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:

The contribution of the acidic domain of MDM2 to p53 and MDM2 stability

Oncogene volume 20, pages 1267–1275 (2001)Cite this article

Abstract

p53 and MDM2 are both degraded by the ubiquitin-proteasome pathway. MDM2 binds p53 and promotes its rapid degradation. MDM2 is an E3 ligase that activates self and p53 ubiquitylation. Moreover, MDM2 nuclear-cytoplasmic shuttling contributes to p53 degradation in the cytoplasm. We have identified a new region of MDM2 which regulates the stability of both p53 and MDM2. The first 50 amino-acids of the MDM2 acidic domain (222–272) contribute to MDM2 and MDM2-mediated p53 degradation by a mechanism which is independent of either MDM2 E3-ligase activity or MDM2 nucleo-cytoplasmic shuttling. The transcriptional coactivator p300 could have been involved, since it binds to the MDM2 acidic domain. However, we found that p300 stabilises MDM2, even in absence of an intact acidic domain, indicating that the MDM2 acidic region contributes to proteolysis independently of p300. We propose that the MDM2 acidic domain is required for unbiquitylated MDM2 and p53 to be degraded by cytoplasmic proteasomes.

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

  • Argentini M, Barboule N, Wasylyk B . 2000 Oncogene 19: 3849–3857

  • Barak Y, Juven T, Haffner R, Oren M . 1993 EMBO J 12: 461–468

  • Blaydes JP, Wynford-Thomas D . 1998 Oncogene 16: 3317–3322

  • Boyd MT, Vlatkovic N, Haines DS . 2000a J. Biol. Chem. 275: 31883–31890

  • Boyd SD, Tsai KY, Jacks T . 2000b Nat. Cell Biol. 2: 563–568

  • Chang YC, Lee YS, Tejima T, Tanaka K, Omura S, Heintz NH, Mitsui Y, Magae J . 1998 Cell Growth Differ. 9: 79–84

  • Chen C, Okayama H . 1987 Mol. Cell. Biol. 7: 2745–2752

  • Chen J, Marechal V, Levine AJ . 1993 Mol. Cell. Biol. 13: 4107–4114

  • Chowdary DR, Dermody JJ, Jha KK, Ozer HL . 1994 Mol. Cell. Biol. 14: 1997–2003

  • Elenbaas B, Dobbelstein M, Roth J, Shenk T, Levine AJ . 1996 Mol. Med. 2: 439–451

  • Fakharzadeh SS, Trusko SP, George DL . 1991 EMBO J. 10: 1565–1569

  • Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM . 2000 J. Biol. Chem. 275: 8945–8951

  • Freedman DA, Levine AJ . 1998 Mol. Cell. Biol. 18: 7288–7293

  • Fuchs SY, Adler V, Buschmann T, Yin Z, Wu X, Jones SN, Ronai Z . 1998 Genes Dev. 12: 2658–2663

  • Ganguli G, Abecassis J, Wasylyk B . 2000 EMBO J. 19: 5135–5147

  • Geyer RK, Yu ZK, Maki CG . 2000 Nat. Cell Biol. 2: 569–573,

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

  • Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao ZX, Kumar S, Howley PM, Livingston DM . 1998 Mol. Cell. 2: 405–415

  • Gu J, Chen D, Rosenblum J, Rubin RM, Yuan ZM . 2000 Mol. Cell. Biol. 20: 1243–1253

  • Haas AL, Siepmann TJ . 1997 FASEB J. 11: 1257–1268

  • Haupt Y, Maya R, Kazaz A, Oren M . 1997 Nature 387: 296–299

  • Hay TJ, Meek DW . 2000 FEBS Lett. 478: 183–186

  • Honda R, Tanaka H, Yasuda H . 1997 FEBS Lett. 420: 25–27

  • Honda R, Yasuda H . 2000 Oncogene 19: 1473–1476

  • Hsieh JK, Chan FS, O'Connor DJ, Mittnacht S, Zhong S, Lu X . 1999 Mol. Cell 3: 181–193

  • Jones SN, Roe AE, Donehower LA, Bradley A . 1995 Nature 378: 206–208

  • Juven-Gershon T, Oren M . 1999 Mol. Med. 5: 71–83

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW . 1991 Cancer Res. 51: 6304–6311

  • Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM . 2000 Mol. Cell 6: 409–419

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

  • Kobet E, Zeng X, Zhu Y, Keller D, Lu H . 2000 Proc. Natl. Acad. Sci. USA 97: 12547–12552

  • Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU, Jentsch S . 1999 Cell 96: 635–644

  • Kubbutat MH, Jones SN, Vousden KH . 1997 Nature 387: 299–303

  • Kubbutat MH, Ludwig RL, Ashcroft M, Vousden KH . 1998 Mol. Cell. Biol. 18: 5690–5698

  • Kubbutat MH, Ludwig RL, Levine AJ, Vousden KH . 1999 Cell Growth Differ. 10: 87–92

  • Leveillard T, Wasylyk B . 1997 J. Biol. Chem. 272: 30651–30661

  • Levine AJ . 1997 Cell 88: 323–331

  • Lohrum MA, Ashcroft M, Kubbutat MH, Vousden KH . 2000 Nat. Cell. Biol. 2: 179–181

  • Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM . 1999 Proc. Natl. Acad. Sci. USA 96: 11364–11369

  • Maki CG . 1999 J. Biol. Chem. 274: 16531–16535

  • Maki CG, Huibregtse JM, Howley PM . 1996 Cancer Res. 56: 2649–2654

  • Maltzman W, Czyzyk L . 1984 Mol. Cell. Biol. 4: 1689–1694

  • Marechal V, Elenbaas B, Piette J, Nicolas JC, Levine AJ . 1994 Mol. Cell. Biol. 14: 7414–7420

  • Momand J, Zambetti GP, Olson DC, George D, Levine AJ . 1992 Cell 69: 1237–1245

  • Montes de Oca Luna R, Wagner DS, Lozano G . 1995 Nature 378: 203–206

  • Moser FG, Dorman BP, Ruddle FH . 1975 J. Cell Biol. 66: 676–680

  • Nelson WG, Kastan MB . 1994 Mol. Cell. Biol. 14: 1815–1823

  • Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B . 1993 Nature 362: 857–860

  • Palmer A, Rivett AJ, Thomson S, Hendil KB, Butcher GW, Fuertes G, Knecht E . 1996 Biochem. J. 316: 401–407

  • Pickart CM . 2000 Nat. Cell Biol. 2: E139–E141

  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA . 1998 Cell 92: 713–723

  • Rivett AJ . 1998 Curr. Opin, Immunol. 10: 110–114

  • Roth J, Dobbelstein M, Freedman DA, Shenk T, Levine AJ . 1998 EMBO J. 17: 554–564

  • Sherr CJ . 1998 Genes Dev. 12: 2984–2991

  • Stommel JM, Marchenko ND, Jimenex GS, Moll UM, Hope TJ, Wahl GM . 1999 EMBO J. 18: 1660–1672

  • Strack PR, Wajnberg EF, Waxman L, Fagan JM . 1992 Int. J. Biochem. 24: 887–895

  • Tao W, Levine AJ . 1999 Proc. Natl. Acad. Sci. USA 96: 3077–3080

  • Treier M, Staszewski LM, Bohmann D . 1994 Cell 78: 787–798

  • Wasylyk C, Salvi R, Argentini M, Dureuil C, Delumeau I, Abecassis J, Debussche L, Wasylyk B . 1999 Oncogene 18: 1921–1934

  • Weber JD, Kuo ML, Bothner B, DiGiammarino EL, Kriwacki RW, Roussel MF, Sherr CJ . 2000 Mol. Cell. Biol. 20: 2517–2528

  • Xie Y, Varshavsky A . 2000 Proc. Natl. Acad. Sci. USA 97: 2497–2502

  • Yu J, Zhang L, Hwang PM, Rago C, Kinzler, KW, Vogelstein B . 1999 Proc. Natl. Acad. Sci. USA 96: 14517–14522

  • Zhang Y, Xiong Y, Yarbrough WG . 1998 Cell 92: 725–734

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH, Levine AJ . 2000 Genes Dev. 14: 981–993

  • Zheng N, Wang P, Jeffrey PD, Pavletich NP . 2000 Cell 102: 533–539

Download references

Acknowledgements

We thank: (1) for the gift of recombinants and antibodies, D Bohmann, T Leveillard and Y Lutz; (2) for invaluable help, the IGBMC facilities staff; (3) for fellowships for M Argentini, the Ligue Régional (Bas-Rhin) contre le Cancer, the Association pour la Recherche sur le Cancer and Ministére de la Recherche et de Technologie; (4) for a fellowship for N Barboule, Rhone-Poulenc; (5) for financial assistance, BioAvenir (Rhone-Poulenc), the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hôpital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, the Fondation pour la Recherche Mèdicale, the Ligue Nationale Française contre le Cancer, the Ligue Régionale (Haut-Rhin) contre le Cancer and the Ligue Régionale (Bas-Rhin) contre le Cancer.

Author information

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 163, Illkirch cédex, 67404, France

    Manuela Argentini, Nadia Barboule & Bohdan Wasylyk

Authors
  1. Manuela Argentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadia Barboule
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bohdan Wasylyk
    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

Argentini, M., Barboule, N. & Wasylyk, B. The contribution of the acidic domain of MDM2 to p53 and MDM2 stability. Oncogene 20, 1267–1275 (2001). https://doi.org/10.1038/sj.onc.1204241

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204241

Keywords

This article is cited by

Search

Advanced search

Quick links