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A common polymorphism acts as an intragenic modifier of mutant p53 behaviour

Abstract

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.

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Figure 1: Binding of a p53 mutant to p73α.
Figure 2: A p53 mutant blocks DNA binding and transactivation by p73.
Figure 3: Binding of mutant p53 to p73 under physiological conditions.
Figure 4: Heteroligomerization of p73 with conformational p53 mutants governed by TP53 codon 72 R/P polymorphism.
Figure 5: p73-mediated growth suppression of SAOS2 cells is blocked by p53 mutants that bind to p73.

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Acknowledgements

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.

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Correspondence to William G. Kaelin Jr.

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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

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