Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Cytokines, Signal Transduction and Diseases

Cytokine-induced restoration of differentiation and cell cycle arrest in v-Myc transformed U-937 monoblasts correlates with reduced Myc activity

Leukemia volume 15, pages 217–227 (2001)Cite this article

Abstract

Deregulated expression of the myc-family of oncogenes in hematopoietic and other cell types plays an important role in tumorigenesis, and results in increased proliferative potential and block of cellular differentiation. We have previously shown that IFN-γ restores phorbol ester-induced differentiation and cell cycle arrest in v-myc transformed human U-937 monoblasts. To investigate whether other cytokine signals could also abrogate such a block, IL-1, IL-3, IL-4, IL-6, IL-7, IL-10, IL-11, LIF, oncostatin M, M-CSF, G-CSF and GM-CSF, and TGFβ1, TNF-α, IFN-α were examined. We show that GM-CSF and IL-6, in combination with the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA), restored differentiation and cell cycle arrest. In contrast, treatment by TGFβ1 ± TPA resulted in an efficient G1/G0 arrest, but did not appear to induce terminal differentiation. Restoration of differentiation and cell cycle arrest was accomplished despite maintained expression of the v-Myc protein. Our results show that the cytokine-induced signals reduced Myc-dependent transcription of an artificial target promoter/reporter gene construct, correlating in most, but not all, cases with decreased association of v- and c-Myc with its essential partner, Max. Thus, cytokine-induced signals may counteract the activity of deregulated Myc, and contribute to the normalization of differentiation, arrest in the G1/G0 phase of the cell cycle, or both.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Henriksson M, Lüscher B . Proteins of the Myc network: essential regulators of cell growth and differentiation Adv Cancer Res 1996 68: 109–182

    CAS  Google Scholar 

  2. Dang CV . c-Myc target genes involved in cell growth, apoptosis, and metabolism Mol Cell Biol 1999 19: 1–11

    CAS  Google Scholar 

  3. Field JK, Spandidos DA . The role of ras and myc oncogenes in human solid tumours and their relevance in diagnosis and prognosis (review) Anticancer Res 1990 10: 1–22

    CAS  Google Scholar 

  4. Spencer CA, Groudine M . Control of c-myc regulation in normal and noeplastic cells Adv Cancer Res 1991 56: 1–48

    CAS  Google Scholar 

  5. Marcu KB, Bossone SA, Patel AJ . myc function and regulation Annu Rev Biochem 1992 61: 809–860

    CAS  Google Scholar 

  6. Coppola JA, Cole MD . Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment Nature 1986 320: 760–763

    CAS  Google Scholar 

  7. Dmitrovsky E, Kuehl WM, Hollis GF, Kirsch IR, Bender TP, Segal S . Expression of a transfected human c-myc oncogene inhibits differentiation of a mouse erythroleukaemia cell line Nature 1986 322: 748–750

    CAS  Google Scholar 

  8. Prochownik EV, Kukowska J . Deregulated expression of c-myc by murine erythroleukaemia cells prevents differentiation Nature 1986 322: 848–850

    CAS  Google Scholar 

  9. Schneider MD, Perryman MB, Payne PA, Spizz G, Roberts R, Olson EN . Autonomous expression of c-myc in BC3H1 cells partially inhibits but does not prevent myogenic differentiation Mol Cell Biol 1987 7: 1973–1977

    CAS  Google Scholar 

  10. Freytag SO . Enforced expression of the c-myc oncogene inhibits cell differentiation by precluding entry into a distinct predifferentiation state in G0/G1 Mol Cell Biol 1988 8: 1614–1624

    CAS  Google Scholar 

  11. Griep AE, Westphal H . Antisense Myc sequences induce differentiation of F9 cells Proc Natl Acad Sci USA 1988 85: 6806–6810

    CAS  Google Scholar 

  12. Larsson LG, Ivhed I, Gidlund M, Pettersson U, Vennström B, Nilsson K . Phorbol ester-induced terminal differentiation is inhibited in human U-937 monoblastic cells expressing a v-myc oncogene Proc Natl Acad Sci USA 1988 85: 2638–2642

    CAS  Google Scholar 

  13. Hoffman Liebermann B, Liebermann DA . 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 11: 2375–2381

    CAS  Google Scholar 

  14. Resnitzky D, Kimchi A . Deregulated c-myc expression abrogates the interferon- and interleukin 6-mediated G0/G1 cell cycle arrest but not other inhibitory repsonses in M1 myeloblastic cells Cell Growth Differ 1991 2: 33–41

    CAS  Google Scholar 

  15. Miner JH, Wold BJ . c-myc inhibition of MyoD and myogenin-initiated myogenic differentiation Mol Cell Biol 1991 11: 2842–2851

    CAS  Google Scholar 

  16. Chisholm O, Stapleton P, Symonds G . Constitutive expression of exogenous myc in myelomonocytic cells: acquisition of a more transformed phenotype and inhibition of differentiation induction Oncogene 1992 7: 1827–1836

    CAS  Google Scholar 

  17. Holt JT, Redner RL, Nienhuis AW . An oligomer complementary to c-myc mRNA inhibits proliferation of HL-60 promyelocytic cells and induces differentiation Mol Cell Biol 1988 8: 963–973

    CAS  Google Scholar 

  18. Blackwood EM, Eisenman RN . Max: a helix–loop–helix zipper protein that forms a sequence-specific DNA-binding complex with Myc Science 1991 251: 1211–1217

    CAS  Google Scholar 

  19. Prednergast GC, Lawe D, Ziff EB . Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation Cell 1991 65: 395–407

    Google Scholar 

  20. Grandori C, Eisenman RN . Myc target genes Trends Biochem Sci 1997 22: 177–181

    CAS  Google Scholar 

  21. Lüscher B, Larsson LG . The basic region/helix–loop–helix/leucine zipper domain of Myc proto-oncoproteins: function and regulation Oncogene 1999 18: 2955–2966

    Google Scholar 

  22. McArthur GA, Laherty CD, Quéva C, Hurlin PJ, Loo L, James L, Grandori C, Gallant P, Shiio Y, Hokanson WC, Bush AC, Cheng PF, Lawrence QA, Pulverer B, Koskinen PJ, Foley KP, Ayer DE, Eisenman RN . The Mad protein family links transcriptional repression to cell differentiation CSH Symp Quant Biol 1998 LXIII: 423–433

    Google Scholar 

  23. Foley KP, Eisenman RN . Two MAD tails: what the recent knockouts of Mad1 and Mxi1 tell us about the MYC/MAX/MAD network Biochim Biophys Acta 1999 1423: M37–47

    CAS  Google Scholar 

  24. Öberg F, Larsson LG, Anton R, Nilsson K . Interferon gamma abrogates the differentiation block in v-myc-expressing U-937 monoblasts Proc Natl Acad Sci USA 1991 88: 5567–5571

    Google Scholar 

  25. Bahram F, Wu S, Öberg F, Luscher B, Larsson LG . Posttranslational regulation of myc function in response to phorbol ester/interferon-gamma-induced differentiation of v-myc-transformed U-937 monoblasts (in process citation) Blood 1999 93: 3900–3912

    CAS  Google Scholar 

  26. Sundström C, Nilsson K . Establishment and characterization of a human histiocytic lymphoma cell line (U-937) Int J Cancer 1976 17: 565–577

    Google Scholar 

  27. Auffray C, Rougeon F . Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA Eur J Biochem 1980 107: 303–314

    CAS  Google Scholar 

  28. Seiler Tuyns A, Birnstiel ML . Structure and expression in L-cells of a cloned H4 histone gene of the mouse J Mol Biol 1981 151: 607–625

    CAS  Google Scholar 

  29. Tso J, Sun XH, Kao TH, Reece KS, Wu R . Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene Nucleic Acids Res 1985 13: 2485–2502

    CAS  Google Scholar 

  30. Larsson L-G, Bahram F, Burkhardt H, Lüscher B . Analysis of the DNA-binding activities of Myc/Max/Mad network complexes during induced differentiation of U-937 monoblasts and F9 teratocarcinoma cells Oncogene 1997 15: 737–748

    CAS  Google Scholar 

  31. Todd RD, Schlossman SF . Analysis of antigenic determinants on human monocytes and macrophages Blood 1982 59: 775–786

    CAS  Google Scholar 

  32. Miller LJ, Schwarting R, Springer TA . Regulated expression of the Mac-1, LFA-1, p150,95 glycoprotein family during leukocyte differentiation J Immunol 1986 137: 2891–2900

    CAS  Google Scholar 

  33. Öberg F, Botling J, Nilsson K . Functional antagonism between vitamin D3 and retinoic acid in the regulation of CD14 and CD23 expression during monocytic differentiation of U-937 cells J Immunol 1993 150: 3487–3495

    Google Scholar 

  34. Osley MA . The regulation of histone synthesis in the cell cycle Annu Rev Biochem 1991 60: 827–861

    CAS  Google Scholar 

  35. Schindler C, Darnell Jr J . Transcriptional responses to polypeptide ligands: the JAK-STAT pathway Annu Rev Biochem 1995 64: 621–651

    CAS  Google Scholar 

  36. Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T, Akira S . STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line Proc Natl Acad Sci USA 1996 93: 3963–3966

    CAS  Google Scholar 

  37. Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell Jr J . Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma Proc Natl Acad Sci USA 1996 93: 7673–7678

    CAS  Google Scholar 

  38. Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY . Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1 Science 1996 272: 719–722

    CAS  Google Scholar 

  39. Bellido T, O'Brien CA, Roberson PK, Manolagas SC . Transcriptional activation of the p21 (WAF1, CIP1, SDI1) gene by interleukin-6 type cytokines. A prerequisite for their pro-differentiating and anti-apoptotic effects on human osteoblastic cells J Biol Chem 1998 273: 21137–21144

    CAS  Google Scholar 

  40. Matsumura I, Ishikawa J, Nakajima K, Oritani K, Tomiyama Y, Miyagawa J, Kato T, Miyazaki H, Matsuzawa Y, Kanakura Y . Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21 (WAF1/Cip1) by STAT5 Mol Cell Biol 1997 17: 2933–2943

    CAS  Google Scholar 

  41. Grant S, Bhalla K, Weinstein B, Pestka S, Mileno MD, Fisher PB . Recombinant human interferon sensitizes resistant myeloid leukemic cells to induction of terminal differentiation Biochem Biophys Res Commun 1985 130: 379–388

    CAS  Google Scholar 

  42. Massague J . TGF-beta signal transduction Annu Rev Biochem 1998 67: 753–791

    CAS  Google Scholar 

  43. De Benedetti F, Falk LA, Ellingsworth LR, Ruscetti FW, Faltynek CR . Synergy between transforming growth factor-beta and tumor necrosis factor-alpha in the induction of monocytic differentiation of human leukemic cell lines Blood 1990 75: 626–632

    CAS  Google Scholar 

  44. Coffey Jr RJ, Bascom CC, Sipes NJ, Graves Deal R, Weissman BE, Moses HL . Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta Mol Cell Biol 1988 8: 3088–3093

    CAS  Google Scholar 

  45. Pietenpol JA, Holt JT, Stein RW, Moses HL . Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation Proc Natl Acad Sci USA 1990 87: 3758–3762

    CAS  Google Scholar 

  46. Alexandrow MG, Kawabata M, Aakre M, Moses HL . Overexpression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1 Proc Natl Acad Sci USA 1995 92: 3239–3243

    CAS  Google Scholar 

  47. Warner BJ, Blain SW, Seoane J, Massague J . Myc downregulation by transforming growth factor beta required for activation of the p15(Ink4b) G(1) arrest pathway Mol Cell Biol 1999 19: 5913–5922

    CAS  Google Scholar 

  48. Ayer DE, Kretzner L, Eisenman RN . Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity Cell 1993 72: 211–222

    CAS  Google Scholar 

  49. Hurlin PJ, Queva C, Koskinen PJ, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA, Eisenman RN . Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation Embo J 1995 14: 5646–5659

    CAS  Google Scholar 

  50. Cultraro CM, Bino T, Segal S . Function of the c-Myc antagonist Mad1 during a molecular switch from proliferation to differentiation Mol Cell Biol 1997 17: 2353–2359

    CAS  Google Scholar 

Download references

Acknowledgements

We thank Nina Hult for important contributions during the early phase of this study and Inger Karlberg for excellent technical assistance. We also thank Drs GR Adolf, S Clark, S Gillis, T Kishimoto and M Sporn for generous gifts of cytokines. This work was supported by grants from the Swedish Cancer Society, the Children Cancer Foundation of Sweden, the von Kantzow Foundation, and the Lovisa and Thielmann Foundation.

Author information

Authors and Affiliations

  1. Department of Genetics and Pathology, Laboratory of Tumor Biology, University of Uppsala, Sweden

    F Öberg, S Wu, K Nilsson & L-G Larsson

  2. Department of Plant Biology, Uppsala Genetic Center, Swedish University of Agricultural Sciences, Uppsala, Sweden

    S Wu, F Bahram & L-G Larsson

Authors
  1. F Öberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Bahram
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L-G Larsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Öberg, F., Wu, S., Bahram, F. et al. Cytokine-induced restoration of differentiation and cell cycle arrest in v-Myc transformed U-937 monoblasts correlates with reduced Myc activity. Leukemia 15, 217–227 (2001). https://doi.org/10.1038/sj.leu.2402025

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402025

Keywords

This article is cited by

Search

Advanced search

Quick links