Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome

Georgiou, Panagiotis; Maroulakou, Ioanna G.; Green, J; Dantis, P.; Spica, Vincenzo Romano; Kottaridis, S. D.; Lautenberger, J. A.; Watson, DI; Papas, T S; Fischinger, Peter J.; Bhat, Nayantara

doi:10.3892/ijo.9.1.9

Cited by 40 publications

(52 citation statements)

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“…These mice also have an increased number of mature B-cells, which have a reduced activation-induced apoptotic response compared with B-cells from wild type animals (23). The possible role of Fli-1 in autoimmunity is further supported by our observation of elevated expression of Fli-1 mRNA in lymphocytes from patients with systemic lupus erythematosus (24). In addition, it has been demonstrated that Fli-1 expression promotes a megakaryocytic phenotype in K562 cells and increases the expression of megakaryocytic genes (25)(26)(27).…”

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confidence: 53%

Ets-dependent Regulation of Target Gene Expression during Megakaryopoiesis

Jackers¹,

Szalai²,

Moussa

et al. 2004

Journal of Biological Chemistry

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Megakaryopoiesis is the process by which hematopoietic stem cells in the bone marrow differentiate into mature megakaryocytes. The expression of megakaryocytic genes during megakaryopoiesis is controlled by specific transcription factors. Fli-1 and GATA-1 transcription factors are required for development of megakaryocytes and promoter analysis has defined in vitro functional binding sites for these factors in several megakaryocytic genes, including GPIIb, GPIX, and C-MPL. Herein, we utilize chromatin immunoprecipitation to examine the presence of Ets-1, Fli-1, and GATA-1 on these promoters in vivo. Fli-1 and Ets-1 occupy the promoters of GPIIb, GPIX, and C-MPL genes in both Meg-01 and CMK11-5 cells. Whereas GPIIb is expressed in both Meg-01 and CMK11-5 cells, GPIX and C-MPL are only expressed in the more differentiated CMK11-5 cells. Thus, in vivo occupancy by an Ets factor is not sufficient to promote transcription of some megakaryocytic genes. GATA-1 and Fli-1 are both expressed in CMK11-5 cells and co-occupy the GPIX and C-MPL promoters. Transcription of all three megakaryocytic genes is correlated with the presence of acetylated histone H3 and phosphorylated RNA polymerase II on their promoters. We also show that exogenous expression of GATA-1 in Meg-01 cells leads to the expression of endogenous c-mpl and gpIX mRNA. Whereas GPIIb, GPIX, and C-MPL are direct target genes for Fli-1, both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. In contrast, GPIIb expression appears to be independent of GATA-1 in Meg-01 cells.Ets family members each contain a conserved winged helixloop-helix DNA binding (ETS) domain that allows recognition of purine-rich DNA sequences with a core GGA(A/T) consensus, designated EBS 1 (Ets binding sequence) (1-3). These transcription factors have critical roles in the transcriptional control of genes important in development, morphogenesis, proliferation, and angiogenesis. Ets factors can function as either positive or negative transcriptional regulators (4, 5) and additional binding of other transcription factors to cis-elements located near EBSs contributes to regulated transcription of specific target genes. Thus, in addition to binding to DNA, Ets transcription factors participate in protein interactions that affect their functions (6, 7).Fli-1, a member of the Ets gene family of transcription factors, performs functions critical for normal development and oncogenesis (for a review, see Ref. 8). Fli-1 is preferentially expressed in cells of hematopoietic lineages and vascular endothelial cells, and has been shown to transcriptionally activate genes, including the stem cell leukemia gene (9), tenascin (10), the stress response gene GADD153 (11), the anti-apoptotic gene Bcl-2 (12) and several megakaryocytic specific genes (see below). Fli-1 also forms ternary complexes through interaction with SRF to bind to SRE elements of fos and Egr-1 promoters (13, 14). Fli-1 protein interaction with other regulatory proteins...

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confidence: 53%

Ets-dependent Regulation of Target Gene Expression during Megakaryopoiesis

Jackers¹,

Szalai²,

Moussa

et al. 2004

Journal of Biological Chemistry

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“…Over-expression of Fli1 in otherwise healthy mice results in an abnormal expansion of autoreactive lymphocytes, production of autoantibodies and the development of an autoimmune kidney disease similar to that observed in murine models of lupus (Zhang et al, 1995). Subsequently, it was observed that Fli1 is over-expressed in the lymphocytes of lupus prone mouse models MRL/lpr and NZB/NZW f1 (Georgiou, 1996;Zhang et al, 2004) and in PBMCs from human lupus patients (Georgiou, 1996). Interestingly, reducing Fli1 levels by approximately 50% in the MRL/lpr mouse model decreased autoantibody production, decreased proteinuria and pathological renal scores, altered the numbers of CD8+ and naive T cells and significantly increased survival (Zhang et al, 2004).…”

Section: Introductionmentioning

confidence: 79%

“…Additionally, we identified a GA n microsatellite in the Fli1 promoter that is polymorphic in lupus prone mice and its length is inversely proportional to promoter activity in a T cell line. Because the immune system and lupus disease expression are sensitive to the levels of Fli1 (Georgiou, 1996;Zhang et al, 1995;Zhang et al, 2004), further studies to decipher the precise control of Fli1 gene expression in lymphocytes will be important for understanding the pathogenesis of lupus and also may provide insight into the role of Fli1 in hematopoietic malignancies. 5' deletion analysis of Fli1 promoter activity in B and T cells.…”

Section: Discussionmentioning

confidence: 99%

Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

Nowling¹,

Fulton²,

Chike-Harris³

et al. 2008

Molecular Immunology

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Fli1 is an Ets family member that is essential for embryonic development. Increasing evidence suggests modulating Fli1 gene expression impacts lymphocyte development/function and is an important mediator in the autoimmune disease lupus. Fli1 is over-expressed in splenic lymphocytes in lupus prone mouse strains and in PBMCs of lupus patients. Presently, it is unknown how Fli1 gene expression is controlled in lymphocytes or how it becomes over-expressed in lupus. Therefore, we examined Fli1 regulation in a murine B cell line and T cell line and identified several cis-regulatory elements within a 230 bp region that contribute to Fli1 promoter activity. Ets factors Elf1, Tel and Fli1 bind in vitro to this region and increase endogenous Fli1 expression when over-expressed in a T cell line. In addition, we determined that a microsatellite located adjacent to the region containing these cis-regulatory elements is polymorphic in three lupus prone mouse strains and that the length of the microsatellite is inversely correlated with promoter activity in a T cell line. These results suggest that several Ets factors, including Fli1 itself, are involved in the transcriptional regulation of Fli1 in lymphocytes. Furthermore, the presence of a polymorphic microsatellite in the Fli1 promoter may contribute to increased Fli1 expression in T cells during lupus disease progression.

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“…Overexpression of Fli1 in all tissues of transgenic mice results in death from progressive immunological renal disease associated with an increased number of autoreactive T and B lymphocytes (41). The possible role of FLI1 in autoimmunity is further supported by our recent observation of elevated expression of FLI1 mRNA in lymphocytes from patients with systemic lupus erythematosus (12). Overexpression of Fli1 results in an increased number of mature B cells, which have a reduced activationinduced apoptotic response compared to B cells from wild-type animals (41).…”

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confidence: 85%

Hemorrhage, Impaired Hematopoiesis, and Lethality in Mouse Embryos Carrying a Targeted Disruption of the Fli1Transcription Factor

Spyropoulos

Pharr

Lavenburg

et al. 2000

Molecular and Cellular Biology

275

297

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The Ets family of transcription factors have been suggested to function as key regulators of hematopoeisis. Here we describe aberrant hematopoeisis and hemorrhaging in mouse embryos homozygous for a targeted disruption in the Ets family member, Fli1. Mutant embryos are found to hemorrhage from the dorsal aorta to the lumen of the neural tube and ventricles of the brain (hematorrhachis) on embryonic day 11.0 (E11.0) and are dead by E12.5. Histological examinations and in situ hybridization reveal disorganization of columnar epithelium and the presence of hematomas within the neuroepithelium and disruption of the basement membrane lying between this and mesenchymal tissues, both of which express Fli1 at the time of hemorrhaging. Livers from mutant embryos contain few pronormoblasts and basophilic normoblasts and have drastically reduced numbers of colony forming cells. These defects occur with complete penetrance of phenotype regardless of the genetic background (inbred B6, hybrid 129/B6, or outbred CD1) or the targeted embryonic stem cell line used for the generation of knockout lines. Taken together, these results provide in vivo evidence for the role of Fli1 in the regulation of hematopoiesis and hemostasis.The human FLI1 gene, which we originally cloned from the leukemia T-cell line, CEM, is a member of the Ets gene family of transcription factors (38). As observed with all other members of the Ets gene family, FLI1 encodes a protein that retains a region of conserved sequence, the Ets domain (37, 38). This minimal 85-amino-acid region has been shown to be the DNAbinding domain. Ets proteins bind to DNA sequences that contain a consensus GGA(A/T) core motif (Ets-binding site) and, in the majority of cases, function as transcriptional activators. Ets proteins control the expression of genes that are critical for the control of cellular proliferation, differentiation, and programmed cell death. The presence of multiple Ets family proteins in a variety of cell types and the overlapping DNA-binding specificity of the Ets proteins have made it difficult to identify target genes that are specific for individual Ets factors. The generation and analysis of targeted disruptions in individual family members, coupled with the identification of such target genes, however, is one approach to understanding the role of Ets transcription factors in normal and dysregulated development. A variety of studies including the analysis of expression of members of the Ets transcription factor family in hematopoietic tissues and cell lines and the generation and analysis of targeted mutations in Ets gene family members in mouse suggest that they play important roles in the regulation of normal hematopoietic development (13,14,29).FLI1 was found to be highly related to the human ERG gene, and we originally named it ERGB to reflect this homology (38). Sequence alignments of the predicted 452-amino-acid protein product of human FLI1 with those of the ERG and mouse Fli1 products (5) demonstrated 80 and 96% similarity, respectively. FLI1 ha...

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Expression of ets family of genes in systemic lupus erythematosus and Sjogren's syndrome

Cited by 40 publications

References 0 publications

Ets-dependent Regulation of Target Gene Expression during Megakaryopoiesis

Ets-dependent Regulation of Target Gene Expression during Megakaryopoiesis

Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes

Hemorrhage, Impaired Hematopoiesis, and Lethality in Mouse Embryos Carrying a Targeted Disruption of the Fli1Transcription Factor

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