Abstract
In vitro studies have shown that p53 mediates a protective response against DNA damage by causing either cell-cycle arrest and DNA repair, or apoptosis. These responses have not yet been demonstrated in humans. A common source of DNA damage in humans is cigarette smoke, which should activate p53 repair mechanisms. As the level of p53 is regulated by MDM2, which targets p53 for degradation, the G-allele of a polymorphism in intron 1 of MDM2 (rs2279744:G/T), that results in higher MDM2 levels, should be associated with a reduced p53 response and hence more DNA damage and corresponding tissue destruction. Similarly, the alleles of rs1042522 in TP53 that encode arginine (G-allele) or proline (C-allele) at codon 72, which cause increased pro-apoptotic (G-allele) or cell-cycle arrest activities (C-allele), respectively, may moderate p53’s ability to prevent DNA damage. To test these hypotheses, we examined lung function in relation to cumulative history of smoking in a population-based cohort. The G-alleles in MDM2 and TP53 were found to be associated with accelerated smoking-related decline in lung function. These data support the hypothesis that p53 protects from DNA damage in humans and provides a potential explanation for the variation in lung function impairment amongst smokers.
Similar content being viewed by others
References
Arif E, Vibhuti A, Deepak D, Singh B, Siddiqui MS, Pasha MAQ (2008) COX2 and p53 risk-alleles coexist in COPD. Clin Chim Acta 397:46–50
Bansal A, van den Boom D, Kammerer S, Honisch C, Adam G, Cantor CR, Kleyn P, Braun A (2002) Association testing by DNA pooling: an effective initial screen. Proc Natl Acad Sci USA 99:16871–16874
Beckman G, Birgander R, Sjalander A, Saha N, Holmberg PA, Kivela A, Beckman L (1994) Is p53 polymorphism maintained by natural selection? Hum Hered 44:266–270
Bojesen SE, Nordestgaard BG (2008) The common germline Arg72Pro polymorphism of p53 and increased longevity in humans. Cell Cycle 7:158–163
Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602
Bond GL, Hu W, Levine AJ (2005) MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5:3–8
Braithwaite AW, Prives CL (2006) p53: more research and more questions. Cell Death Differ 13:877–880
Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014
Donehower LA, Harvey M, Slagle BL, Mcarthur MJ, Montgomery CA, Butel JS, Bradley A (1992) Mice deficient for P53 are developmentally normal but susceptible to spontaneous tumors. Nature 356:215–221
Dumont P, Leu JI, Della PAIII, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33:357–365
Fan R, Wu MT, Miller D, Wain JC, Kelsey KT, Wiencke JK, Christiani DC (2000) The p53 codon 72 polymorphism and lung cancer risk. Cancer Epidemiol Biomark Prevent 9:1037–1042
Hancox RJ, Poulton R, Greene JM, Filsell S, McLachlan CR, Rasmussen F, Taylor DR, Williams MJ, Williamson A, Sears MR (2007) Systemic inflammation and lung function in young adults. Thorax 62:1064–1068
Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, El Naggar AK, Lozano G (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861–872
Lee YL, Chen W, Tsai WK, Lee JC, Chiou HL, Shih CM, Wang YC (2006) Polymorphisms of p53 and p21 genes in chronic obstructive pulmonary disease. J Lab Clin Med 147:228–233
Leu JI, Dumont P, Hafey M, Murphy ME, George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6:443–450
Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH (1990) Germ line P53 mutations in a familial syndrome of breast-cancer, sarcomas, and other neoplasms. Science 250:1233–1238
Matakidou A, Eisen T, Houlston RS (2003) TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis. Mutagenesis 18:377–385
Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245
Murphy ME (2006) Polymorphic variants in the p53 pathway. Cell Death Differ 13:916–920
Orsted DD, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG (2007) Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population. J Exp Med 204:1295–1301
Pim D, Banks L (2004) p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer 108:196–199
Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J (2007) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:532–555
Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbison GP, Sears MR (2002) Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med 165:1480–1488
Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison GP, Silva PA, Poulton R (2003) A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. N Engl J Med 349:1414–1422
Standardization of Spirometry (1995) 1994 Update. Am J Respir Critical Care Med 152:1107–1136
Thomas M, Kalita A, Labrecque S, Pim D, Banks L, Matlashewski G (1999) Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol Cell Biol 19:1092–1100
van Heemst D, Mooijaart SP, Beekman M, Schreuder J, de Craen AJM, Brandt BW, Slagboom PE, Westendorp RGJ (2005) Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol 40:11–15
Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604
Yu ZK, Geyer RK, Maki CG (2000) MDM2-dependent ubiquitination of nuclear and cytoplasmic P53. Oncogene 19:5892–5897
Acknowledgments
This work was supported by the Health Research Council of New Zealand (03/27); Dunedin School of Medicine Strategic Research Initiative Grant; the US National Institute of Mental Health (grants MH45070, MH49414 and MH077874), and the UK Medical Research Council (G0100527). DNA collection and extraction was funded by the University of Wisconsin. Dr. Sears holds the AstraZeneca Chair in Respiratory Epidemiology at McMaster University. Avshalom Caspi holds a Royal Society Wolfson Merit Award. Professor Braithwaite is a Cancer Institute NSW Programme Leader. We are grateful to the Study members and their parents for their continued support. We also thank Dr. Phil A. Silva, the study founder. Mr. T. Manley is thanked for assistance with the genotyping. The authors have no conflicting financial interests.
These studies were carried out according to current New Zealand standards with ethical approval and informed individual consents.
Author information
Authors and Affiliations
Corresponding author
Additional information
Christene R. McLachlan is deceased.
Rights and permissions
About this article
Cite this article
Hancox, R.J., Poulton, R., Welch, D. et al. Accelerated decline in lung function in cigarette smokers is associated with TP53/MDM2 polymorphisms. Hum Genet 126, 559–565 (2009). https://doi.org/10.1007/s00439-009-0704-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-009-0704-z