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 Paper
  • Published:

c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells

Oncogene volume 19, pages 2194–2204 (2000)Cite this article

Abstract

c-myc protooncogene positively regulates cell proliferation and overexpression of c-myc is found in many solid tumors and leukemias. In the present study we used the K562 human myeloid leukemia cell line as a model to study the functional interaction between c-Myc and p53. Using two different methods, we generated K562 transfectant cell lines with conditional expression of either c-Myc or p53. The cells expressed the p53Vall35 mutant, which adopts a wild-type conformation at 32°C, while c-Myc induction was achieved with a zinc-inducible expression vector. We found that p53 in wild-type conformation induces growth arrest and apoptosis of K562. Expression of c-Myc significantly attenuated apoptosis and impaired the transcriptional activity of p53 on p21WAF1, Bax and cytomegalovirus promoters. The impairment of p21WAF1 transactivation by c-Myc was confirmed by transfection of a c-Myc-estrogen receptor fusion protein and by induction of c-myc by zinc in transfected cells. Also, p53-mediated up-regulation of p21WAF1 mRNA protein were significantly reduced by c-Myc, while Bax levels were unaffected. Consistently, c-Myc increased cyclin-dependent kinase 2 activity in K562 cells expressing p53 in wild-type conformation. These results suggest that c-Myc overexpression may antagonize the pro-apoptotic function of p53, thus providing a molecular mechanism for the frequently observed deregulation of c-myc in human cancer.

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

  • Adachi J, Ookawa K, Shiseki M, Okazaki T, Tsuchida S, Morishita K and Yokota J . 1996 Cell Growth Differ 7: 879–886

  • Ahuja H, Bar-Eli M, Arlin Z, Advan-i S, Allen SL, Goldman J, Snyder D, Foti A and Cline M . 1991 J Clin Invest 7: 2042–2047

  • Alarcon RM, Rupnow BA, Graeber TG, Knox SJ and Giaccia AJ . 1996 Cancer Res 56: 4315–4319

  • Alimena G, De Cuia MR, Diverio D, Gastaldi R and Nanni M . 1987 Cancer Genet Cytogenet 26: 39–50

  • Amati B, Alevizopoulos K and Vlach J . 1998 Front Biosci 3: d250–d268

  • Amundson SA, Myers TG and Fornace AJ Jr . 1998 Oncogene 17: 3287–3299

  • Bates A and Vousden KH . 1999 Cell Mol Life Sci 55: 28–37

  • Beck Z, Bacsi A, Kovacs E, Kiss J, Kiss A, Balogh E, Telek B, Toth FD, Andirko I, Olah E, Udvardy M and Rak K . 1998 Leuk Lymphoma 30: 293–306

  • Bellon T, Lopez-Rodriguez C, Rubio MA, Jochems G, Bernabeu C and Corbi AL . 1994 Eur J Immunol 24: 41–47

  • Berns EM, Klijn JG, van Putten WL, van Staveren IL, Portengen H and Foekens JA . 1992 Cancer Res 52: 1107–1113

  • Bi S, Lanza F and Goldman JM . 1993 Leukemia 7: 1840–1845

  • Blyth K, Terry A, O'Hara M, Baxter EW, Campbell M, Stewart M, Donehower LA, Onions DE, Neil JC and Cameron ER . 1995 Oncogene 10: 1717–1723

  • Bouchard C, Staller P and Eilers M . 1998 Trends Cell Biol 8: 202–206

  • Cañelles M, Delgado MD, Hyland KM, Lerga A, Richard C, Dang CV and Leon J . 1997 Oncogene 14: 1315–1327

  • Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamp RD and Coffey RJ . 1997 Nat Med 3: 1233–1241

  • Dang CV . 1999 Mol Cell Biol 19: 1–11

  • Delgado MD, Lerga A, Cañelles M, Gómez-Casares MT and Leon J . 1995 Oncogene 10: 1659–1665

  • Delgado MD, Vaque JP, Arozarena I, López-Ilasaca MA, Martinez C, Crespo P and León J . 2000 Oncogene 19: 783–790

  • Donzelli M, Bernardi R, Negri C, Prosperi E, Padovan L, Lavialle C, Brison O and Scovassi AI . 1999 Oncogene 18: 439–448

  • Ehinger M, Bergh G, Johnsson E, Gullberg U and Olsson I . 1997 Cell Growth Differ 8: 1127–1137

  • Ehinger M, Nilsson E, Persson AM, Olsson I and Gullberg U . 1995 Cell Growth Differ 6: 9–17

  • Eischen CM, Weber JD, Roussel MF, Sherr CJ and Cleveland JL . 1999 Genes Dev 13: 2658–2669

  • Felsher DW and Bishop JM . 1999 Mol Cell 4: 199–207

  • Feinstein E, Gale RP, Reed J and Canaani E . 1992 Oncogene 7: 1853–1859

  • Frazier MW, He X, Wang J, Gu Z, Cleveland JL and Zambetti GP . 1998 Mol Cell Biol 18: 3735–3743

  • Garte SJ . 1993 Crit Rev Oncog 4: 435–449

  • Gottlieb TM and Oren M . 1996 Biochim Biophys Acta 1287: 77–102

  • Grandori C and Eisenman RN . 1997 Trends Biochem Sci 22: 177–181

  • Grignani F, Lombardi L, Inghirami G, Sterna SL, Cechova K and Dalla-Favera R . 1990 EMBO J 9: 3913–3922

  • Gutierrez MI, Bhatia K, Siwarski D, Wolff L, Magrath IT, Mushinski JF and Huppi K . 1992 Cancer Res 52: 1032–1235

  • Hagiyama H, Adachi T, Yoshida T, Nomura T, Miyasaka N, Honjo T and Tsubata T . 1999 Oncogene 18: 4091–4098

  • Handa H, Hegde UP, Kotelnikov VM, Mundle SD, Dong LM, Burke P, Rose S, Gaskin F, Raza A and Preisler HD . 1997 Leuk Res 21: 479–489

  • Hansen R and Oren M . 1997 Curr Op Genet Dev 7: 46–51

  • Henriksson M and Lüscher B . 1996 Adv Cancer Res 68: 109–182

  • Hermeking H and Eick D . 1994 Science 265: 2091–2094

  • Hermeking H, Funk JO, Reichert M, Ellwart JW and Eick D . 1995 Oncogene 11: 1409–1415

  • Hoffman B and Liebermann DA . 1998 Oncogene 17: 3351–3357

  • Hsu B, Marin MC, el-Naggar AK, Stephens LC, Brisbay S and McDonnell TJ . 1995 Oncogene 11: 175–179

  • Hueber AO, Zornig M, Lyon D, Suda T, Nagata S and Evan GI . 1997 Science 278: 1305–1309

  • Hueber A-O and Evan GI . 1998 Trends Genet 14: 364–367

  • Jackson P, Bos E and Braithwaite AW . 1993 Oncogene 8: 589–597

  • Jennings BA and Mills KI . 1998 Leuk Res 22: 899–903

  • Kirch HC, Flaswinkel S, Rumpf H, Brockmann D and Esche H . 1999 Oncogene 18: 2728–2738

  • Kirsch DG and Kastan MB . 1999 J Clin Oncol 17: 3158–3168

  • Ko LJ and Prives C . 1996 Genes Dev 10: 1054–1072

  • Kobayashi T, Consoli U, Andreeff M, Shiku H, Deisseroth AB and Zhang W . 1995 Oncogene 11: 2311–2316

  • Kremenetskaya OS, Logacheva NP, Baryshnikov AY, Chumakov PM and Kopnin BP . 1997 Oncol Res 9: 155–166

  • Law JC, Ritke MK, Yalowich JC, Leder GH and Ferrell RE . 1993 Leuk Res 17: 1045–1050

  • Levine AJ . 1997 Cell 88: 323–331

  • Littlewood TD, Hancock DC, Danielian PS, Parker MG and Evan GI . 1995 Nucleic Acids Res 23: 1686–1690

  • Lotem J and Sachs L . 1995 Proc Natl Acad Sci USA 92: 9672–9676

  • Mateyak MK, Obaya AJ, Sedivy JM . 1999 Mol Cell Biol 19: 4672–4683

  • McGahon AJ, Nishioka WK, Martin SJ, Mahboubi A, Cotter TG and Green DR . 1995 J Biol Chem 270: 22625–22631

  • Melo JV . 1996 Leukemia 10: 751–756

  • Metz T, Harris AW and Adams JM . 1995 Cell 82: 29–36

  • Michalovitz D, Halevy O and Oren M . 1990 Cell 62: 671–680

  • Mitchell KO and El-Deiry WS . 1999 Cell Growth Differ 19: 223–230

  • Miller D, Miller DJ, Garcia JV and Lynch CM . 1993 Meth Enzymol 217: 581–599

  • Milner J and Medcalf EA . 1990 J Mol Biol 216: 481–484

  • Moberg KH, Tyndall WA and Hall DJ . 1992 Cell Biochem 49: 208–215

  • Nakai H and Misawa S . 1995 Leuk Lymphoma 19: 213–221

  • Newcomb EW . 1995 Leuk Lymphoma 17: 211–221

  • Peller S, Yona R, Kopilova Y, Prokocimer M, Goldfinger N, Uysal A, Karabulut HG, Tukun A, Bokesoy I, Tuncman G and Rotter V . 1998 Genes Chrom Cancer 21: 2–7

  • Poluha W, Poluha DK, Chang B, Crosbie NE, Schonhoff CM, Kilpatrick DL and Ross RH . 1996 Mol Cell Biol 16: 1335–1341

  • Polyak K, Waldman T, He TC, Kinzler KW and Vogelstein B . 1996 Genes Dev 10: 1945–1952

  • Preisler HD, Agarwal R, Sato H, Singh PK, Wang ZQ and Sandberg AA . 1990 Eur J Cancer 26: 960–965

  • Prokocimer M and Rotter V . 1994 Blood 84: 2391–2411

  • Ragimov N, Krauskopf A, Navot N, Rotter V, Oren M and Aloni Y . 1993 Oncogene 8: 1183–1193

  • Reisman D, Elkind NB, Roy B, Beamon J and Rotter V . 1993 Cell Growth Differ 4: 57–65

  • Roy B, Beamon J, Balint E and Reisman D . 1994 Mol Cell Biol 14: 7805–7815

  • Rupnow BA, Alarcon RM, Giaccia AJ and Knox J . 1998 Cell Death Differ 5: 141–147

  • Sakamuro D, Eviner V, Elliott KJ, Showe L, White E and Prendergast GC . 1995 Oncogene 11: 2411–2418

  • Selvakumaran M, Lin HK, TjinThamSjin R, Reed JC, Liebermann DA and Hoffman B . 1994 Mol Cell Biol 14: 2352–2360

  • Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW . 1997 Cell 88: 593–602

  • Sheikh MS, Rochefort H and Garcia M . 1995 Oncogene 11: 1899–1905

  • Sonenshein GE . 1997 J Immunol 158: 1994–1997

  • Stahler F and Roemer K . 1998 Oncogene 17: 3507–3512

  • Stuppia L, Calabrese G, Peila R, Guanciali-Franchi P, Morizio E, Spadano A and Palka G . 1997 Cancer Genet Cytogenet 98: 28–35

  • Subler MA, Martin DW and Deb S . 1992 J Virol 66: 4757–4762

  • Taylor WR, Egan SE, Mowat M, Greenberg AH and Wright JA . 1992 Oncogene 7: 1383–1390

  • Thompson EB . 1998 Annu Rev Physiol 60: 575–600

  • Trepel M, Scheding S, Groscurth P, Horny HP, Malipiero U, Brugger W, Dichgans J and Weller M . 1997 Leukemia 11: 1842–1849

  • Trudel M, Lanoix J, Barisoni L, Blouin MJ, Desforges M, L'Italien C and D'Agati V . 1997 J Exp Med 186: 1873–18784

  • Waikel RL, Wang X-J and Roop DR . 1999 Oncogene 18: 4870–4878

  • Wagner AJ, Kokontis JM and Hay N . 1994 Genes Dev 8: 2817–2830

  • Wallace-Brodeur RR and Lowe SW . 1999 Cell Mol Life Sci 54: 64–75

  • Wu R, Bellas RE, Shen J and Sonenshein GE . 1998 J Exp Med 187: 1671–1679

  • Yin XY, Crove L, Datta NS, Long MW and Prochownik EV . 1999 Oncogene 18: 1177–1184

  • Zeng Y-X and El-Deiry . 1996 Oncogene 12: 1557–1564

  • Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ and Roussel MF . 1998 Genes Dev 12: 2424–2433

Download references

Acknowledgements

We thank Pilar Frade and Rosa Blanco for technical assistance, and Kathleen Cho, Nicholas Cowan, Riccardo Dalla Favera, Robert Eisenman, Abelardo López-Rivas, Stanley Korsmeyer, Trevor Littlewood, Moshe Oren and Manuel Serrano for plasmids and antibodies. We are gratefully indebted to Dirk Eick and Moshe Oren for helpful comments on the manuscript. This work has been supported by grant PM98-0109, Spanish Ministry of Education and Culture, and Biomed 96-3532 from European Community.

Author information

Authors and Affiliations

  1. Departamento de Biologia Molecular, Grupo de Biologia Molecular del Cáncer, Unidad Asociada al Centro de Investigaciones Biológicas, Universidad de Cantabria, Spain

    Eva Ceballos, M Dolores Delgado, Pilar Gutierrez & Javier León

  2. Servicio de Hematología, Hospital Marqués de Valdecilla, Santander, Spain

    Carlos Richard

  3. Institute of Molecular Biology and Tumor Research, Phillips University, Marburg, Germany

    Daniel Müller & Martin Eilers

  4. Department of Hematology, Lund University, Lund, Sweden

    Mats Ehinger & Urban Gullberg

Authors
  1. Eva Ceballos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Dolores Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pilar Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos Richard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Eilers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mats Ehinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Urban Gullberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Javier León
    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

Ceballos, E., Delgado, M., Gutierrez, P. et al. c-Myc antagonizes the effect of p53 on apoptosis and p21WAF1 transactivation in K562 leukemia cells. Oncogene 19, 2194–2204 (2000). https://doi.org/10.1038/sj.onc.1203541

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203541

Keywords

This article is cited by

Search

Advanced search

Quick links