CoChat
Sign Up
Cited by 565Cytokine Signaling Pathways and InteractionsAcute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processes

A central role for Stat3 in IL‐6‐induced regulation of growth and differentiation in M1 leukemia cells.

Open access
Nakajima, K., Yamanaka, Y., Nakae, K., Kojima, H., Ichiba, M., Kiuchi, N., Kitaoka, T., Fukada, T. +2 more·1996·The EMBO Journal
DOI 10.1002/j.1460-2075.1996.tb00734.xPMC PMC451995
Open this paper in CoChat — free account

Abstract

Interleukin-6 (IL-6) induces either differentiation or growth of a variety of cells. Little is known about the molecular basis of this cellular decision. The family of signal transducer and activator of transcription (Stat) proteins are involved in signaling through a variety of cytokine and growth factor receptors, although their biological roles have not been established. To address whether Stat proteins play roles in IL-6-induced growth or differentiation, we introduced two types of mutant Stat3 acting in a dominant-negative manner into M1 leukemic cells which respond to IL-6 with growth arrest and terminal differentiation. We show that dominant-negative forms of Stat3 inhibited both IL-6-induced growth arrest at G(0)/G1 and macrophage differentiation in the M1 transformants. Blocking of Stat activation resulted in inhibition of IL-6-induced repression of c-myb and c-myc. Furthermore, IL-6 enhanced the growth of M1 cells primarily through shortening the length of the G1 period when Stat3 was suppressed. Thus IL-6 generates both growth-enhancing signals and growth arrest- and differentiation-inducing signals at the same time. Stat3 may be a key molecule which determines the cellular decision from cell growth to differentiation in M1 cells.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/j.1460-2075.1996.tb00734.x

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Phosphorylation of gp130 leads to dimerization of gp130 and activation of STAT1 and STAT3 as well as the SHP2-RAS-MAPK pathway.

    “The phosphorylation of gp130 leads to dimerization of gp130 and activation of STAT1 and STAT3 as well as the SHP2-RAS-MAPK pathway (where SHP2 is Src homology 2 [SH2] domain-containing protein tyrosine phosphatase) (20-22).”

    From The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury (2005) · cites this paper as [21]

    The Abstract describes IL-6-induced Stat activation, particularly Stat3, in M1 leukemia cells. The available passages do not establish that gp130 phosphorylation causes gp130 dimerization or activates STAT1 and the SHP2–RAS–MAPK pathway; those parts of the attributed claim are unsupported. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 46

  1. Akira S., Nishio Y., Inoue M., Wang X. J., Wei S., Matsusaka T., Yoshida K., Sudo T., Naruto M., Kishimoto T. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell. 1994 Apr 8;77(1):63–71. doi: 10.1016/0092-8674(94)90235-6. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  2. Bazan J. F. A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL-6 receptors, and the p75 IL-2 receptor beta-chain. Biochem Biophys Res Commun. 1989 Oct 31;164(2):788–795. doi: 10.1016/0006-291x(89)91528-3. [DOI] [PubMed] [Google Scholar] · DOI
  3. Coffer P., Lutticken C., van Puijenbroek A., Klop-de Jonge M., Horn F., Kruijer W. Transcriptional regulation of the junB promoter: analysis of STAT-mediated signal transduction. Oncogene. 1995 Mar 2;10(5):985–994. [PubMed] [Google Scholar]
  4. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  5. Fujitani Y., Nakajima K., Kojima H., Nakae K., Takeda T., Hirano T. Transcriptional activation of the IL-6 response element in the junB promoter is mediated by multiple Stat family proteins. Biochem Biophys Res Commun. 1994 Jul 29;202(2):1181–1187. doi: 10.1006/bbrc.1994.2053. [DOI] [PubMed] [Google Scholar] · DOI
  6. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar] · DOI
  7. Guschin D., Rogers N., Briscoe J., Witthuhn B., Watling D., Horn F., Pellegrini S., Yasukawa K., Heinrich P., Stark G. R. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 1995 Apr 3;14(7):1421–1429. doi: 10.1002/j.1460-2075.1995.tb07128.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  8. Harroch S., Revel M., Chebath J. Interleukin-6 signaling via four transcription factors binding palindromic enhancers of different genes. J Biol Chem. 1994 Oct 21;269(42):26191–26195. [PubMed] [Google Scholar]
  9. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar] · DOI
  10. Hibi M., Nakajima K., Hirano T. IL-6 cytokine family and signal transduction: a model of the cytokine system. J Mol Med (Berl) 1996 Jan;74(1):1–12. doi: 10.1007/BF00202068. [DOI] [PubMed] [Google Scholar] · DOI
  11. Hoffman-Liebermann B., Liebermann D. A. Interleukin-6- and leukemia inhibitory factor-induced terminal differentiation of myeloid leukemia cells is blocked at an intermediate stage by constitutive c-myc. Mol Cell Biol. 1991 May;11(5):2375–2381. doi: 10.1128/mcb.11.5.2375-2381.1991. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  12. Hoffman-Liebermann B., Liebermann D. A. Suppression of c-myc and c-myb is tightly linked to terminal differentiation induced by IL6 or LIF and not growth inhibition in myeloid leukemia cells. Oncogene. 1991 Jun;6(6):903–909. [PubMed] [Google Scholar]
  13. Horvath C. M., Wen Z., Darnell J. E., Jr A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev. 1995 Apr 15;9(8):984–994. doi: 10.1101/gad.9.8.984. [DOI] [PubMed] [Google Scholar] · DOI
  14. Ihle J. N., Kerr I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 1995 Feb;11(2):69–74. doi: 10.1016/s0168-9525(00)89000-9. [DOI] [PubMed] [Google Scholar] · DOI
  15. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson D. J. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. doi: 10.1016/0092-8674(92)90634-o. [DOI] [PubMed] [Google Scholar] · DOI
  16. Kojima H., Nakajima K., Hirano T. 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):547–554. [PubMed] [Google Scholar]
  17. Levy N., Yonish-Rouach E., Oren M., Kimchi A. Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression. Mol Cell Biol. 1993 Dec;13(12):7942–7952. doi: 10.1128/mcb.13.12.7942-7952.1993. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. Liebermann D. A., Hoffman B., Steinman R. A. Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways. Oncogene. 1995 Jul 6;11(1):199–210. [PubMed] [Google Scholar]
  19. Matsuda T., Yamanaka Y., Hirano T. Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells. Biochem Biophys Res Commun. 1994 Apr 29;200(2):821–828. doi: 10.1006/bbrc.1994.1525. [DOI] [PubMed] [Google Scholar] · DOI
  20. Melamed D., Tiefenbrun N., Yarden A., Kimchi A. Interferons and interleukin-6 suppress the DNA-binding activity of E2F in growth-sensitive hematopoietic cells. Mol Cell Biol. 1993 Sep;13(9):5255–5265. doi: 10.1128/mcb.13.9.5255-5265.1993. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  21. Miyaura C., Onozaki K., Akiyama Y., Taniyama T., Hirano T., Kishimoto T., Suda T. Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1). FEBS Lett. 1988 Jul 4;234(1):17–21. doi: 10.1016/0014-5793(88)81293-6. [DOI] [PubMed] [Google Scholar] · DOI
  22. Murakami M., Hibi M., Nakagawa N., Nakagawa T., Yasukawa K., Yamanishi K., Taga T., Kishimoto T. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993 Jun 18;260(5115):1808–1810. doi: 10.1126/science.8511589. [DOI] [PubMed] [Google Scholar] · DOI
  23. Murakami M., Narazaki M., Hibi M., Yawata H., Yasukawa K., Hamaguchi M., Taga T., Kishimoto T. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11349–11353. doi: 10.1073/pnas.88.24.11349. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  24. Nakajima K., Kusafuka T., Takeda T., Fujitani Y., Nakae K., Hirano T. 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):3027–3041. doi: 10.1128/mcb.13.5.3027-3041.1993. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. Nakajima K., Matsuda T., Fujitani Y., Kojima H., Yamanaka Y., Nakae K., Takeda T., Hirano T. Signal transduction through IL-6 receptor: involvement of multiple protein kinases, stat factors, and a novel H7-sensitive pathway. Ann N Y Acad Sci. 1995 Jul 21;762:55–70. doi: 10.1111/j.1749-6632.1995.tb32314.x. [DOI] [PubMed] [Google Scholar] · DOI
  26. Nakajima K., Wall R. Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma. Mol Cell Biol. 1991 Mar;11(3):1409–1418. doi: 10.1128/mcb.11.3.1409-1418.1991. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  27. Paonessa G., Graziani R., De Serio A., Savino R., Ciapponi L., Lahm A., Salvati A. L., Toniatti C., Ciliberto G. Two distinct and independent sites on IL-6 trigger gp 130 dimer formation and signalling. EMBO J. 1995 May 1;14(9):1942–1951. doi: 10.1002/j.1460-2075.1995.tb07186.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  28. Pearse R. N., Feinman R., Shuai K., Darnell J. E., Jr, Ravetch J. V. Interferon gamma-induced transcription of the high-affinity Fc receptor for IgG requires assembly of a complex that includes the 91-kDa subunit of transcription factor ISGF3. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4314–4318. doi: 10.1073/pnas.90.9.4314. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  29. Pennica D., Shaw K. J., Swanson T. A., Moore M. W., Shelton D. L., Zioncheck K. A., Rosenthal A., Taga T., Paoni N. F., Wood W. I. Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem. 1995 May 5;270(18):10915–10922. doi: 10.1074/jbc.270.18.10915. [DOI] [PubMed] [Google Scholar] · DOI
  30. Qui M. S., Green S. H. PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. Neuron. 1992 Oct;9(4):705–717. doi: 10.1016/0896-6273(92)90033-a. [DOI] [PubMed] [Google Scholar] · DOI
  31. Resnitzky D., Tiefenbrun N., Berissi H., Kimchi A. Interferons and interleukin 6 suppress phosphorylation of the retinoblastoma protein in growth-sensitive hematopoietic cells. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):402–406. doi: 10.1073/pnas.89.1.402. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. Sadowski H. B., Shuai K., Darnell J. E., Jr, Gilman M. Z. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science. 1993 Sep 24;261(5129):1739–1744. doi: 10.1126/science.8397445. [DOI] [PubMed] [Google Scholar] · DOI
  33. Selvakumaran M., Liebermann D. A., Hoffman-Liebermann B. Deregulated c-myb disrupts interleukin-6- or leukemia inhibitory factor-induced myeloid differentiation prior to c-myc: role in leukemogenesis. Mol Cell Biol. 1992 Jun;12(6):2493–2500. doi: 10.1128/mcb.12.6.2493-2500.1992. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  34. Shabo Y., Lotem J., Rubinstein M., Revel M., Clark S. C., Wolf S. F., Kamen R., Sachs L. The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood. 1988 Dec;72(6):2070–2073. [PubMed] [Google Scholar]
  35. Stahl N., Boulton T. G., Farruggella T., Ip N. Y., Davis S., Witthuhn B. A., Quelle F. W., Silvennoinen O., Barbieri G., Pellegrini S. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994 Jan 7;263(5143):92–95. doi: 10.1126/science.8272873. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  36. Stahl N., Farruggella T. J., Boulton T. G., Zhong Z., Darnell J. E., Jr, Yancopoulos G. D. Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science. 1995 Mar 3;267(5202):1349–1353. doi: 10.1126/science.7871433. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  37. Steinman R. A., Hoffman B., Iro A., Guillouf C., Liebermann D. A., el-Houseini M. E. Induction of p21 (WAF-1/CIP1) during differentiation. Oncogene. 1994 Nov;9(11):3389–3396. [PubMed] [Google Scholar]
  38. Traverse S., Gomez N., Paterson H., Marshall C., Cohen P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J. 1992 Dec 1;288(Pt 2):351–355. doi: 10.1042/bj2880351. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  39. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  40. Wegenka U. M., Buschmann J., Lütticken C., Heinrich P. C., Horn F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol Cell Biol. 1993 Jan;13(1):276–288. doi: 10.1128/mcb.13.1.276-288.1993. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  41. Wegenka U. M., Lütticken C., Buschmann J., Yuan J., Lottspeich F., Müller-Esterl W., Schindler C., Roeb E., Heinrich P. C., Horn F. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. Mol Cell Biol. 1994 May;14(5):3186–3196. doi: 10.1128/mcb.14.5.3186-3196.1994. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  42. Yamanaka Y., Nakajima K., Fukada T., Hibi M., Hirano T. 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):1557–1565. [PMC free article] [PubMed] [Google Scholar]
  43. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828. doi: 10.1126/science.3136546. [DOI] [PubMed] [Google Scholar] · DOI
  44. Yin T., Taga T., Tsang M. L., Yasukawa K., Kishimoto T., Yang Y. C. Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J Immunol. 1993 Sep 1;151(5):2555–2561. [PubMed] [Google Scholar]
  45. Yuan J., Wegenka U. M., Lütticken C., Buschmann J., Decker T., Schindler C., Heinrich P. C., Horn F. The signalling pathways of interleukin-6 and gamma interferon converge by the activation of different transcription factors which bind to common responsive DNA elements. Mol Cell Biol. 1994 Mar;14(3):1657–1668. doi: 10.1128/mcb.14.3.1657-1668.1994. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  46. Zhong Z., Wen Z., Darnell J. E., Jr Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994 Apr 1;264(5155):95–98. doi: 10.1126/science.8140422. [DOI] [PubMed] [Google Scholar] · DOI · Paper page

Cited by

Sorted by citations

Authors
Nakajima, K., Yamanaka, Y., Nakae, K., Kojima, H., Ichiba, M., Kiuchi, N., Kitaoka, T., Fukada, T., Hibi, M., & Hirano, T.
Affiliations
The University of Osaka (JP)
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
1996-07-01
Volume
15
Issue
14
Pages
3651-3658
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1002/j.1460-2075.1996.tb00734.x
PMC
PMC451995
OpenAlex
W1496109170
Cited by
565
References
1
Citations by year
2026: 1 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 11 · 2016: 8 · 2015: 8 · 2014: 13 · 2013: 14 · 2012: 15
FWCI
16.49
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Naito Foundation
  • Fondation pour la Recherche Médicale
  • Japan Society for the Promotion of Science
  • Japan Science and Technology Agency
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords
STAT3, interleukin-6, macrophage differentiation, growth arrest, G0/G1 phase, dominant-negative STAT3, MYB, c-Myc, cytokine signaling, cell fate determination
MeSH terms
Animals, Base Sequence, Binding Sites, Cell Differentiation, Cell Division, DNA-Binding Proteins, Humans, Membrane Glycoproteins, Mice, Inbred C57BL, Molecular Sequence Data, Oligodeoxyribonucleotides, Proto-Oncogene Proteins, Tumor Cells, Cultured, Signal Transduction, Leukemia, Myeloid, Acute, Trans-Activators, Antigens, CD, Interleukin-6, G1 Phase, Proto-Oncogene Proteins c-myc, Sequence Deletion, Proto-Oncogene Proteins c-myb, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review