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.
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.
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
Corresponding author
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209387
- Springer Nature Limited
Keywords
This article is cited by
-
Single loss of a Trp53 allele triggers an increased oxidative, DNA damage and cytokine inflammatory responses through deregulation of IκBα expression
Cell Death & Disease (2021)
-
A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo
Oncogene (2018)
-
Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in a p53-dependent manner
Oncogenesis (2017)
-
Carcinogenic polycyclic aromatic hydrocarbons induce CYP1A1 in human cells via a p53-dependent mechanism
Archives of Toxicology (2016)
-
Expression of vimentin and survivin in clear cell renal cell carcinoma and correlation with p53
Clinical and Translational Oncology (2015)