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PMID: 9874564 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

STAT3 is required for the gp130-mediated full activation of the c-myc gene.

The Journal of experimental medicine ·Vol. 189 ·No. 1 ·1999-01-04 ·Pages 63-73

Kiuchi N, Nakajima K, Ichiba M, Fukada T, Narimatsu M, Mizuno K, Hibi M, Hirano T

Abstract

The signal transducers and activators of transcription (STAT) family members have been implicated in regulating the growth, differentiation, and death of normal and transformed cells in response to either extracellular stimuli, including cytokines and growth factors, or intracellular tyrosine kinases. c-myc expression is coordinately regulated by multiple signals in these diverse cellular responses. We show that STAT3 mostly mediates the rapid activation of the c-myc gene upon stimulation of the interleukin (IL)-6 receptor or gp130, a signal transducing subunit of the receptor complexes for the IL-6 cytokine family. STAT3 does so most likely by binding to cis-regulatory region(s) of the c-myc gene. We show that STAT3 binds to a region overlapping with the E2F site in the c-myc promoter and this site is critical for the c-myc gene promoter- driven transcriptional activation by IL-6 or gp130 signals. This is the first identification of the linkage between a member of the STAT family and the c-myc gene activation, and also explains how the IL-6 family of cytokines is capable of inducing the expression of the c-myc gene.

MeSH Terms
Animals Antigens, CD/genetics B-Lymphocytes/metabolism Binding Sites/genetics Carrier Proteins Cell Cycle Proteins Cytokine Receptor gp130 DNA-Binding Proteins/analysis,genetics E2F Transcription Factors Gene Expression Regulation/genetics Genes, Reporter/genetics Genes, myc/genetics Membrane Glycoproteins/genetics Mice Nuclear Proteins/analysis Promoter Regions, Genetic/genetics RNA, Messenger/genetics Receptors, Granulocyte Colony-Stimulating Factor/genetics Receptors, Interleukin-6/genetics Retinoblastoma-Binding Protein 1 STAT3 Transcription Factor Signal Transduction Trans-Activators/genetics Transcription Factor DP1 Transcription Factors/genetics Transcription, Genetic/genetics Transcriptional Activation Transfection/genetics
Chemicals
Antigens, CD Arid4a protein, mouse Carrier Proteins Cell Cycle Proteins DNA-Binding Proteins E2F Transcription Factors Il6st protein, mouse Membrane Glycoproteins Nuclear Proteins RNA, Messenger Receptors, Granulocyte Colony-Stimulating Factor Receptors, Interleukin-6 Retinoblastoma-Binding Protein 1 STAT3 Transcription Factor Stat3 protein, mouse Trans-Activators Transcription Factor DP1 Transcription Factors Cytokine Receptor gp130
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Kiuchi N
Division of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
Nakajima K
Ichiba M
Fukada T
Narimatsu M
Mizuno K
Hibi M
Hirano T
References (87)
87 references, click to expand
  1. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3801-4 PMID: 9108058
  2. STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction.
    Immunity. 1997 Apr;6(4):449-57 PMID: 9133424
  3. Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs.
    Mol Cell Biol. 1997 Jun;17(6):3295-304 PMID: 9154828
  4. SH2 signaling in a lower eukaryote: a STAT protein that regulates stalk cell differentiation in dictyostelium.
    Cell. 1997 Jun 13;89(6):909-16 PMID: 9200609
  5. Functionally distinct isoforms of STAT5 are generated by protein processing.
    Immunity. 1997 Jun;6(6):691-701 PMID: 9208842
  6. Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet?
    Immunity. 1997 Jul;7(1):1-11 PMID: 9252115
  7. STATs and gene regulation.
    Science. 1997 Sep 12;277(5332):1630-5 PMID: 9287210
  8. Jaks and Stats in cytokine signaling.
    Stem Cells. 1997;15 Suppl 1:105-11; discussion 112 PMID: 9368330
  9. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F.
    Immunity. 1997 Nov;7(5):679-89 PMID: 9390691
  10. An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction.
    Immunity. 1997 Nov;7(5):691-701 PMID: 9390692
  11. Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells.
    Mol Cell Biol. 1998 Mar;18(3):1525-33 PMID: 9488469
  12. Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein.
    J Biol Chem. 1998 Mar 13;273(11):6132-8 PMID: 9497331
  13. Interleukin 6 and its receptor: ten years later.
    Int Rev Immunol. 1998;16(3-4):249-84 PMID: 9505191
  14. Stat proteins control lymphocyte proliferation by regulating p27Kip1 expression.
    Mol Cell Biol. 1998 Apr;18(4):1996-2003 PMID: 9528771
  15. Stat3 activation by Src induces specific gene regulation and is required for cell transformation.
    Mol Cell Biol. 1998 May;18(5):2545-52 PMID: 9566874
  16. Stat3 activation is required for cellular transformation by v-src.
    Mol Cell Biol. 1998 May;18(5):2553-8 PMID: 9566875
  17. Signaling mechanisms through gp130: a model of the cytokine system.
    Cytokine Growth Factor Rev. 1997 Dec;8(4):241-52 PMID: 9620640
  18. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor.
    Cell. 1983 Dec;35(3 Pt 2):603-10 PMID: 6606489
  19. Activation of c-myc gene transcription by Rous sarcoma virus infection.
    Jpn J Cancer Res. 1985 Feb;76(2):75-8 PMID: 2984071
  20. Identification of a cellular transcription factor involved in E1A trans-activation.
    Cell. 1986 Apr 25;45(2):219-28 PMID: 2938741
  21. Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter.
    Mol Cell Biol. 1993 May;13(5):3027-41 PMID: 8386318
  22. Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130.
    J Exp Med. 1994 Apr 1;179(4):1337-42 PMID: 8145045
  23. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
    Science. 1994 Jun 3;264(5164):1415-21 PMID: 8197455
  24. Interleukin-3-dependent expression of the c-myc and c-fos proto-oncogenes in hemopoietic cell lines.
    EMBO J. 1986 Feb;5(2):317-23 PMID: 3086085
  25. Recombinant interleukin 2 regulates levels of c-myc mRNA in a cloned murine T lymphocyte.
    Mol Cell Biol. 1985 Dec;5(12):3361-8 PMID: 3879814
  26. Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription.
    Mol Cell Biol. 1986 Apr;6(4):1050-7 PMID: 2431274
  27. Modulation of proto-oncogene expression by colony stimulating factors.
    Biochem Biophys Res Commun. 1987 Nov 13;148(3):1001-8 PMID: 2446603
  28. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.
    Nature. 1988 Mar 3;332(6159):83-5 PMID: 3258060
  29. Interleukin-6 (B-cell stimulatory factor 2)-dependent growth of a Lennert's lymphoma-derived T-cell line (KT-3).
    Blood. 1988 Nov;72(5):1826-8 PMID: 3052631
  30. Induction of c-fos and c-myc expression during B cell activation by IL-4 and immunoglobulin binding ligands.
    J Immunol. 1989 Aug 1;143(3):1032-9 PMID: 2787345
  31. Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl.
    Mol Cell Biol. 1989 Dec;9(12):5685-95 PMID: 2555703
  32. Interleukin-6 stimulates c-myc expression and proliferation of cultured vascular smooth muscle cells.
    Biochem Int. 1990;20(3):445-53 PMID: 2346497
  33. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors.
    Science. 1995 Mar 3;267(5202):1349-53 PMID: 7871433
  34. Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity.
    Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3041-5 PMID: 7708771
  35. Cytokine signaling through nonreceptor protein tyrosine kinases.
    Science. 1995 Apr 14;268(5208):251-5 PMID: 7716517
  36. Jaks and Stats in signaling by the cytokine receptor superfamily.
    Trends Genet. 1995 Feb;11(2):69-74 PMID: 7716810
  37. A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain.
    Genes Dev. 1995 Apr 15;9(8):984-94 PMID: 7774815
  38. Mechanism of active transcriptional repression by the retinoblastoma protein.
    Nature. 1995 Jun 29;375(6534):812-5 PMID: 7596417
  39. Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor: possible link with the c-myc induction pathway.
    Immunity. 1995 Jan;2(1):89-100 PMID: 7600304
  40. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein.
    Science. 1995 Jul 7;269(5220):81-3 PMID: 7541555
  41. Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor.
    J Biol Chem. 1995 Sep 1;270(35):20775-80 PMID: 7657660
  42. A role for the adenovirus inducible E2F transcription factor in a proliferation dependent signal transduction pathway.
    EMBO J. 1990 Jul;9(7):2179-84 PMID: 2141565
  43. E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor.
    Proc Natl Acad Sci U S A. 1989 May;86(10):3594-8 PMID: 2524830
  44. Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma.
    Mol Cell Biol. 1991 Mar;11(3):1409-18 PMID: 1705005
  45. The E2F transcription factor is a cellular target for the RB protein.
    Cell. 1991 Jun 14;65(6):1053-61 PMID: 1828392
  46. Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling.
    Nature. 1991 Sep 26;353(6342):361-3 PMID: 1833648
  47. Interleukin-7 induces N-myc and c-myc expression in normal precursor B lymphocytes.
    Genes Dev. 1992 Jan;6(1):61-70 PMID: 1730410
  48. E2F transcription factor is a target for the RB protein and the cyclin A protein.
    Cold Spring Harb Symp Quant Biol. 1991;56:157-62 PMID: 1840249
  49. Retinoblastoma protein switches the E2F site from positive to negative element.
    Nature. 1992 Jul 16;358(6383):259-61 PMID: 1321348
  50. NF-kappa B-like factors mediate interleukin 1 induction of c-myc gene transcription in fibroblasts.
    J Exp Med. 1992 Sep 1;176(3):787-92 PMID: 1512542
  51. Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation.
    EMBO J. 1992 Oct;11(10):3541-9 PMID: 1396555
  52. c-myc gene activation as a permanent trait of RSV-infected quail cells.
    Int J Cancer. 1993 Apr 1;53(6):983-7 PMID: 8386142
  53. The Janus protein tyrosine kinase family and its role in cytokine signaling.
    Adv Immunol. 1995;60:1-35 PMID: 8607368
  54. STAT activation by epidermal growth factor (EGF) and amphiregulin. Requirement for the EGF receptor kinase but not for tyrosine phosphorylation sites or JAK1.
    J Biol Chem. 1996 Apr 19;271(16):9185-8 PMID: 8621573
  55. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1.
    Science. 1996 May 3;272(5262):719-22 PMID: 8614832
  56. Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation.
    EMBO J. 1996 Apr 1;15(7):1557-65 PMID: 8612579
  57. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells.
    Immunity. 1996 Mar;4(3):313-9 PMID: 8624821
  58. JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells.
    J Biol Chem. 1996 May 24;271(21):12681-6 PMID: 8647882
  59. Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation.
    EMBO J. 1996 May 15;15(10):2425-33 PMID: 8665850
  60. IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s).
    Oncogene. 1996 Feb 1;12(3):547-54 PMID: 8637711
  61. Activation and association of Stat3 with Src in v-Src-transformed cell lines.
    Mol Cell Biol. 1996 Apr;16(4):1595-603 PMID: 8657134
  62. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins.
    Mol Cell Biol. 1996 Apr;16(4):1759-69 PMID: 8657151
  63. Proteins of the Myc network: essential regulators of cell growth and differentiation.
    Adv Cancer Res. 1996;68:109-82 PMID: 8712067
  64. Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells.
    Leukemia. 1995 Sep;9(9):1499-507 PMID: 7658719
  65. Critical role of the interleukin 2 (IL-2) receptor gamma-chain-associated Jak3 in the IL-2-induced c-fos and c-myc, but not bcl-2, gene induction.
    Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8724-8 PMID: 7568005
  66. ERM, a PEA3 subfamily of Ets transcription factors, can cooperate with c-Jun.
    J Biol Chem. 1995 Oct 6;270(40):23795-800 PMID: 7559555
  67. Jak-STAT signaling induced by the v-abl oncogene.
    Science. 1995 Sep 29;269(5232):1875-7 PMID: 7569929
  68. v-Abl activates c-myc transcription through the E2F site.
    Mol Cell Biol. 1995 Dec;15(12):6535-44 PMID: 8524218
  69. Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src.
    Nature. 1995 Nov 30;378(6556):509-12 PMID: 7477410
  70. Essential role of Stat6 in IL-4 signalling.
    Nature. 1996 Apr 18;380(6575):627-30 PMID: 8602263
  71. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene.
    Nature. 1996 Apr 18;380(6575):630-3 PMID: 8602264
  72. Identification of a Stat gene that functions in Drosophila development.
    Cell. 1996 Feb 9;84(3):421-30 PMID: 8608596
  73. Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation.
    Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2077-82 PMID: 8700888
  74. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells.
    EMBO J. 1996 Jul 15;15(14):3651-8 PMID: 8670868
  75. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.
    Nature. 1996 Jul 11;382(6587):171-4 PMID: 8700208
  76. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice.
    Nature. 1996 Jul 11;382(6587):174-7 PMID: 8700209
  77. Cdc25 cell-cycle phosphatase as a target of c-myc.
    Nature. 1996 Aug 8;382(6591):511-7 PMID: 8700224
  78. Unique signal transduction of Eyk: constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase.
    EMBO J. 1996 Sep 2;15(17):4515-25 PMID: 8887543
  79. Naturally occurring dominant negative variants of Stat5.
    Mol Cell Biol. 1996 Nov;16(11):6141-8 PMID: 8887644
  80. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice.
    Science. 1996 Nov 22;274(5291):1379-83 PMID: 8910279
  81. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis.
    Immunity. 1996 Nov;5(5):449-60 PMID: 8934572
  82. In vitro activation of Stat3 by epidermal growth factor receptor kinase.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13704-8 PMID: 8942998
  83. The JAK-STAT pathway in Drosophila.
    Trends Genet. 1997 Mar;13(3):105-10 PMID: 9066269
  84. Induction of c-myc transcription by the v-Abl tyrosine kinase requires Ras, Raf1, and cyclin-dependent kinases.
    Genes Dev. 1997 Mar 1;11(5):654-62 PMID: 9119229
  85. The p120-v-Abl protein interacts with E2F-1 and regulates E2F-1 transcriptional activity.
    J Biol Chem. 1997 Apr 4;272(14):8905-11 PMID: 9083010
  86. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression.
    J Interferon Cytokine Res. 1997 Mar;17(3):121-34 PMID: 9085936
  87. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3627-32 PMID: 9108028
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.189.1.63
Published
1999-01-04
Pages
63-73
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC1887683
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.189.1.63 PMC Full Text View journal details
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