Disease relevance of Ets1

• Arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy are significantly diminished in Ets1-/- mice compared with control mice in response to Ang II [1].
• A CAT construct driven by the long terminal repeat of the human T cell leukemia virus, HTLV-1 was found to be trans-activated by both Ets1 and Ets2 in NIH3T3 and HeLa cells [2].
• C-ets 1 is also expressed in stromal cells of invasive carcinomas [3].
• Provirus insertion in Tpl-1, an Ets-1-related oncogene, is associated with tumor progression in Moloney murine leukemia virus-induced rat thymic lymphomas [4].
• 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 [5].

High impact information on Ets1

• Here we demonstrate a role for the Ets1 and Ets2 transcription factors based on their ability to activate the p16INK4a promoter through an ETS-binding site and their patterns of expression during the lifespan of human diploid fibroblasts [6].
• Here we show, by using RAG-2-deficient blastocyst complementation, that Ets-1 deficiency has dramatic, but different, effects on development and function of T- and B-lineage cells [7].
• To study the role of Ets-1 in T-cell development and function we have used the RAG-2-/- complementation system and murine embryonic stem (ES) cells containing homozygous deletions in the Ets-1 gene (Ets-1-/-) [8].
• Following T-cell activation, the specific DNA binding activity of Ets-1 is inactivated by transient phosphorylation, suggesting a function in the transition from the resting to activated state [7].
• In contrast, Ets-1-deficient B cells were present in normal numbers but a large proportion were IgM plasma cells [7].

Chemical compound and disease context of Ets1

• Antagonizing Ets-1 might be of benefit in attenuating CCN2 expression in fibrosis, arthritis and cancer, and may be useful in modulating the outcome of these disorders [9].

Biological context of Ets1

• To investigate the possibility that Ets1 and Ets2 are transcriptional activators, we analyzed the ability of these proteins to trans-activate promoter/enhancer sequences in transient co-transfection experiments [2].
• We show that mouse ES cells lacking Ets1 are deficient in their ability to undergo UV-induced apoptosis, similar to p53 null ES cells [10].
• The Ets1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenetic processes such as organ formation [11].
• Our data show that Ets1 expression increases in embryos after implantation and during organogenesis such that it is expressed in all the organs of day-15 embryos studied [11].
• In later fetal stages, Ets1 expression is predominant in the lymphoid tissues, brain, and organs that are undergoing branching morphogenesis (e.g., lung) but is dramatically reduced in other organs such as the stomach and intestine [11].

Anatomical context of Ets1

• In view of the high level expression of Ets1 in lymphoid cells, Ets1 could be part of the transcription complex which mediates the response to Tax1 and the control of HTLV-1 replication [2].
• Ets1 is required for p53 transcriptional activity in UV-induced apoptosis in embryonic stem cells [10].
• We observed significantly decreased numbers of NK T cells in the thymus, spleen, and liver of Ets1-deficient mice [12].
• AML1/Runx1 recruits calcineurin to regulate granulocyte macrophage colony-stimulating factor by Ets1 activation [13].
• This review will examine in detail the role and possible targets of Ets1 and Ets2 in osteoblast differentiation and bone formation [14].

Associations of Ets1 with chemical compounds

• The former domain can bind in vitro, in a cooperative manner, factors related to nuclear factor 1 and Ets1; the latter domain contains a type 3 directly repeated sequence that was shown to be able to bind the retinoid X and triiodothyronine receptors [15].
• In vitro interactions between nuclear proteins and uncoupling protein gene promoter reveal several putative transactivating factors including Ets1, retinoid X receptor, thyroid hormone receptor, and a CACCC box-binding protein [15].
• Thus the multiple functions of RA in bone cells are likely to be mediated in part by Ets1 [14].
• Using two-dimensional tryptic phosphopeptide analysis and site-directed mutagenesis, we found that Ets1 was phosphorylated on threonine 38, a residue conserved in several Ets proteins [16].
• In addition, the expression of Ets1 can be induced in MC3T3-E1 and fetal rat calvaria cells by retinoic acid (RA) which is known to exert profound effects on skeletal growth and development, bone turnover, and induce specific cellular responses in bone cells [14].

Physical interactions of Ets1

• Previously, we identified an Ets-1-binding site located at -49/-47 in the promoter of Pcyt1a as an important transcriptional element involved in basal CTalpha transcription (Sugimoto, H., Sugimoto, S., Tatei, K., Obinata, H., Bakovic, M., Izumi, T., and Vance, D. E. (2003) J. Biol. Chem. 278, 19716-19722) [17].
• Ets1 bound to two Ets-binding sites located in the proximal region of the VE-cadherin promoter [18].
• The constructs having a mutant Ets-1 binding site or lacking this site failed to respond to Ets-1 activation of Npr1 gene transcription [19].
• In this report we show that GST-c-Ets-1 fusion protein binds specifically to the EndoA enhancer unit sequence by gel shift analysis [20].
• Our results indicate that Ets-1 physically interacts with Blimp-1, which leads to a block in Blimp-1 DNA binding activity and a reduction in the ability of Blimp-1 to repress target genes without interfering with Blimp-1 protein levels [21].

Regulatory relationships of Ets1

• Phosphorylation of Ets1 regulates the complementation of a CSF-1 receptor impaired in mitogenesis [16].
• Finally, overexpression of Ets-1 induced the expression of SERCA3 in endothelial cells and in fibroblasts [22].
• In addition, the Ets-1 DNA-binding domain is sufficient to play the functional role of Ets-1 in trans-activating the DOR promoter [23].
• Importantly, antisense Ets-1 demonstrates an ability to repress the activity of the GM-CSF reporter [24].
• In parallel, both a dominant negative mutant of Ets members and an Ets1 anti-sense oligonucleotide inhibited VE-cadherin expression in endothelial cells [18].

Other interactions of Ets1

• More generally, Ets1 and Ets2 could regulate transcription of cellular genes [2].
• After synchronizing the cell cycle in NIH3T3 cells, CTalpha mRNA increased at the S-M phase corresponding to an increase of Ets-1 mRNA and a decrease of Net mRNA [17].
• Heterologous expression studies in Drosophila Schneider cells confirmed that the constitutive expression of this gene is controlled by Ets-1 and requires the presence both of the Sp1 and Sp3 transcription factors [25].
• In the present work, we have investigated the expression of both c-ets 1 and u-PA, a putative target gene of the Ets 1 proteins, within a biological model which includes both embryonic and tumoral aspects [3].
• The deletion of the DNA binding and carboxyl-terminal transactivation domains of HIF-2alpha, respectively, created dominant negative mutants that suppressed transactivation by the wild type protein and failed to synergize with Ets-1 [26].

Analytical, diagnostic and therapeutic context of Ets1

• Chromatin immunoprecipitations demonstrated that Ets1 was required for the formation of a stable p53-DNA complex under physiological conditions and activation of histone acetyltransferase activity [10].
• In situ hybridization analysis demonstrates that expression of Ets1 occurs in mesenchymal cells of developing organs, in the nervous system, and in forming bone [11].
• Chromatin immunoprecipitation assays verified that Sp1, Sp3 and Ets-1 can bind the promoter in vivo [27].
• This pattern of expression is similar to that of the Ets1 transcription factor during osteogenic differentiation of MC3T3-E1 cells, and we used immunohistochemistry to show that, in vivo, Ets1 protein is coexpressed with RNF11 in osteoblasts [28].
• Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases [29].

References