf1 exhibit differential localization in human endometrium across the menstrual cycle and alternate isoforms in cultured endometrial cells [29].

Analytical, diagnostic and therapeutic context of ETS2

• In situ hybridization analyses of ETS1 and ETS2 expression during mouse embryogenesis, have shown a pattern similar to that of p53 gene expression [11].
• By Northern blot analysis, several clones showed differential patterns of mRNA expression in the NIH 3T3-, ETS1-, and ETS2-expressing cell lines [16].
• The rapid induction of Ets2 after treatment of chicken bone marrow-derived macrophages by cMGF is blunted after down-regulation or inactivation of PKC, suggesting a role of PKC in the cMGF-induced signal transduction pathway [8].
• Furthermore, in vitro translated Ets2 binds specifically to the -10 Ets motif in electrophoretic mobility shift assays [30].
• Immunoprecipitation analysis revealed that Sp1, Ets1, and Ets2 form a transcriptionally active complex [31].

References