The ETS Family Member Tel Antagonizes the Fli-1 Phenotype in Hematopoietic Cells

Kwiatkowski, Boguslaw A.; Zielinska-Kwiatkowska, Anna; Bauer, Thomas; Hickstein, Dennis D.

doi:10.1006/bcmd.2000.0282

Cited by 20 publications

(18 citation statements)

References 23 publications

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“…In contrast, we have no evidence that TEL2 is involved in erythroid differentiation, because overexpression of TEL2 in the human chronic myeloid leukemia cell line K562 did not affect its erythroid differentiation induced by sodium butyrate. 1 In addition, overexpression of TEL1 blocks megakaryocytic differentiation of K562 cells induced by overexpression of Fli-1 (50). TEL1 can interact with FLI-1 through the PNT domain (15), suggesting that the heterodimerization of these ETS factors may interfere with differentiation of the cells.…”

Section: Discussionmentioning

confidence: 99%

TEL2, an ETS Factor Expressed in Human Leukemia, Regulates Monocytic Differentiation of U937 Cells and Blocks the Inhibitory Effect of TEL1 on Ras-Induced Cellular Transformation

Kawagoe

Potter²,

Ellis³

et al. 2004

Cancer Research

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Section: Discussionmentioning

confidence: 99%

TEL2, an ETS Factor Expressed in Human Leukemia, Regulates Monocytic Differentiation of U937 Cells and Blocks the Inhibitory Effect of TEL1 on Ras-Induced Cellular Transformation

Kawagoe

Potter²,

Ellis³

et al. 2004

Cancer Research

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“…The ETS gene TEL can inhibit FLI1 induction of model reporter gene constructs and TEL/FLI1 complexes can be immunoprecipitated from cells overexpressing these two genes (Kwiatkowski et al, 1998). Overexpression of TEL antagonizes FLI1 induced megakaryocytic dierentiation in the K562 leukemia cell line suggesting a biological correlate to the apparent physical interaction of these two proteins (Kwiatkowski et al, 2000). Finally forced expression of FLI1 both antagonizes and is antagonized by a variety of nuclear hormone receptors in a hormone dependent manner but direct physical interaction between these two transcription factor classes has not yet been documented (Darby et al, 1997).…”

Section: Fli1 Has Been Linked To Normal and Malignant Hematopoietic Cmentioning

confidence: 99%

Biology of EWS/ETS fusions in Ewing's family tumors

2001

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Tumor-associated chromosomal translocations lead to the formation of chimeric fusions between the EWS gene and one of ®ve dierent ETS transcription factors in Ewing's family tumors (EFTs). The resultant EWS/ETS proteins promote oncogenesis in a dominant fashion in model systems and are necessary for continued growth of EFT cell lines. EWS belongs to a family of genes that encode proteins that may serve as adapters between the RNA polymerase II complex and RNA splicing factors. EWS/ETS fusions have biochemical characteristics of aberrant transcription factors and appear to promote abnormal cellular growth by transcriptionally modulating a network of target genes. Early evidence suggests that EWS/ETS proteins may also impact gene expression through alteration in RNA processing. Elucidation of EWS/ETS target gene networks in the context of other signaling pathways will hopefully lead to biology based therapeutic strategies for EFT. Oncogene (2001) 20, 5747 ± 5754.

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“…Fli1 interaction with other proteins can either be positive (e.g., GATA-1 [14,23], serum response factor [SRF] [10,65], and Pax-5 [16,34]) or antagonistic (TEL [27,62], EKLF [60], and retinoic acid receptor [RAR] [11]). Although carboxyterminal truncation of Fli1 (retaining positions 1 to 375) has been reported to not have a significant effect on DNA binding specificity in vitro (35), the CTA domain is required for maximal activation of promoter-reporters, as shown by in vitro transient-transfection studies (49).…”

Section: Cd42mentioning

confidence: 99%

Thrombocytopenia in Mice Lacking the Carboxy-Terminal Regulatory Domain of the Ets Transcription Factor Fli1

Moussa¹,

LaRue²,

Abangan³

et al. 2010

Molecular and Cellular Biology

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Targeted disruption of the Fli1 gene results in embryonic lethality. To dissect the roles of functional domains in Fli1, we recently generated mutant Fli1 mice that express a truncated Fli1 protein (Fli1 ⌬CTA ) that lacks the carboxy-terminal regulatory (CTA) domain. Heterozygous Fli1⌬CTA mice are viable, while homozygous mice have reduced viability. Early postnatal lethality accounts for 30% survival of homozygotes to adulthood. The peripheral blood of these viable Fli1 ⌬CTA /Fli1 ⌬CTA homozygous mice has reduced platelet numbers. Platelet aggregation and activation were also impaired and bleeding times significantly prolonged in these mutant mice. Analysis of mRNA from total bone marrow and purified megakaryocytes from Fli1 ⌬CTA /Fli1 ⌬CTA mice revealed downregulation of genes associated with megakaroyctic development, including c-mpl, gpIIb, gpIV, gpIX, PF4, NF-E2, MafG, and Rab27B. While Fli1 and GATA-1 synergistically regulate the expression of multiple megakaryocytic genes, the level of GATA-1 present on a subset of these promoters is reduced in vivo in the Fli1 ⌬CTA /Fli1 ⌬CTA mice, providing a possible mechanism for the impared transcription observed. Collectively, these data showed for the first time a hemostatic defect associated with the loss of a specific functional domain of the transcription factor Fli1 and suggest previously unknown in vivo roles in megakaryocytic cell differentiation.The Friend leukemia integration 1 (Fli1) gene is a member of the Ets gene family of transcription factors, which bind to the DNA consensus sequence GGA(A/T) (20,54,66). Fli1 is preferentially expressed in cells of hematopoietic lineages and vascular endothelial cells and has been shown to transactivate megakaryocytic (MK) genes, including those encoding GATA-1 (53, 66), glycoprotein IIb (gpIIb) (29,64,69), gpVI (19), gpIX, gpIb (14), and c-mpl (13, 23). It has been demonstrated that Fli1 expression promotes megakaryocytic differentiation in K562 cells (3). Viral integration and insertional activation of Fli-1 are associated with hematological cancers, including erythroleukemia induced by Friend murine leukemia virus (Friend-MuLV) (4), granulocytic leukemia induced by the Graffi virus (12), primitive stem cell tumors induced by the 10A1 isolate of MuLV (42), and non-T, non-B lymphomas induced by the Cas-Br virus (6). Overexpression of Fli1 results in an increased number of mature B cells, which have a reduced activation-induced apoptotic response compared to B cells from wild-type animals (68). Taken together, these results suggested that Fli1 plays significant roles in hematopoiesis. To clarify the physiological role of Fli1 in hematopoiesis, we (58) and others (18) generated mice with a targeted disruption of Fli1. Fli1 homozygous mutant (Fli1 Ϫ/Ϫ ) embryos showed hemorrhage from the dorsal aorta into the lumen of the neural tube and the ventricles of the brain beginning on embryonic day 11.0 (E11.0) and were dead on or before day E12.0. In addition, severe dysmegakaryopoiesis (18, 25) and vascular defects (18) wer...

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The ETS Family Member Tel Antagonizes the Fli-1 Phenotype in Hematopoietic Cells

Cited by 20 publications

References 23 publications

TEL2, an ETS Factor Expressed in Human Leukemia, Regulates Monocytic Differentiation of U937 Cells and Blocks the Inhibitory Effect of TEL1 on Ras-Induced Cellular Transformation

TEL2, an ETS Factor Expressed in Human Leukemia, Regulates Monocytic Differentiation of U937 Cells and Blocks the Inhibitory Effect of TEL1 on Ras-Induced Cellular Transformation

Biology of EWS/ETS fusions in Ewing's family tumors

Thrombocytopenia in Mice Lacking the Carboxy-Terminal Regulatory Domain of the Ets Transcription Factor Fli1

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