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.

  • Short Report
  • Published:

Multiple lysine mutations in the C-terminus of p53 make it resistant to degradation mediated by MDM2 but not by human papillomavirus E6 and induce growth inhibition in MDM2-overexpressing cells

Oncogene volume 21, pages 2605–2610 (2002)Cite this article

Abstract

We have recently shown that lysine mutations in p53's putative C-terminal acetylation sites result in increased stability and cytoplasmic distribution of the p53 protein in a human lung cancer cell line. In the present study, we showed that when lysine residues 372, 373, 381, and 382 of p53 were substituted with alanine, the resulting A4 protein was resistant to MDM2-mediated proteosomal degradation but was highly sensitive to human papillomavirus E6-mediated proteolysis. When A4 and wild-type p53 were transfected into MDM2-overexpressing MCF-7 cells, A4 significantly reduced colony formation in vitro, when compared with wild-type p53. Our results suggest that A4 exerts a growth-inhibitory effect more efficiently than wild-type p53 does in cell lines that overexpress MDM2 and may therefore be a better therapeutic tool than wild-type p53 for certain cancers in which MDM2 is amplified or overexpressed.

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

Similar content being viewed by others

References

  • An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM . 1998 Nature 392: 405–408

  • Ashcroft M, Vousden KH . 1999 Oncogene 18: 7637–7643

  • Buschmann T, Lin Y, Aithmitti N, Fuchs SY, Lu H, Resnick-Silverman L, Manfredi JJ, Ronai Z, Wu X . 2001 J. Biol. Chem. 276: 13852–13857

  • Chen J, Wu X, Lin J, Levine AJ . 1996 Mol. Cell. Biol. 16: 2445–2452

  • Finlay CA . 1993 Mol. Cell. Biol. 13: 301–306

  • Freedman DA, Wu L, Levine AJ . 1999 Cell. Mol. Life Sci. 55: 96–107

  • Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z . 1998b Oncogene 17: 2543–2547

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

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

  • Haupt Y, Barak Y, Oren M . 1996 EMBO J. 15: 1596–1606

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

  • Honda R, Yasuda H . 1999 EMBO J. 18: 22–27

  • Huibregtse JM, Scheffner M, Beaudenon S, Howley PM . 1995 Proc. Natl. Acad. Sci. USA 92: 2563–2567

  • Huibregtse JM, Scheffner M, Howley PM . 1991 EMBO J. 13: 4129–4135

  • Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A . 1998 Proc. Natl. Acad. Sci. USA 95: 15608–15612

  • 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, Vousden KH . 1998 Mol. Med. Today 4: 250–256

  • Levine AJ . 1997 Cell 88: 323–331

  • Maheswaran S, Englert C, Bennett P, Heinrich G, Haber DA . 1995 Genes Dev. 9: 2143–2156

  • May P, May E . 1999 Oncogene 18: 7621–7636

  • Meng RD, Shih H, Prabhu NS, George DL, El Deiry WS . 1998 Clin. Cancer Res. 4: 251–259

  • Momand J, Zambetti GP . 1997 J. Cell Biochem. 64: 343–352

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

  • Nakamura S, Roth JA, Mukhopadhyay T . 2000 Mol. Cell. Biol. 20: 9391–9398

  • Nakamura S, Gomyo Y, Roth JA, Mukhopadhyay T . 2002 Oncogene in press

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

  • Oren M . 1999 J. Biol. Chem. 274: 36031–36034

  • Oren M, Rotter V . 1999 Cell Mol. Life Sci. 55: 9–11

  • Prives C . 1998 Cell 95: 5–8

  • Querido E, Marcellus RC, Lai A, Charbonneau R, Teodoro JG, Ketner G, Branton PE . 1997 J. Virol. 71: 3788–3798

  • Reihsaus E, Kohler M, Kraiss S, Oren M, Montenarh M . 1990 Oncogene 5: 137–145

  • Rodriguez MS, Desterro JM, Lain S, Lane DP, Hay RT . 2000 Mol. Cell Biol. 20: 8458–8467

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM . 1990 Cell 63: 1129–1136

  • Talis AL, Huibregtse JM, Howley PM . 1998 J. Biol. Chem. 273: 6439–6445

  • Thomas M, Matlashewski G, Pim D, Banks L . 1996 Oncogene 13: 265–273

  • Tiemann F, Zerrahn J, Deppert W . 1995 J. Virol. 69: 6115–6121

  • Wadgaonkar R, Collins T . 1999 J. Biol. Chem. 274: 13760–13767

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

Download references

Acknowledgements

We thank Marjorie Johnson for her technical assistance, Kerry Wright, Ph.D. (Scientific Publications Dept.) for editing assistance, Carmelita Concepcion and Peggy James for preparation of this manuscript. This work was partially supported by grants from the National Cancer Institute and the National Institutes of Health (P01 CA78778-01A1) (JA Roth); SPORE (2P50-CA70970-04); a developmental grant from the NCI for the University of Texas MD Anderson Cancer Center SPORE (P50-CA70907) in lung cancer (T Mukhopadhyay), by gifts to the Division of Surgery, from Tenneco and Exxon for the Core Laboratory Facility; by the UT MD Anderson Cancer Center Support Core Grant (CA 16672); by a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8), the WM Keck Foundation, and a sponsored research agreement with Introgen Therapeutics, Inc. (SR93-004-1).

Author information

Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, Section of Thoracic Molecular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 445, Texas, 77030, Houston, TX, USA

    Seiichi Nakamura, Jack A Roth & Tapas Mukhopadhyay

  2. Department of Tumor Biology, The University of Texas M.D., Anderson Cancer Center, 1515 Holcombe Blvd., Box 445, Texas, 77030, Houston, TX, USA

    Jack A Roth

Authors
  1. Seiichi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jack A Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tapas Mukhopadhyay
    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

Nakamura, S., Roth, J. & Mukhopadhyay, T. Multiple lysine mutations in the C-terminus of p53 make it resistant to degradation mediated by MDM2 but not by human papillomavirus E6 and induce growth inhibition in MDM2-overexpressing cells. Oncogene 21, 2605–2610 (2002). https://doi.org/10.1038/sj.onc.1205343

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205343

Keywords

This article is cited by

Search

Advanced search

Quick links