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Dennis K. Watson - One of the best experts on this subject based on the ideXlab platform.
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Thymomegaly, microsplenia, and defective homeostatic proliferation of peripheral lymphocytes in p51-ETS1 isoform-specific null mice.
Molecular and cellular biology, 2007Co-Authors: Tsukasa Higuchi, Dennis K. Watson, Robin C. Muise-helmericks, Frank Bartel, Masahiro Masuya, Takao Deguchi, Kelly W. Henderson, Michael J. Kern, Demetri D. SpyropoulosAbstract:ETS1 is a member of the Ets winged helix-turn-helix transcription factor family. Ets transcription factors are activators and repressors of transcription, important in the development of organisms throughout the Metazoa (9, 10, 22, 38, 48, 50). Previous ETS1 knockout mice show partial perinatal lethality. Surviving mice and chimeras derived from ETS1-targeted cells exhibit pan-lymphoid defects. These defects include reduced numbers of thymocytes, lymphoid cells in the spleen, and NK and NKT cells; loss of detectable NK and NKT cell activity; decreased proliferation and elevated apoptosis in mature T cells (4, 6, 40, 58); increased differentiation of B cells to plasma cells with elevated serum immunoglobulin M; B-cell receptor signaling defects (12); abnormalities in T-cell receptor (TCR) β-selection in thymopoiesis; and an ineffective Th1 response (11, 19). Complicating the assessment of ETS1 function is the fact that ETS1-null mice have been studied not only on a mixed genetic background (C57BL/6 × 129Sv) predisposed to autoimmunity (53) but also with a line of ETS1-null mice that expresses a very low level of a neomorphic protein (∼1 to 5%) lacking the pointed domain of ETS1 (7, 59). These ETS1-null mice present with a deficiency in CD8+ thymocyte development and an elevated proportion of single-positive effector memory (CD62L− CD44+) cells in both CD4+ and CD8+ peripheral T-cell populations (7). The mammalian ETS1 gene produces two major protein isoforms, full-length p51-ETS1 and p42-ETS1, which arise from alternative splicing of exon VII of ETS1 hnRNA with no disruption in the reading frame (5, 24, 29). The p51-ETS1 and p42-ETS1 isoforms have common and distinctive physical properties that allow for both functional redundancy and isoform-specific activities. Shared domains include the Pointed (PNT), transactivation, and ETS DNA binding domains. The domain encoded by exon VII has been identified as a negative regulator and modulator of DNA binding, a mediator of homo- and heterotypic protein-protein interactions, and a target of calcium-mediated phosphorylation (2, 8, 14, 28, 46). Collectively, these distinctions contribute to the ETS1 isoform-specific modulation of particular ETS1 target genes. Exon VII-mediated homotypic and AML1 (Runx1)-ETS1 heterotypic protein-protein interactions augment transcription of MMP-3 and granulocyte-macrophage colony-stimulating factor, respectively (2, 35, 36). Conversely, other target genes, such as the VE-cadherin gene, are transcriptionally activated more strongly by the p42-ETS1 variant in a cell context-specific manner (33). These distinctions are physiologically relevant; ectopic expression of the p42-ETS1 isoform but not the full-length p51-ETS1 isoform in DLD-1 colon cancer cells restores Fas-mediated apoptosis (32). A similar proapoptotic role for the p42-ETS1 isoform has been suggested for MDA-MB-231 invasive breast cancer cells (3). While much work characterizing the functions of ETS1 has been done, relatively little is known about the interplay between the two protein isoforms in mediating these functions in vivo. To extend the functional assessment of ETS1 protein isoforms in vivo, we have generated ETS1ΔVII gene-targeted mice, which express only the p42-ETS1 isoform (lacking the full-length p51-ETS1 isoform). Analyses of ETS1ΔVII mice have demonstrated a requirement for the full-length p51-ETS1 isoform in the regulation of lymphopoiesis and homeostasis. Genes important in these processes and misexpressed in ETS1ΔVII homozygotes include those for p16Ink4a, p27Kip1, and CD44 and provide possible mechanisms for the phenotypes observed.
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Caspase-1 Is a Direct Target Gene of ETS1 and Plays a Role in ETS1-Induced Apoptosis
Cancer research, 2005Co-Authors: Huiping Pei, Yair Adereth, Tien Hsu, Dennis K. WatsonAbstract:ETS1, the founding member of Ets transcriptional factor family, plays an important role in cell proliferation, differentiation, lymphoid cell development, transformation, angiogenesis, and apoptosis. Previous work has shown that ETS1 represses tumorigenicity of colon carcinoma cells in vivo, and that the p42-ETS1 protein bypasses a defect in apoptosis in colon carcinoma cells through the up-regulation of caspase-1 expression. In this report, we show that expression of p42-ETS1 inhibits tumorigenicity of colon cancer DLD-1 cells through induction of apoptosis in vivo. In support of the hypothesis that caspase-1 might be a target involved in the sensitization of DLD-1 cells to Fas-induced apoptosis by ETS1, overexpression of caspase-1 bypasses Fas-induced apoptosis in these cells as well. Furthermore, ETS1-mediated apoptosis was observed in MOP8 cells, a transformed mouse NIH3T3 cell line. To determine whether ETS1 activates the transcription of caspase-1, luciferase reporters driven by the wild-type and mutant caspase-1 promoters were generated. Both p51-ETS1 and p42-ETS1 transactivated the caspase-1 transcription and a functional Ets binding site is identified in the caspase-1 promoter. Wild-type caspase-1 promoter (pGL3-ICE) was strongly transactivated by ETS1 and this transactivation was dramatically diminished by the mutation of the potential Ets binding site (−525 bp). In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed complex formation between this binding site and ETS1 proteins. Taken together, ETS1 transcriptionally induces the expression of caspase-1; as such, the regulatory control of caspase-1 expression by ETS1 may underlie the apoptotic susceptibility modulated by ETS1 in specific tumor cells.
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interleukins 2 and 15 regulate ETS1 expression via erk1 2 and mnk1 in human natural killer cells
Journal of Biological Chemistry, 2005Co-Authors: Eric M. Grund, Dennis K. Watson, Demetri D. Spyropoulos, Robin C MuisehelmericksAbstract:Abstract Interleukins (IL)-2 and IL-15 regulate natural killer (NK) cell proliferation, survival, and cytolytic activity. ETS1 is a transcription factor expressed early in NK cell differentiation. Because IL-2Rβ, IL-2Rγ, IL-15, and ETS1 knock-out mice similarly lack NK cells, we explored a molecular connection between IL-2R signaling and ETS1. Here we report the post-transcriptional regulation of ETS1 by IL-2R signaling in human NK cells. IL-2 and IL-15 stimulation leads to increased ETS1 protein levels with no significant change in mRNA levels. Pulse and pulse-chase experiments show that IL-2 stimulation results in both a marked increase in the nascent translation of ETS1 and an increased protein half-life. Pharmacological inhibition of MEK specifically blocks IL-2- and IL-15-induced translation, whereas p38, phosphatidylinositol 3-kinase, and mTOR inhibitors had no effect on ETS1 levels. Fli1, an Ets family member, exhibited a different mechanism of regulation, illustrating the specificity of IL-2R β and γ subunit signaling on the regulation of ETS1 expression. Expression of a dominant negative form of MNK1, a regulator of the translation initiation factor eIF4E, blocks the expression of ETS1 as do the dominant negative forms of the common IL-2R β and γ chains. Expression of ETS1 is regulated similarly in normal peripheral human NK cells. Taken together, our findings provide a direct link between IL-2R subunit signaling and ETS1 expression and helps to explain the interdependence of the IL-2R subunits and ETS1 for NK cell development and function.
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SP100 inhibits ETS1 activity in primary endothelial cells.
Oncogene, 2004Co-Authors: John S Yordy, Huiping Pei, Omar Moussa, Damien Chaussabel, Dennis K. WatsonAbstract:SP100 was first identified as a nuclear autoimmune antigen and is a constituent of the nuclear body. SP100 interacts with the ETS1 transcription factor, and we have previously shown that SP100 reduces ETS1-DNA binding and inhibits ETS1 transcriptional activity on the MMP1 and uPA promoters. We now demonstrate that SP100 expression is upregulated by interferons, which have been shown to be antiangiogenic, in primary endothelial cells. As ETS1 is functionally important in promoting angiogenesis, we tested the hypothesis that ETS1 activity is negatively modulated by SP100 in endothelial cells. SP100 directly antagonizes ETS1-mediated morphological changes in human umbilical vein endothelial cell (HUVEC) network formation and reduces HUVEC migration and invasion. To further understand the functional relationship between ETS1 and SP100, cDNA microarray analysis was utilized to assess reprogramming of gene expression by ETS1 and SP100. A subset of the differentially regulated genes, including heat-shock proteins (HSPs) H11, HSPA1L, HSPA6, HSPA8, HSPE1 and AXIN1, BRCA1, CD14, CTGF (connective tissue growth factor), GABRE (gamma-aminobutyric acid A receptor epsilon), ICAM1, SNAI1, SRD5A1 (steroid-5-alpha-reductase 1) and THY1, were validated by real-time PCR and a majority showed reciprocal expression in response to ETS1 and SP100. Interestingly, genes that are negatively regulated by ETS1 and upregulated by SP100 have antimigratory or antiangiogenic properties. Collectively, these data indicate that SP100 negatively modulates ETS1-dependent downstream biological processes.
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Interleukins 2 and 15 Regulate ETS1 Expression via ERK1/2 and MNK1 in Human Natural Killer Cells
The Journal of biological chemistry, 2004Co-Authors: Eric M. Grund, Dennis K. Watson, Demetri D. Spyropoulos, Robin C. Muise-helmericksAbstract:Abstract Interleukins (IL)-2 and IL-15 regulate natural killer (NK) cell proliferation, survival, and cytolytic activity. ETS1 is a transcription factor expressed early in NK cell differentiation. Because IL-2Rβ, IL-2Rγ, IL-15, and ETS1 knock-out mice similarly lack NK cells, we explored a molecular connection between IL-2R signaling and ETS1. Here we report the post-transcriptional regulation of ETS1 by IL-2R signaling in human NK cells. IL-2 and IL-15 stimulation leads to increased ETS1 protein levels with no significant change in mRNA levels. Pulse and pulse-chase experiments show that IL-2 stimulation results in both a marked increase in the nascent translation of ETS1 and an increased protein half-life. Pharmacological inhibition of MEK specifically blocks IL-2- and IL-15-induced translation, whereas p38, phosphatidylinositol 3-kinase, and mTOR inhibitors had no effect on ETS1 levels. Fli1, an Ets family member, exhibited a different mechanism of regulation, illustrating the specificity of IL-2R β and γ subunit signaling on the regulation of ETS1 expression. Expression of a dominant negative form of MNK1, a regulator of the translation initiation factor eIF4E, blocks the expression of ETS1 as do the dominant negative forms of the common IL-2R β and γ chains. Expression of ETS1 is regulated similarly in normal peripheral human NK cells. Taken together, our findings provide a direct link between IL-2R subunit signaling and ETS1 expression and helps to explain the interdependence of the IL-2R subunits and ETS1 for NK cell development and function.
Lee Ann Garrett-sinha - One of the best experts on this subject based on the ideXlab platform.
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ETS1 Controls the Development of B Cell Autoimmune Responses in a Cell-Intrinsic Manner.
ImmunoHorizons, 2019Co-Authors: Alex Sunshine, David Goich, Alifa Stith, Katherine Sortino, Justin Dalton, Sarah Metcalfe, Eric C. Svensson, Lee Ann Garrett-sinhaAbstract:ETS1 is emerging as a key transcription factor that is required to prevent autoimmunity in mice and humans. ETS1 is expressed in both B and T cells, and mice lacking ETS1 are characterized by excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies. In humans, genome-wide association studies have detected associations of single nucleotide polymorphisms in the human ETS1 gene with autoimmune diseases, including lupus. An increased fraction of CD4+ T cells from ETS1−/− mice have an activated effector-memory phenotype, and there are aberrations in differentiation that contribute to the autoimmune phenotype. In vitro studies of B cells suggest that ETS1 may have B cell–intrinsic effects as well. To confirm B cell–intrinsic roles for ETS1, we crossed CD19-Cre mice to mice with a floxed allele of ETS1. Mice with a B cell–specific deletion of ETS1 show increases in B cell activation, numbers of Ab-secreting cells, and levels of autoantibodies, despite the fact that T cells are normal. However, when compared with conventional ETS1 knockout mice, mice with B cell–specific loss of ETS1 have a significantly milder phenotype. These results demonstrate that ETS1 is required in B cells to prevent autoimmune responses but that loss of ETS1 activity in other cell types is required for maximal autoimmune phenotypes.
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Genome-Wide Identification of Target Genes for the Key B Cell Transcription Factor ETS1
Frontiers in immunology, 2017Co-Authors: Prontip Saelee, Alyssa Kearly, Stephen L. Nutt, Lee Ann Garrett-sinhaAbstract:Background: The transcription factor ETS1 is highly expressed in B lymphocytes. Loss of ETS1 leads to premature B cell differentiation into antibody-secreting cells (ASCs), secretion of autoantibodies and development of autoimmune disease. Despite the importance of ETS1 in B cell biology, few ETS1 target genes are known in these cells. Results: To obtain a more complete picture of the function of ETS1 in regulating B cell differentiation we performed ETS1 ChIP-seq in primary mouse B cells to identify >10,000 binding sites, many of which were localized near genes that play important roles in B cell activation and differentiation. Although ETS1 bound to many sites in the genome, it was required for regulation of less than five percent of them as evidenced by gene expression changes in B cells lacking ETS1. The cohort of genes whose expression was altered included numerous genes that have been associated with autoimmune disease susceptibility. We focused our attention on four such ETS1 target genes Ptpn22, Stat4, Egr1 and Prdm1 to assess how they might contribute to ETS1 function in limiting ASC formation. We found that dysregulation of these particular targets cannot explain altered ASC differentiation in the absence of ETS1. Conclusions: We have identified genome-wide binding targets for ETS1 in B cells and determined that a relatively small number of these putative target genes require ETS1 for their normal expression. Interestingly, a cohort of genes associated with autoimmune-disease susceptibility are among those that are regulated by ETS1. Identification of the target genes of ETS1 in B cells will help provide a clearer picture of how ETS1 regulates B cell responses and how its loss promotes autoantibody secretion.
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Genetic Interaction between Lyn, ETS1, and Btk in the Control of Antibody Levels
Journal of immunology (Baltimore Md. : 1950), 2015Co-Authors: Jessica M. Mayeux, Prontip Saelee, Lee Ann Garrett-sinha, Brian Skaug, Wei Luo, Lisa Russell, Shinu John, Hansaa Abbasi, Anne B. SatterthwaiteAbstract:Tight control of B cell differentiation into plasma cells (PCs) is critical for proper immune responses and the prevention of autoimmunity. The ETS1 transcription factor acts in B cells to prevent PC differentiation. ETS1(-/-) mice accumulate PCs and produce autoantibodies. ETS1 expression is downregulated upon B cell activation through the BCR and TLRs and is maintained by the inhibitory signaling pathway mediated by Lyn, CD22 and SiglecG, and SHP-1. In the absence of these inhibitory components, ETS1 levels are reduced in B cells in a Btk-dependent manner. This leads to increased PCs, autoantibodies, and an autoimmune phenotype similar to that of ETS1(-/-) mice. Defects in inhibitory signaling molecules, including Lyn and ETS1, are associated with human lupus, although the effects are more subtle than the complete deficiency that occurs in knockout mice. In this study, we explore the effect of partial disruption of the Lyn/ETS1 pathway on B cell tolerance and find that Lyn(+/-)ETS1(+/-) mice demonstrate greater and earlier production of IgM, but not IgG, autoantibodies compared with Lyn(+/-) or ETS1(+/-) mice. We also show that Btk-dependent downregulation of ETS1 is important for normal PC homeostasis when inhibitory signaling is intact. ETS1 deficiency restores the decrease in steady state PCs and Ab levels observed in Btk(-/-) mice. Thus, depending on the balance of activating and inhibitory signals to ETS1, there is a continuum of effects on autoantibody production and PC maintenance. This ranges from full-blown autoimmunity with complete loss of ETS1-maintaining signals to reduced PC and Ab levels with impaired ETS1 downregulation.
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Regulation of the intracellular localization of the transcription factor ETS1 (IRM10P.754)
Journal of Immunology, 2014Co-Authors: Justin Dalton, Sarah J. Blair, Lee Ann Garrett-sinhaAbstract:ETS1 is a DNA binding transcription factor that regulates B and T cell responses. To activate transcription ETS1 must be present in the nucleus of the cell. The major isoform of ETS1 (designated p54) has both a nuclear localization signal (NLS) and a nuclear export signal (NES). We have identified a novel isoform of ETS1 (p68) having an alternate N-terminus with 71 distinct amino acids that replace the first 28 amino acids of p54. Unexpectedly, we found that transfected p68 is localized in the cytoplasm of cells, rather than the nucleus where p54 is found, despite the fact that p68 contains both the NLS and NES sequences of ETS1. This suggests that sequences in the first 28 amino acids of p54 ETS1 regulate its nuclear localization. Contained within this region of p54 ETS1 is a lysine residue (K15) known to undergo sumoylation. We made point mutations in this site (to either alanine or arginine) and showed that this residue is essential for nuclear localization of ETS1. Studies are currently underway to determine whether sumoylation of ETS1 is required for its nuclear localization. Interestingly, there may be a conserved mechanism that regulates nuclear localization of Ets proteins. This interpretation is based on our observation that another Ets family member Elf5 also requires an intact N-terminus to be localized within the nucleus of the cell. Our studies predict that nuclear localization of Ets proteins may be a regulated event and under the control of signaling pathways.
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Aberrant epidermal differentiation and disrupted ΔNp63/Notch regulatory axis in ETS1 transgenic mice.
Biology open, 2013Co-Authors: Shu Shien Chin, Satrajit Sinha, Priyadharsini Nagarajan, Rose-anne Romano, Lee Ann Garrett-sinhaAbstract:Summary The transcription factor ETS1 is expressed at low levels in epidermal keratinocytes under physiological conditions, but is over-expressed in cutaneous squamous cell carcinoma (SCC). We previously showed that over-expression of ETS1 in differentiated keratinocytes of the skin leads to significant pro-tumorigenic alterations. Here, we further extend these studies by testing the effects of over-expressing ETS1 in the proliferative basal keratinocytes of the skin, which includes the putative epidermal stem cells. We show that induction of the ETS1 transgene in the basal layer of skin during embryogenesis results in epidermal hyperplasia and impaired differentiation accompanied by attenuated expression of spinous and granular layer markers. A similar hyper-proliferative skin phenotype was observed when the transgene was induced in the basal layer of the skin of adult mice leading to hair loss and open sores. The ETS1-mediated phenotype is accompanied by a variety of changes in gene expression including alterations in Notch signaling, a crucial mediator of normal skin differentiation. Finally, we show that ETS1 disrupts Notch signaling in part via its ability to upregulate ΔNp63, an established transcriptional repressor of several of the Notch receptors. Given the established tumor suppressive role for Notch signaling in skin tumorigenesis, the demonstrated ability of ETS1 to interfere with this signaling pathway may be important in mediating its pro-tumorigenic activities.
Jürgen Dittmer - One of the best experts on this subject based on the ideXlab platform.
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The role of the transcription factor ETS1 in carcinoma.
Seminars in cancer biology, 2015Co-Authors: Jürgen DittmerAbstract:ETS1 belongs to the large family of the ETS domain family of transcription factors and is involved in cancer progression. In most carcinomas, ETS1 expression is linked to poor survival. In breast cancer, ETS1 is primarily expressed in the triple-negative subtype, which is associated with unfavorable prognosis. ETS1 contributes to the acquisition of cancer cell invasiveness, to EMT (epithelial-to-mesenchymal transition), to the development of drug resistance and neo-angiogenesis. The aim of this review is to summarize the current knowledge on the functions of ETS1 in carcinoma progression and on the mechanisms that regulate ETS1 activity in cancer.
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ETS1 is an effector of protein kinase Calpha in cancer cells.
Oncogene, 2004Co-Authors: Martina Vetter, Ralph K. Lindemann, Sibylle G. Blumenthal, Joachim Manns, Sebastian Wesselborg, Christoph Thomssen, Jürgen DittmerAbstract:PKCα and ETS1 are both associated with breast cancer progression. Our previous studies suggested that these proteins are likely to functionally interact with one another. Here, we show that attenuation of endogenous PKCα expression (siPα) by RNA interference leads to reduced ETS1 protein expression in a variety of cancer cells. Pulse-chase experiments and treatment with proteasome inhibitor MG-132 revealed that siPα interferes with both ETS1 protein synthesis and stability. The effect of siPα on ETS1 expression could be partially prevented by KN-93, suggesting that calcium/calmodulin-dependent kinase II (CaMKII), a modulator of ETS1 activity, may play a role in PKCα-dependent ETS1 regulation. In contrast, ETS1-regulating kinases ERK1/2 were not found to be involved in this process. To assess the importance of the PKCα/ETS1 interaction, we compared the biological responses of MDA-MB-231 cells to PKCα- and ETS1-specific siRNAs (siE1). While only siPα induced changes in cellular morphology and anchorage-independent growth, both siRNAs similarly affected cellular responses to the antitumor drug mithramycin A and to UV light. Microarray analyses further showed that the expression of a certain set of genes was equally affected by siPα and siE1. The data suggest that ETS1 serves as an effector for PKCα to fulfil certain functions in cancer cells.
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Importance of ETS1 proto-oncogene for breast cancer progression.
Zentralblatt fur Gynakologie, 2004Co-Authors: Jürgen Dittmer, Vetter M, Kölbl HAbstract:Ets proteins are transcription factors, which share a unique DNA binding domain, the Ets domain. Some members of the Ets family are implicated in tumorigenesis. ETS1, the founder of the Ets family, is predominantly expressed in invasive tumors and able to activate certain genes encoding ECM-degrading proteases. We used RNA-interference in combination with DNA chip analysis to identify ETS1-regulated genes in MDA-MB-231 breast cancer cells. Of the ETS1-responsive proteases, matrix metalloproteases MMP1 and MMP9, but not MMP3 or uPA, showed reduced RNA levels when endogenous ETS1 expression was suppressed. These data suggest that ETS1 regulates only a certain subset of ECM-degrading proteases. How ETS1 is regulated in invasive breast cancer cells is unknown. The observations that protein kinase C inhibitors abrogated ETS1 expression and that protein kinase C was able to increase ETS1-dependent transcription imply that protein kinase C is a potential regulator of ETS1 activity in breast cancer cells.
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Splicing variant ΔVII-ETS1 is downregulated in invasive ETS1-expressing breast cancer cells
International journal of oncology, 2003Co-Authors: Pia Ballschmieter, Melanie Braig, Ralph K. Lindemann, Alfred Nordheim, Jürgen DittmerAbstract:Transcription factor ETS1 is expressed in invasive breast cancer cells. In T-cells, the splicing variant DeltaVII-ETS1 is naturally produced along with full length ETS1 (fl-ETS1). Though its function is unknown, the lack of important inhibitory domains predicts a regulatory role of DeltaVII-ETS1 in fl-ETS1-controlled transcription. Examining the expression status of DeltaVII-ETS1 in invasive ETS1-producing MDA-MB-231 breast cancer cells, we found that the DeltaVII-ETS1 protein could only be detected when nuclear proteins from these cells were fractionated by ionic exchange chromatography. When overexpressed, DeltaVII-ETS1 was found to be partially degraded in breast cancer cells, but not in Jurkat T-cells or SK-Mel melanoma cells. In contrast, no proteolytic products resulted from ectopic expression of fl-ETS1 suggesting that breast cancer cells are able to specifically cleave DeltaVII-ETS1. Overexpression of DeltaVII-ETS1 reduced survival of MDA-MB-231 cells, but not of MCF-7 cells. A mutant version of DeltaVII-ETS1, lacking first 129 N-terminal amino acids, had no effect. These data suggest that ETS1-producing invasive breast cancer cells specifically downregulate DeltaVII-ETS1, as it may be able to adversely affect the survival of these cells.
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Protein kinase Calpha regulates ETS1 transcriptional activity in invasive breast cancer cells.
International journal of oncology, 2003Co-Authors: Ralph K. Lindemann, Pia Ballschmieter, Melanie Braig, Alfred Nordheim, Theresa A. Guise, Jürgen DittmerAbstract:We have previously shown that PKC inhibitors interfere with the ETS1/Smad3-dependent regulation of parathyroid hormone-related protein (PTHrP) P3 promoter activity by TGFbeta in invasive MDA-MB-231 breast cancer cells. By examining PKC expression in a variety of breast cancer cell lines, the protein level of PKCalpha was found to be much higher in ETS1-expressing MDA-MB-231 and MDA-MB-435 breast cancer cells than in ETS1-deficient MCF-7 and SK-BR3 cells. No correlation of ETS1 expression with the expression of other PKC subtypes (PKCbeta1, PKCbeta2, PKCdelta or PKCepsilon) could be observed. In contrast to MDA-MB-231 cells, PKCalpha-deficient MCF-7 cells do not support ETS1-induced activation of the PTHrP P3 promoter suggesting that PKCalpha may be important for ETS1 activity. A constitutively active form of PKCalpha was found to potentiate the P3 promoter activation by ETS1 alone and in synergy with Smad3. PKCalpha, but not PKCepsilon, also induced phosphorylation of the ETS1 protein. Both PKCalpha effects on ETS1 depended on the exon VII domain of ETS1. Using verapamil and ionomycin, we could show that PKCalpha induces ETS1 phosphorylation independent of calcium mobilization. Collectively, our data suggest that PKCalpha may regulate ETS1 activity in invasive breast cancer cells.
Gi-cheon Kim - One of the best experts on this subject based on the ideXlab platform.
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ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes
Frontiers in oncology, 2020Co-Authors: Gi-cheon Kim, Choong-gu Lee, Ravi Verma, Dipayan Rudra, Taemook Kim, Keunsoo Kang, Jong Hee Nam, Young Ho Kim, Ho Keun KwonAbstract:ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1 high BRCA patients showed better prognosis and longer survival compared to ETS1 low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.
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the transcription factor ETS1 suppresses t follicular helper type 2 cell differentiation to halt the onset of systemic lupus erythematosus
Immunity, 2018Co-Authors: Chan Johng Kim, Gi-cheon Kim, Choong-gu Lee, Juyang Jung, Ambarnil Ghosh, Syed Nurul Hasan, Sungmin Hwang, Hyeji Kang, Changhon Lee, Dipayan RudraAbstract:Summary Single-nucleotide polymorphisms in ETS1 are associated with systemic lupus erythematosus (SLE). ETS1−/− mice develop SLE-like symptoms, suggesting that dysregulation of this transcription factor is important to the onset or progression of SLE. We used conditional deletion approaches to examine the impact of ETS1 expression in different immune cell types. ETS1 deletion on CD4+ T cells, but not B cells or dendritic cells, resulted in the SLE autoimmunity, and this was associated with the spontaneous expansion of T follicular helper type 2 (Tfh2) cells. ETS1−/− Tfh2 cells exhibited increased expression of GATA-3 and interleukin-4 (IL-4), which induced IgE isotype switching in B cells. Neutralization of IL-4 reduced Tfh2 cell frequencies and ameliorated disease parameters. Mechanistically, ETS1 suppressed signature Tfh and Th2 cell genes, including Cxcr5, Bcl6, and Il4ra, thus curbing the terminal Tfh2 cell differentiation process. Tfh2 cell frequencies in SLE patients correlated with disease parameters, providing evidence for the relevance of these findings to human disease.
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Upregulation of ETS1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness.
Oncogenesis, 2018Co-Authors: Gi-cheon Kim, Choong-gu Lee, Ravi Verma, Dipayan Rudra, Taemook Kim, Keunsoo Kang, Jong Hee Nam, Ho Keun Kwon, Young Ho KimAbstract:Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (ETS1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of ETS1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the ETS1 promoter region (−540/−80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate ETS1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with ETS1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in ETS1 expression, which led to alterations of ETS1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of ETS1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for ETS1-mediated metastatic breast cancer.
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upregulation of ETS1 expression by nfatc2 and nfkb1 rela promotes breast cancer cell invasiveness
Oncogenesis, 2018Co-Authors: Gi-cheon Kim, Choong-gu Lee, Ravi Verma, Dipayan Rudra, Taemook Kim, Keunsoo Kang, Jong Hee Nam, Ho Keun Kwon, Young Ho KimAbstract:Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (ETS1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of ETS1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the ETS1 promoter region (−540/−80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate ETS1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with ETS1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in ETS1 expression, which led to alterations of ETS1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of ETS1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for ETS1-mediated metastatic breast cancer.
Young Ho Kim - One of the best experts on this subject based on the ideXlab platform.
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ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes
Frontiers in oncology, 2020Co-Authors: Gi-cheon Kim, Choong-gu Lee, Ravi Verma, Dipayan Rudra, Taemook Kim, Keunsoo Kang, Jong Hee Nam, Young Ho Kim, Ho Keun KwonAbstract:ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1 high BRCA patients showed better prognosis and longer survival compared to ETS1 low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.
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Upregulation of ETS1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness.
Oncogenesis, 2018Co-Authors: Gi-cheon Kim, Choong-gu Lee, Ravi Verma, Dipayan Rudra, Taemook Kim, Keunsoo Kang, Jong Hee Nam, Ho Keun Kwon, Young Ho KimAbstract:Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (ETS1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of ETS1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the ETS1 promoter region (−540/−80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate ETS1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with ETS1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in ETS1 expression, which led to alterations of ETS1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of ETS1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for ETS1-mediated metastatic breast cancer.
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upregulation of ETS1 expression by nfatc2 and nfkb1 rela promotes breast cancer cell invasiveness
Oncogenesis, 2018Co-Authors: Gi-cheon Kim, Choong-gu Lee, Ravi Verma, Dipayan Rudra, Taemook Kim, Keunsoo Kang, Jong Hee Nam, Ho Keun Kwon, Young Ho KimAbstract:Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (ETS1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of ETS1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the ETS1 promoter region (−540/−80 bp from TSS) that contains elements responsible for associating with NFATs and NF-κBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate ETS1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with ETS1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in ETS1 expression, which led to alterations of ETS1-mediated transcription programs including tumor invasiveness-related genes. Proper regulation of ETS1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for ETS1-mediated metastatic breast cancer.