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 Communication
  • Published:

Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency

Oncogene volume 25, pages 3463–3470 (2006)Cite this article

Abstract

A haploid genotype may be insufficient to support normal wild-type function. Such haplo-insufficiency has recently been documented for numerous tumour suppressor genes. p53 is a crucial tumour suppressor governing DNA repair, cell cycle arrest and apoptosis via its role as a stress-responsive transcription factor. p53 haplo-insufficiency has been observed in vivo with human familial cancer in Li–Fraumeni Syndrome (LFS) and in mouse p53-knockout models of LFS. The increased tumorigenesis associated with loss of one p53 allele has been attributed to reduced p53-dependent stress responses. However, the underlying biochemical basis for such attenuated responses in p53+/− cells remains unclear. Here we have determined basal p53 messenger RNA (mRNA) and protein levels, and compared the p53 stress response in p53+/+, p53+/− and p53−/− isogenic clones derived from HCT116 cells. Basal expression of p53 in p53+/− cells was 25% relative to p53+/+ cells, and this differential was maintained following oncogenic stress. This deficiency was manifested at both p53 mRNA and protein levels and resulted in attenuated p53 stress responses, in particular for p21waf1 upregulation and survivin downregulation, and reduced G1 arrest and apoptosis. These observations identify a molecular basis for wild-type p53 haplo-insufficiency, which may explain the attenuated tumour-suppressive phenotype observed in cells with a single wild-type p53 allele and in humans with LFS.

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

  • Allison S, Milner J . (2003). Cancer Res 63: 6674–6679.

  • Bean LJ, Stark GR . (2001). Oncogene 20: 1076–1084.

  • Bienz-Tadmor B, Zakhut-Houri R, Libresco S, Givol D, Oren M . (1985). EMBO J 4: 3209–3213.

  • Blagosklonny MV . (2000). FASEB J 14: 1901–1907.

  • Bode AM, Dong Z . (2004). Nat Rev Cancer 4: 793–805.

  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y et al. (2004). Science 303: 2011–2015.

  • Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP et al. (1998). Science 282: 1497–1501.

  • Camplejohn RS, Perry P, Hodgson SV, Turner G, Williams A, Upton C et al. (1995). Br J Cancer 722: 654–662.

  • Cook WD, McCaw BJ . (2000). Oncogene 19: 3434–3438.

  • Deffie A, Wu H, Reinke V, Lozano G . (1993). Mol Cell Biol 13: 3415–3423.

  • de Moor CH, Meijer H, Lissenden S . (2005). Semin Cell Dev Biol 16: 49–58.

  • El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J et al. (1994). Cancer Res 54: 1169–1174.

  • Espinosa JM, Emerson BM . (2001). Mol Cell 1: 57–69.

  • Espinosa JM, Verdun RE, Emerson BM . (2003). Mol Cell 12: 1015–1027.

  • Fojo T . (2002). Drug Resist Updat 5: 209–216.

  • Ford J, Jiang M, Milner J . (2005). Cancer Res 65: 10457–10463.

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

  • Fu L, Ma W, Benchimol S . (1999). Oncogene 18: 6419–6424.

  • Geng L, Parant JM, Lang G, Chau P, Chavez-Reyes A, El-Naggar AK et al. (2004). Nat Genet 36: 63–68.

  • Giannakou ME, Partridge L . (2004). Trends Cell Biol 14: 408–412.

  • Gottlieb E, Haffner R, King A, Asher G, Gruss P, Lonai P et al. (1997). EMBO J 16: 1381–1390.

  • Hemann MT, Fridman JS, Zilfou JT, Hernando E, Paddison PJ, Cordon-Cardo C et al. (2003). Nat Genet 33: 396–400.

  • Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M . (2002). J Biol Chem 277: 3247–3257.

  • Hofseth LJ, Hussain SP, Harris CC . (2004). Trends Pharmacol Sci 25: 177–181.

  • Hollstein M, Sidransky D, Vogelstein B, Harris CC . (1991). Science 253: 49–53.

  • Hu VW, Heikka DS, Dieffenbach PB, Ha L . (2001). FASEB J 15: 1562–1568.

  • Iwakuma T, Lozano G . (2003). Mol Cancer Res 1: 993–1000.

  • Kaeser MD, Iggo RD . (2002). Proc Natl Acad Sci USA 99: 95–100.

  • Komarova EA, Gudkov AV . (1998). Semin Cancer Biol 8: 389–400.

  • Latonen L, Laiho M . (2005). Biochim Biophys Acta 1755: 71–89.

  • Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A et al. (2001). Cell 107: 137–148.

  • Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S et al. (2002). Oncogene 21: 2613–2622.

  • Mirzayans R, Pollock S, Scott A, Gao CQ, Murray D . (2003). Oncogene 22: 5562–5571.

  • Nemoto S, Fergusson MM, Finkel T . (2004). Science 306: 2105–2108.

  • Parant JM, Lozano G . (2003). Hum Mutat 21: 321–326.

  • Payne SR, Kemp CJ . (2005). Carcinogenesis 26: 2031–2045.

  • Rogel A, Popliker M, Webb CG, Oren M . (1985). Mol Cell Biol 5: 2851–2855.

  • Rubbi C, Milner J . (2003). EMBO J 22: 975–986.

  • Santarosa M, Ashworth A . (2004). Biochem Biophys Acta 1654: 105–122.

  • Soussi T, Lozano G . (2005). Biochem Biophys Res Commun 331: 834–842.

  • Varley JM, Evans DG, Birch JM . (1997). Br J Cancer 76: 1–14.

  • Venkatachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D et al. (1998). EMBO J 17: 4657–4667.

  • Venkatachalam S, Tyner SD, Pickering CR, Boley S, Recio L, French JE et al. (2001). Toxicol Pathol 29 (Suppl.): 147–154.

  • Vogelstein B, Lane D, Levine AJ . (2000). Nature 408: 307–310.

  • Vousden KH . (2002). Biochim Biophys Acta 1602: 47–59.

  • Vousden KH, Lu X . (2002). Nat Rev Cancer 2: 594–604.

  • Waldman T, Kinzler KW, Vogelstein B . (1995). Cancer Res 55: 5187–5190.

  • Williams KJ, Boyle JM, Birch JM, Norton JD, Scott D . (1997). Oncogene 14: 277–282.

  • Yanokura M, Takase K, Yamamoto K, Teraoka H . (2000). Int J Radiat Biol 76: 295–303.

Download references

Acknowledgements

We thank Dr Carlos Rubbi, Dr Jack Ford, Dr Ming Jiang and Dr Simon Allison for primer design and much advice. We thank Bert Vogelstein for generously making available the HCT116 isogenic clones of p53+/+, +/− and −/−. Grant support: Yorkshire Cancer Research (J Milner).

Author information

Authors and Affiliations

  1. Department of Biology, YCR p53 Research Laboratory, University of York, York, UK

    C J Lynch & J Milner

Authors
  1. C J Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Milner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Milner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lynch, C., Milner, J. Loss of one p53 allele results in four-fold reduction of p53 mRNA and protein: a basis for p53 haplo-insufficiency. Oncogene 25, 3463–3470 (2006). https://doi.org/10.1038/sj.onc.1209387

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209387

Keywords

This article is cited by

Search

Advanced search

Quick links