The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kaelin, W.G. The emerging p53 gene family. J. Natl Cancer Inst. 91, 594–598 (1999).
Mateu, M. & Ferssht, A. Mutually compensatory mutations during evolution of the tetramerization domain of tumor suppressor p53 lead to impaired hetero-oligomerizaton. Proc. Natl Acad. Sci. USA 96, 3595–3599 (1999).
Marin, M.C., Jost, C., DeCaprio, J.A., Caput, D. & Kaelin, W.G. Viral oncoproteins discriminate between p53 and the p53 homolog p73. Mol. Cell. Biol. 18, 6316– 6324 (1998).
Kaghad, M. et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809–819 ( 1997).
De Laurenzi, V. et al. Two new p73 splice variants, γ and δ, with different transcriptional activity. J. Exp. Med. 188, 1763–1768 (1998).
Davison, T. et al. p73 and p63 are homotetramers capable of weak heterotypic interactions with each other but not with p53. J. Biol. Chem. 274, 18709–18714 (1999).
Levine, A. et al. The spectrum of mutations at the p53 locus. Ann. NY Acad. Sci. 768, 111–128 (1995).
Harris, N. et al. Molecular basis for heterogeneity of the human p53 protein. Mol. Cell. Biol. 6, 4650–4656 (1986).
Zambetti, G.R. & Levine, A.J. A comparison of the biological activities of wild-type and mutant p53. FASEB J. 7, 855–865 (1993).
Orfy, K., Legros, Y., Auguin, C. & Soussi, T. Analysis of the most representative tumor-derived p53 mutants reveals changes in protein conformation are not correlated with loss of transactivation or inhibition of cell proliferation . EMBO J. 13, 3496–3504 (1994).
Yang, A. et al. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death inducing, and dominant-negative activities. Mol. Cell 2, 305–316 ( 1998).
Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–708 (1999).
Mills, A.A. et al. p63 is a p53 homologue required for limb and epidermal morphogenesis . Nature 398, 708–713 (1999).
Jost, C., Marin, M. & Kaelin, W.G. p73 is a human p53-related protein that can induce apoptosis . Nature 389, 191–194 (1997).
Kovalev, S., Marchenko, N., Swendemann, S., LaQuaglia, M. & Moll, U.M. Expression level, allelic origin and mutation analysis of the p73 gene in neuroblastoma tumors and cell lines . Cell. Growth Differ. 9, 897– 903 (1998).
Brash, D. et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc. Natl Acad. Sci. USA 88, 10124–10128 (1991).
McGregor, J. et al. p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. Oncogene 14, 1737–1740 (1997).
Brachman, D.G. et al. Occurrence of p53 gene deletions and human papilloma virus infection in human head and neck cancer. Cancer Res. 52, 4832–4836 (1992).
Di Como, C., Gaiddon, C. & Prives, C. p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol. Cell. Biol. 19, 1438–1449 (1999).
Hollstein, M.K. et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551– 3555 (1994).
Dittmer, D. et al. Gain of function mutations in p53. Nature Genet . 4, 42–46 ( 1993).
Shaulsky, G., Goldfinger, N. & Rotter, V. Alterations in tumor development in vivo mediated by expression of wild type or mutant p53 proteins. Cancer Res. 51, 5232–5237 (1991).
Halevy, O., Michalovitz, D. & Oren, M. Different tumor-derived p53 mutants exhibit distinct biological activities. Science 250, 113– 116 (1990).
Li, R. et al. Mutant p53 protein expression interferes with p53-independent apoptotic pathways. Oncogene 16, 3269– 3277 (1998).
Blandino, G., Levine, A. & Oren, M. Mutant p53 gain of function: differential effects of different p53 mutants on resistence of cultured cells to chemotherapy. Oncogene 2, 477–485 ( 1999).
Gong, J. et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399, 806–809 (1999).
Sakamuro, D., Sabbatini, P., White, E. & Prendergast, G.C. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15, 887–898 ( 1997).
Walker, K. & Levine, A. Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc. Natl Acad. Sci. USA 93, 15335–15340 (1996).
Murata, M. et al. Analysis of a germ line polymorphism of the p53 gene in lung cancer patients; discrete results with smoking history. Carcinogenesis 17, 261–264 ( 1996).
Weston, A. et al. Determination of the allelic frequencies of an L-myc and a p53 polymorphism in human lung cancer. Carcinogenesis 15, 583–587 (1994).
Jin, X. et al. Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype. Carcinogenesis 16, 2205–2208 (1995).
Birgander, R. et al. p53 polymorphisms and haplotypes in lung cancer. Carcinogenesis 16, 2233–2236 (1995).
Kawajiri, K., Nakachi, K., Imai, K., Watanabe, J. & Hayashi, S.-I. Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis 14, 1085–1089 (1993).
Zhang, W., Hu, G. & Deisseroth, A. Polymorphism at codon 72 of the p53 gene in human acute myelogenous leukemia. Gene 117, 271– 275 (1992).
Rosenthal, A. et al. p53 codon 72 polymorphism and risk of cervical cancer in UK . Lancet 352, 871–872 (1998).
Minaguchi, T. et al. No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection. Cancer Res. 20, 4585– 4586 (1998).
Hildesheim, A. et al. p53 polymorphism and risk of cervical cancer. Nature 396, 531–532 ( 1998).
Helland, A. et al. p53 polymorphism and risk of cervical cancer. Nature 396, 530–531 ( 1998).
Josefsson, A. et al. p53 polymorphism and risk of cervical cancer. Nature 396, 531 (1998).
Lanham, S., Campbell, I., Watt, P. & Gornall, R. p53 polymorphism and risk of cervical cancer. Lancet 352, 1631 (1998).
Storey, A. et al. p53 polymorphism and risk of cervical cancer. Nature 396, 532 (1998).
Beckman, G. et al. Is p53 polymorphism maintained by natural selection. Hum. Hered. 44, 266–270 (1994).
Baker, S.J., Markowitz, S., Fearon, E., Willson, B. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249 , 912–915 (1990).
Hinds, P.W. et al. Mutant p53 cDNAs from human colorectal carcinomas can cooperate with ras in transformation of primary rate cells. Cell Growth Differ . 1, 571–580 ( 1990).
Crook, T., Marston, N., Sara, E. & Vousden, K. Transcriptional activation by p53 correlates with suppression of growth but not transformation . Cell 79, 817–827 (1994).
Unger, T., Mietz, J., Scheffner, M., Yee, C. & Howley, P. Functional domains of wild-type and mutant p53 proteins involved in transcriptional regulation, transdominant inhibition, and transformation suppression. Mol. Cell. Biol. 13, 5186–5194 (1993).
El-Deiry, W.S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 ( 1993).
Nigro, J.M. et al. Mutations in the p53 gene occur in diverse human tumour types . Nature 342, 705–708 (1989).
Jones, M. & Nakamura, Y. Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosomes Cancer 1, 89–90 (1992).
We thank D. Brash, C. Maki and members of the Kaelin and Crook Laboratory for useful discussions; C. DiComo and C. Prives for sharing their data before publication; A. Fernandez for support and discussions; and L. Billingham and D. Moffit for statistical advice. M.C.M. is funded by an NIH training grant to D.F.C.I., L.A.B. is funded by the Medical Research Coucil, J.O. by the Leukemia Research Fund, M.S.I. is funded by American Cancer Society and I.G.Y. by British Council in Turkey. T.C. is supported by the Leopold Muller Trust and W.G.K. is a Howard Hughes Medical Institute assistant investigator. This work was sponsored in part by the National Cancer Institute, DHHS, under contract with ABL.
Howard Hughes Medical Institute
About this article
Cite this article
Marin, M., Jost, C., Brooks, L. et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 25, 47–54 (2000). https://doi.org/10.1038/75586
Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance
Science Advances (2020)
Current Gene Therapy (2020)
Targeted next generation sequencing identifies somatic mutations in a cohort of Egyptian breast cancer patients
Journal of Advanced Research (2020)
Oral squamous cell carcinoma of the tongue dorsum with multiple cancer-associated mutations in the TP53 gene
Oral Oncology (2020)