Abstract
Mouse strains with humanised p53 genes have been constructed to expand the arsenal of gene-targeted models available to investigate p53 biology. Normal polymorphic p53 variants, post-translational modification sites, and different classes of human tumour p53 mutants are being investigated in a mouse model in which both endogenous p53 alleles have had the majority of their coding sequences replaced with the homologous human sequence. New strategies to generate sets of mutant mice and cell lines efficiently and reproducibly are being developed to explore the complexities of oncogenic properties acquired by different p53 mutants.
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References
Attardi LD, Donehower LA (2005) Probing p53 biological functions through the use of genetically engineered mouse models. Mutat Res 576:4–21
Baroni TE, Wang T, Qian H, Dearth LR, Truong LN, Zeng J et al (2004) A global suppressor motif for p53 cancer mutants. Proc Natl Acad Sci USA 101:4930–4935
Belteki G, Gertsenstein M, Ow DW, Nagy A (2003) Site-specific cassette exchange and germline transmission with mouse ES cells expressing phiC31 integrase. Nat Biotechnol 21:321–324
Bond GL, Levine AJ (2007) A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumour genetics to influence cancer in humans. Oncogene 26:1317–1323
Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9:701–713
Capecchi MR (2005) Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nat Rev Genet 6:507–512
Chalberg TW, Portlock JL, Olivares EC, Thyagarajan B, Kirby PJ, Hillman RT et al (2006) Integration specificity of phage phiC31 integrase in the human genome. J Mol Biol 357:28–48
Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362:849–852
Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS et al (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221
Donehower LA, Lozano G (2009) 20 years studying p53 functions in genetically engineered mice. Nat Rev Cancer 9:831–841
Dudgeon C, Kek C, Dmeidov ON, Saito S, Fernandes K, Diot A et al (2006) Tumor susceptibility and apoptosis defect in a mouse strain expressing a human p53 transgene. Cancer Res 66:2928–2936
Feng L, Hollstein M, Xu Y (2006) Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence. Cell Cycle 5:2812–2819
Frank A, Leu J, Zho Y, Devarajan K, Nedelko T, Klein-Szanto A, Hollstein M, Murphy ME (2011) The codon 72 polymorphism of p53 regulates interaction with NF-kB and transactivation of genes involved in immunity and inflammation. Mol Cell Biol 31:1201–1213
Fraser JA, Vojtesek B, Hupp TR (2010) A novel p53 phosphorylation site within the MDM2 ubiquitination signal. J Biol Chem 285:37762–37772
Freese KK, Tuveson DA (2007) Maximizing mouse cancer models. Nat Rev Cancer 7:645–658
Glaser S, Anastassiadis K, Stewart AF (2005) Current issues in mouse genome engineering. Nat Genet 37:1187–1193
Goh AM, Coffill CR, Lane DP (2010) The role of mutant p53 in human cancer. J Pathol 223:116–126
Groth AC, Olivares EC, Thyagarajan B, Calos MP (2000) A phage integrase directs efficient site-specific integration in human cells. Proc Natl Acad Sci USA 97:5995–6000
Hahn WC, Weinberg RA (2002) Modelling the molecular circuitry of cancer. Nat Rev Cancer 2:331–341
Hainaut P, Hollstein M (2000) The first ten thousand mutations. Adv Cancer Res 77:81–137
Hergenhahn M, Luo JL, Hollstein M (2003) p53 designer genes for the modern mouse. Cell Cycle 3:738–741
Hollstein M, Hainaut P (2010) Massively regulated genes: the example of TP53. J Pathol 220:164–173
Hu W, Feng Z, Atwal GS, Levine AJ (2008) p53: a new player in reproduction. Cell Cycle 7:848–852
Ishizaki H, Song GY, Srivastava T, Carroll KD, Shahabi V, Manuel ER (2010) Heterologous prime/boost immunization with p53-based vaccines combined with toll-like receptor stimulation enhances tumor regression. J Immunother 33:609–617
Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, Weinberg RA (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4:1–7
Kenzelmann Broz D, Attardi LD (2010) In vivo analysis of p53 tumor suppressor function using genetically engineered mouse models. Carcinogenesis 31:1311–1318
Kruse JP, Gu W (2009) Modes of p53 regulation. Cell 137:609–622
Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM et al (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861–972
Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E et al (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol 7:165–171
Liu DP, Song H, Xu Y (2010) A common gain of function of p53 cancer mutants in inducing genetic instability. Oncogene 29:949–956
Liu Z, Hergenhahn M, Schmeiser HH, Wogan GN, Hong A, Hollstein M (2004) Human tumor p53 mutations are selected for in mouse embryonic fibroblasts harboring a humanized p53 gene. Proc Natl Acad Sci USA 101:2963–2968
Liu Z, Muehlbauer KR, Schmeiser HH, Hergenhahn M, Belharazem D, Hollstein M (2005) p53 mutations in benzo(a)pyrene-exposed human p53 knock-in murine fibroblasts correlate with p53 mutations in human lung tumors. Cancer Res 65:2583–2587
Lozano G (2010) Mouse models of p53 functions. Cold Spring Harb Perspect Biol 2:a001115
Luo JL, Yang Q, Tong WM, Hergenhahn M, Wang ZQ, Hollstein M (2001) Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool. Oncogene 20:320–328
Murray-Zmijewski F, Slee EA, Lu X (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nature Rev Mol Cell Biol 9:702–712
Nedelko T, Arlt VM, Phillips DH, Hollstein M (2009) TP53 mutation signature supports involvement of aristolochic acid in the aetiology of endemic nephropathy-associated tumors. Int J Cancer 124:987–990
Nelson CM, Bissell MJ (2006) Of extracellular matrix, scaffolds, and signalling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol 22:287–309
Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T et al (2000) p53AIP1, a potential mediator of p53-dependent apoptosis and its regulation by Ser-46-phosphorylated p53. Cell 102:849–862
Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT et al (2004) Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119:847–860
Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2(1):a001008
Otsuka K, Kato S, Kakudo Y, Mashiko S, Shibata H, Ishioka C (2007) The screening of the second-site suppressor mutations of the common p53 mutants. Int J Cancer 121:559–561
Pfeifer GP, Besaratinia A (2009) Mutational spectra of human cancer. Hum Genet 125:493–506
Raymond CS, Soriano P (2007) High-efficiency FLP and PhiC31 site-specific recombination in mammalian cells. PLoS One 2:e162
Reinbold M, Luo JL, Nedelko T, Jerchow B, Murphy ME, Whibley C et al (2008) Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72. Oncogene 27:2788–2794
Song GY, Gibson G, Haq W, Huang EC, Srivasta T, Hollstein M, Daftarian P, Wang Z, Diamond D, Ellenhorn JDI (2007a) An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer Immunol Immunother 56:1193–1205
Song H, Hollstein M, Xu Y (2007b) p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat Cell Biol 9:573–580
Soussi T, Caron de Fromentel C, May P (1990) Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5:945–952
Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS, McMahon SB (2006) Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell 24:841–851
Tang W, Ehrlich I, Wolff SB, Michalski AM, Wolf S, Hasan MT et al (2009) Faithful expression of multiple proteins via 2A-peptide self-processing: a versatile and reliable method for manipulating brain circuits. J Neurosci 29:8621–8629
Tang Y, Zhao W, Chen Y, Zhao Y, Gu W (2008) Acetylation is indispensable for p53 activation. Cell 133:612–626
Toledo F, Wahl GM (2006) Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Rev Cancer 6:909–923
Toledo F, Liu CW, Lee CJ, Wahl GM (2006) RMCE-ASAP: a gene targeting method for ES and somatic cells to accelerate phenotype analyses. Nucleic Acids Res 34:e92
Van Dyke T, Jacks T (2002) Cancer modelling in the modern era: progress and challenges. Cell 108:135–144
Vom Brocke J, Schmeiser HH, Reinbold M, Hollstein M (2006) MEF immortalization to investigate the ins and outs of mutagenesis. Carcinogenesis 27:2141–2147
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431
Wahl GM (2006) Mouse bites dogma: how mouse models are changing our views of how P53 is regulated in vivo. Cell Death Differ 13:973–983
Wei QX, Odell AF, van der Hoeven F, Hollstein M (2011) Rapid derivation of genetically related mutants from embryonic cells harbouring a recombinase-specific Trp53 platform. Cell Cycle 10:1261–1270
Whibley C, Pharoah PD, Hollstein M (2009) p53 polymorphisms: cancer implications. Nature Rev Cancer 9:95–107
Whibley C, Odell AF, Nedelko T, Balaburski G, Murphy M, Liu Z et al (2010) Wild-type and Hupki (human p53 knock-in) murine embryonic fibroblasts: p53/ARF pathway disruption in spontaneous escape from senescence. J Biol Chem 285:11326–11335
Xu Y (2008) Induction of genetic instability by gain-of-function p53 cancer mutants. Oncogene 27:3501–3507
Zhu F, Dolle MET, Berton TR, Kuiper RV, Capps C, Espejo A et al (2010) Mouse models for the p53 R72P polymorphism mimic human phenotypes. Cancer Res 70:5851–5859
Acknowledgements
The Hollstein laboratory acknowledges the financial support from Yorkshire Cancer Research, Cancer Research UK, and core support from the German Cancer Research Center. The Xu laboratory is funded by grants from NIH and California Institute for Regenerative Medicine.
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Hollstein, M., Xu, Y. (2013). Humanised Mouse Models: Targeting the Murine p53 Locus with Human Sequences. In: Hainaut, P., Olivier, M., Wiman, K. (eds) p53 in the Clinics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3676-8_6
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DOI: https://doi.org/10.1007/978-1-4614-3676-8_6
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