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PMID: 12556498 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Functional cross-antagonism between transcription factors FLI-1 and EKLF.

Molecular and cellular biology ·Vol. 23 ·No. 4 ·2003-02-00 ·Pages 1390-402

Starck J, Cohet N, Gonnet C, Sarrazin S, Doubeikovskaia Z, Doubeikovski A, Verger A, Duterque-Coquillaud M, Morle F

Abstract

FLI-1 is an ETS family transcription factor which is overexpressed in Friend erythroleukemia and contributes to the blockage of differentiation of erythroleukemic cells. We show here that FLI-1 represses the transcriptional activity of the beta-globin gene promoter in MEL cells and interacts with two of its critical transactivators, GATA-1 and EKLF. Unexpectedly, FLI-1 enhances the stimulating activity of GATA-1 on a GATA-1-responsive promoter but represses that of EKLF on beta-globin and an EKLF-responsive artificial promoters. This repressive effect of FLI-1 requires the ETS DNA binding domain and its association with either the N- or C-terminal domain, which themselves interact with EKLF but not with GATA-1. Furthermore, the FLI-1 ETS domain alone behaves as an autonomous repression domain when linked to the Gal4 DNA binding domain. Taken together, these data indicate that FLI-1 represses EKLF-dependent transcription due to the repression activity of its ETS domain and its indirect recruitment to erythroid promoters by protein-protein interaction with EKLF. Reciprocally, we also show that EKLF itself represses the FLI-1-dependent megakaryocytic GPIX gene promoter, thus further suggesting that functional cross-antagonism between FLI-1 and EKLF might be involved in the control of the erythrocytic versus megakaryocytic differentiation of bipotential progenitors.

MeSH Terms
Acetamides/pharmacology Animals Base Sequence Cell Differentiation/physiology Cells, Cultured DNA/metabolism DNA-Binding Proteins/genetics,metabolism Erythrocytes/cytology,physiology Erythroid-Specific DNA-Binding Factors GATA1 Transcription Factor Globins/drug effects,genetics Kruppel-Like Transcription Factors Mice Molecular Sequence Data Platelet Glycoprotein GPIb-IX Complex/genetics Promoter Regions, Genetic Protein Structure, Tertiary Proto-Oncogene Protein c-fli-1 Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-ets Recombinant Proteins/genetics,metabolism Trans-Activators/genetics,metabolism Transcription Factors/genetics,metabolism Transcription, Genetic
Chemicals
Acetamides DNA-Binding Proteins Erythroid-Specific DNA-Binding Factors Fli1 protein, mouse GATA1 Transcription Factor Gata1 protein, mouse Kruppel-Like Transcription Factors Platelet Glycoprotein GPIb-IX Complex Proto-Oncogene Protein c-fli-1 Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets Recombinant Proteins Trans-Activators Transcription Factors erythroid Kruppel-like factor Globins DNA hexamethylene bisacetamide
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Starck Joëlle
Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, 69622 Villeurbanne, France.
Cohet Nathalie
Gonnet Colette
Sarrazin Sandrine
Doubeikovskaia Zina
Doubeikovski Alexandre
Verger Alexis
Duterque-Coquillaud Martine
Morle François
References (80)
80 references, click to expand
  1. Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification.
    Science. 2000 Nov 10;290(5494):1127-31 PMID: 11073444
  2. The role of Fli-1 in normal cell function and malignant transformation.
    Oncogene. 2000 Dec 18;19(55):6482-9 PMID: 11175364
  3. PU.1, a shared transcriptional regulator of lymphoid and myeloid cell fates.
    Cold Spring Harb Symp Quant Biol. 1999;64:13-20 PMID: 11232277
  4. Site-specific acetylation by p300 or CREB binding protein regulates erythroid Krüppel-like factor transcriptional activity via its interaction with the SWI-SNF complex.
    Mol Cell Biol. 2001 Apr;21(7):2413-22 PMID: 11259590
  5. Diversification of haematopoietic stem cells to specific lineages.
    Nat Rev Genet. 2000 Oct;1(1):57-64 PMID: 11262875
  6. Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow.
    Blood. 1996 Aug 15;88(4):1284-96 PMID: 8695846
  7. Increased expression of the ETS-related transcription factor FLI-1/ERGB correlates with and can induce the megakaryocytic phenotype.
    Cell Growth Differ. 1996 Nov;7(11):1525-34 PMID: 8930402
  8. Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation.
    Oncogene. 1997 Jan 9;14(1):123-31 PMID: 9010239
  9. Overexpression of PU.1 induces growth and differentiation inhibition and apoptotic cell death in murine erythroleukemia cells.
    Blood. 1997 Feb 15;89(4):1383-93 PMID: 9028962
  10. Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias.
    Oncogene. 1997 Mar 20;14(11):1259-68 PMID: 9178886
  11. A shortened life span of EKLF-/- adult erythrocytes, due to a deficiency of beta-globin chains, is ameliorated by human gamma-globin chains.
    Blood. 1997 Aug 1;90(3):1291-9 PMID: 9242564
  12. Cooperation of Spi-1/PU.1 with an activated erythropoietin receptor inhibits apoptosis and Epo-dependent differentiation in primary erythroblasts and induces their Kit ligand-dependent proliferation.
    EMBO J. 1997 Sep 15;16(18):5639-53 PMID: 9312023
  13. Production and characterization of mouse monoclonal antibodies to wild-type and oncogenic FLI-1 proteins.
    Hybridoma. 1997 Oct;16(5):457-64 PMID: 9388029
  14. Functional interference between retinoic acid or steroid hormone receptors and the oncoprotein Fli-1.
    Oncogene. 1997 Dec 18;15(25):3067-82 PMID: 9444955
  15. The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS.
    J Biol Chem. 1998 Feb 27;273(9):4838-42 PMID: 9478924
  16. Erythroid Krüppel-like factor (EKLF) is active in primitive and definitive erythroid cells and is required for the function of 5'HS3 of the beta-globin locus control region.
    EMBO J. 1998 Apr 15;17(8):2334-41 PMID: 9545245
  17. Molecular and transcriptional regulation of megakaryocyte differentiation.
    Stem Cells. 2001;19(5):397-407 PMID: 11553848
  18. PU.1 and hematopoiesis: lessons learned from gene targeting experiments.
    Semin Immunol. 1998 Apr;10(2):111-8 PMID: 9618756
  19. Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation.
    Oncogene. 1998 Jun 11;16(23):2989-95 PMID: 9662331
  20. Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains.
    Oncogene. 1998 Jun 25;16(25):3261-8 PMID: 9681824
  21. A transcription factor party during blood cell differentiation.
    Curr Opin Genet Dev. 1998 Oct;8(5):545-51 PMID: 9794826
  22. Spi-1/PU.1 proto-oncogene induces opposite effects on monocytic and erythroid differentiation of K562 cells.
    Biochem Biophys Res Commun. 1998 Nov 18;252(2):383-91 PMID: 9826539
  23. Reduction of DNA binding activity of the GATA-1 transcription factor in the apoptotic process induced by overexpression of PU.1 in murine erythroleukemia cells.
    Exp Cell Res. 1998 Nov 25;245(1):186-94 PMID: 9828115
  24. Spi-1/PU.1 is a positive regulator of the Fli-1 gene involved in inhibition of erythroid differentiation in friend erythroleukemic cell lines.
    Mol Cell Biol. 1999 Jan;19(1):121-35 PMID: 9858537
  25. Physical and functional interactions between the transcription factor PU.1 and the coactivator CBP.
    Oncogene. 1999 Feb 18;18(7):1495-501 PMID: 10050886
  26. FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts.
    Oncogene. 1999 Feb 25;18(8):1597-608 PMID: 10102630
  27. Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1.
    Blood. 1999 Apr 15;93(8):2637-44 PMID: 10194443
  28. Unexpected and coordinated expression of Spi-1, Fli-1, and megakaryocytic genes in four Epo-dependent cell lines established from transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen.
    Exp Hematol. 1999 Apr;27(4):630-41 PMID: 10210321
  29. Fli-1, an Ets-related transcription factor, regulates erythropoietin-induced erythroid proliferation and differentiation: evidence for direct transcriptional repression of the Rb gene during differentiation.
    Mol Cell Biol. 1999 Jun;19(6):4452-64 PMID: 10330185
  30. Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells.
    Genes Dev. 1999 Jun 1;13(11):1398-411 PMID: 10364157
  31. Histone deacetylase 1 can repress transcription by binding to Sp1.
    Mol Cell Biol. 1999 Aug;19(8):5504-11 PMID: 10409740
  32. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1.
    Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8705-10 PMID: 10411939
  33. The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis.
    Cell Death Differ. 1999 Jul;6(7):599-608 PMID: 10453070
  34. Temporal recruitment of the mSin3A-histone deacetylase corepressor complex to the ETS domain transcription factor Elk-1.
    Mol Cell Biol. 2001 Apr;21(8):2802-14 PMID: 11283259
  35. Unanticipated repression function linked to erythroid Krüppel-like factor.
    Mol Cell Biol. 2001 May;21(9):3118-25 PMID: 11287616
  36. Transcription factors: bound to activate or repress.
    Trends Biochem Sci. 2001 Apr;26(4):211-3 PMID: 11295539
  37. Novel transactivation domain in erythroid Kruppel-like factor (EKLF).
    J Biol Chem. 2001 Mar 16;276(11):8239-43 PMID: 11092887
  38. Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway.
    J Biol Chem. 2001 Jun 15;276(24):20839-48 PMID: 11278621
  39. EWS/FLI alters 5'-splice site selection.
    J Biol Chem. 2001 Jun 22;276(25):22317-22 PMID: 11301318
  40. Regulation of transcription factor YY1 by acetylation and deacetylation.
    Mol Cell Biol. 2001 Sep;21(17):5979-91 PMID: 11486036
  41. Defective megakaryopoiesis and abnormal erythroid development in Fli-1 gene-targeted mice.
    Int J Hematol. 2001 Jun;73(4):463-8 PMID: 11503960
  42. Inducible expression of the megakaryocyte-specific gene glycoprotein IX is mediated through an Ets binding site and involves upstream activation of extracellular signal-regulated kinase.
    Cell Growth Differ. 2001 Aug;12(8):435-45 PMID: 11504709
  43. The POU domain factor Skin-1a represses the keratin 14 promoter independent of DNA binding. A possible role for interactions between Skn-1a and CREB-binding protein/p300.
    J Biol Chem. 2001 Aug 31;276(35):33036-44 PMID: 11429405
  44. Hematopoietic development: a balancing act.
    Curr Opin Genet Dev. 2001 Oct;11(5):513-9 PMID: 11532392
  45. Histone deacetylase 3 associates with and represses the transcription factor GATA-2.
    Blood. 2001 Oct 1;98(7):2116-23 PMID: 11567998
  46. Alterations of the phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways in the erythropoietin-independent Spi-1/PU.1 transgenic proerythroblasts.
    Blood. 2001 Oct 15;98(8):2372-81 PMID: 11588033
  47. In vivo complex formation of PU.1 with HDAC1 associated with PU.1-mediated transcriptional repression.
    Oncogene. 2001 Sep 20;20(42):6039-47 PMID: 11593411
  48. Identification of interaction partners for two closely-related members of the ETS protein family, FLI and ERG.
    Gene. 2001 Aug 22;274(1-2):169-77 PMID: 11675009
  49. Purification of human recombinant GATA-1 from bacteria: implication for protein-protein interaction studies.
    Protein Expr Purif. 2001 Dec;23(3):426-31 PMID: 11722179
  50. Direct regulation of BCL-2 by FLI-1 is involved in the survival of FLI-1-transformed erythroblasts.
    EMBO J. 2002 Feb 15;21(4):694-703 PMID: 11847117
  51. Oncogene cooperativity in Friend erythroleukemia: erythropoietin receptor activation by the env gene of SFFV leads to transcriptional upregulation of PU.1, independent of SFFV proviral insertion.
    Oncogene. 2002 Feb 14;21(8):1272-84 PMID: 11850847
  52. Interaction between the hematopoietic Ets transcription factor Spi-B and the coactivator CREB-binding protein associated with negative cross-talk with c-Myb.
    Cell Growth Differ. 2002 Feb;13(2):69-75 PMID: 11864910
  53. Inhibition of CBP-mediated protein acetylation by the Ets family oncoprotein PU.1.
    Mol Cell Biol. 2002 Jun;22(11):3729-43 PMID: 11997509
  54. Transcriptional regulation of erythropoiesis: an affair involving multiple partners.
    Oncogene. 2002 May 13;21(21):3368-76 PMID: 12032775
  55. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias.
    Nature. 1988 Jan 21;331(6153):277-80 PMID: 2827041
  56. The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites.
    EMBO J. 1990 Jul;9(7):2241-6 PMID: 2162765
  57. Transcriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1.
    Genes Dev. 1990 Nov;4(11):1886-98 PMID: 2276623
  58. Friend virus-induced erythroleukemia and the multistage nature of cancer.
    Cell. 1991 Sep 6;66(5):831-4 PMID: 1889087
  59. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins.
    Mol Cell Biol. 1993 May;13(5):2776-86 PMID: 7682653
  60. The erythroid Krüppel-like factor transactivation domain is a critical component for cell-specific inducibility of a beta-globin promoter.
    Mol Cell Biol. 1995 Feb;15(2):852-60 PMID: 7823951
  61. Role of erythroid Kruppel-like factor in human gamma- to beta-globin gene switching.
    J Biol Chem. 1995 Jan 27;270(4):1955-9 PMID: 7829533
  62. A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins.
    Nucleic Acids Res. 1995 May 25;23(10):1686-90 PMID: 7784172
  63. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes.
    Mol Cell Biol. 1995 Dec;15(12):6961-70 PMID: 8524263
  64. Spi-1/PU.1 transgenic mice develop multistep erythroleukemias.
    Mol Cell Biol. 1996 May;16(5):2453-63 PMID: 8628313
  65. Functional interaction of GATA1 with erythroid Krüppel-like factor and Sp1 at defined erythroid promoters.
    Blood. 1996 Mar 1;87(5):1793-801 PMID: 8634425
  66. The transcription factor Spi-1/PU.1 binds RNA and interferes with the RNA-binding protein p54nrb.
    J Biol Chem. 1996 May 10;271(19):11177-81 PMID: 8626664
  67. Analysis of the thrombopoietin receptor (MPL) promoter implicates GATA and Ets proteins in the coregulation of megakaryocyte-specific genes.
    Blood. 1996 Jun 1;87(11):4678-85 PMID: 8639837
  68. Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia.
    Mol Cell Biol. 1996 Jun;16(6):2708-18 PMID: 8649378
  69. Analysis of the megakaryocyte glycoprotein IX promoter identifies positive and negative regulatory domains and functional GATA and Ets sites.
    J Biol Chem. 1996 Aug 2;271(31):18554-60 PMID: 8702504
  70. Transforming activity of EWS/FLI is not strictly dependent upon DNA-binding activity.
    Oncogene. 1999 Sep 30;18(40):5592-7 PMID: 10523836
  71. FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells.
    Leukemia. 2000 Mar;14(3):439-45 PMID: 10720139
  72. GATA-1 interacts with the myeloid PU.1 transcription factor and represses PU.1-dependent transcription.
    Blood. 2000 Apr 15;95(8):2543-51 PMID: 10753833
  73. Negative and translation termination-dependent positive control of FLI-1 protein synthesis by conserved overlapping 5' upstream open reading frames in Fli-1 mRNA.
    Mol Cell Biol. 2000 May;20(9):2959-69 PMID: 10757781
  74. mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity.
    J Biol Chem. 2000 May 19;275(20):15594-9 PMID: 10748098
  75. Epo regulates erythroid proliferation and differentiation through distinct signaling pathways: implication for erythropoiesis and Friend virus-induced erythroleukemia.
    Oncogene. 2000 May 4;19(19):2296-304 PMID: 10822380
  76. Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor.
    Mol Cell Biol. 2000 Aug;20(15):5643-52 PMID: 10891501
  77. Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia.
    Immunity. 2000 Aug;13(2):167-77 PMID: 10981960
  78. Biologic significance of GATA-1 activities in Ras-mediated megakaryocytic differentiation of hematopoietic cell lines.
    Blood. 2000 Oct 1;96(7):2440-50 PMID: 11001896
  79. PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding.
    Blood. 2000 Oct 15;96(8):2641-8 PMID: 11023493
  80. SPI-1 transforming properties depend upon specifically activated forms of the EPOR.
    Oncogene. 2000 Oct 19;19(44):5106-10 PMID: 11042699
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.4.1390-1402.2003
Published
2003-02-00
Pages
1390-402
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC141137
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.23.4.1390-1402.2003 PMC Full Text View journal details
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