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A novel genetic modifier of p53, mop1, results in embryonic lethality

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Abstract

The heterogeneity that occurs in the tumor spectrum and latency in Li-Fraumeni syndrome (LFS) patients with inherited mutations in p53 suggest risk modifiers at loci other than the major gene. We developed a mouse model to investigate these risk modifiers. Inbred CE/J mice, which succumb to multiple types of tumors similar to those found in LFS, were crossed with the p53-null 129/Sv (129-Trp53tm1Tyj) mouse. In this cross, we uncovered evidence for a genetic modifier of p53, mop1, based on an unexpected mix of genotypes in the F2 progeny from Mendelian expectations. A model in which a recessive CE/J allele in combination with p53 heterozygosity or homozygosity results in lethality most closely fits the data. Using simple-sequence length polymorphism analysis of the entire genome, we identified a putative chromosomal region for this modifier of p53 on mouse chromosome 11 centromeric to p53.

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References

  • N Almog V Rotter (1997) ArticleTitleInvolvement of p53 in cell differentiation and development Biochim Biophys Acta 1333 F1–27 Occurrence Handle9294016 Occurrence Handle1:CAS:528:DyaK2sXksFagur4%3D

    PubMed  CAS  Google Scholar 

  • JF Armstrong MH Kaufman DJ Harrison AR Clarke (1995) ArticleTitleHigh-frequency developmental abnormalities in p53-deficient mice Curr Biol 5 931–936 Occurrence Handle10.1016/S0960-9822(95)00183-7 Occurrence Handle1:CAS:528:DyaK2MXnsVCis78%3D Occurrence Handle7583151

    Article  CAS  PubMed  Google Scholar 

  • C Barlow M Liyanage PB Moens CX Deng T Ried A Wynshaw-Boris (1997) ArticleTitlePartial rescue of the prophase I defects of Atm-deficient mice by p53 and p21 null alleles Nat Genet 17 462–466 Occurrence Handle10.1038/ng1297-462 Occurrence Handle1:CAS:528:DyaK2sXnvFWrsrk%3D Occurrence Handle9398851

    Article  CAS  PubMed  Google Scholar 

  • CA Bascom-Slack LO Ross DS Dawson (1997) ArticleTitleChiasmata, crossovers, and meiotic chromosome segregation Advances in Genetics 35 253 Occurrence Handle9348650 Occurrence Handle1:STN:280:DyaK1c%2FgvFaluw%3D%3D

    PubMed  CAS  Google Scholar 

  • J Choi LA Donehower (1999) ArticleTitlep53 in embryonic development: maintaining a fine balance Cell Mol Life Sci 55 38–47 Occurrence Handle10.1007/s000180050268 Occurrence Handle1:CAS:528:DyaK1MXhtV2lsL0%3D Occurrence Handle10065150

    Article  CAS  PubMed  Google Scholar 

  • RW Cottingham Jr., RM Idury AA Schaffer (1993) ArticleTitleFaster sequential genetic linkage computations Am J Hum Genet 53 252–263 Occurrence Handle8317490 Occurrence Handle1682239

    PubMed  PubMed Central  Google Scholar 

  • LA Donehower M Harvey BL Slagle MJ McArthur CA Montgomery Jr., JS Butel A Bradley (1992) ArticleTitleMice deficient for p53 are developmentally normal but susceptible to spontaneous tumours Nature 356 215–221 Occurrence Handle10.1038/356215a0 Occurrence Handle1:CAS:528:DyaK38XitFajsLc%3D Occurrence Handle1552940

    Article  CAS  PubMed  Google Scholar 

  • LA Donehower M Harvey H Vogel MJ McArthur CA Montgomery Jr., SH Park T Thompson RJ Ford A Bradley (1995) ArticleTitleEffects of genetic background on tumorigenesis in p53-deficient mice Mol Carcinog 14 16–22 Occurrence Handle10.1002/mc.2940140105 Occurrence Handle1:CAS:528:DyaK2MXotlKmsbs%3D Occurrence Handle7546219

    Article  CAS  PubMed  Google Scholar 

  • O Eizenberg A Faber-Elman E Gottlieb M Oren V Rotter M Schwartz (1996) ArticleTitlep53 plays a regulatory role in differentiation and apoptosis of central nervous system-associated cells Mol Cell Biol 16 5178–185 Occurrence Handle10.1128/MCB.16.9.5178 Occurrence Handle1:CAS:528:DyaK28XltFKjtLc%3D Occurrence Handle8756675 Occurrence Handle231518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • SC Evans G Lozano (1997) ArticleTitleThe Li-Fraumeni syndrome: an inherited susceptibility to cancer Mol Med Today 3 390–395 Occurrence Handle10.1016/S1357-4310(97)01105-2 Occurrence Handle1:CAS:528:DyaK2sXmt1Cmtbg%3D Occurrence Handle9302689

    Article  CAS  PubMed  Google Scholar 

  • SC Evans B Mims KM McMasters CJ Foster M deAndrade CI Amos LC Strong G Lozano (1998) ArticleTitleExclusion of a p53 germline mutation in a classic Li-Fraumeni syndrome family Hum Genet 102 681–686 Occurrence Handle10.1007/s004390050761 Occurrence Handle1:CAS:528:DyaK1cXktFKltrw%3D Occurrence Handle9703430

    Article  CAS  PubMed  Google Scholar 

  • T Frebourg N Barbier YX Yan JE Garber M Dreyfus J Fraumeni SuffixJr. FP Li SH Friend (1995) ArticleTitleGerm-line p53 mutations in 15 families with Li-Fraumeni syndrome Am J Hum Genet 56 608–615 Occurrence Handle7887414 Occurrence Handle1801151 Occurrence Handle1:CAS:528:DyaK2MXltlehtLw%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • R Hakem JL Pompa Particlede la A Elia J Potter TW Mak (1997) ArticleTitlePartial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation Nat Genet 16 298–302 Occurrence Handle10.1038/ng0797-298 Occurrence Handle1:CAS:528:DyaK2sXktFGnt7g%3D Occurrence Handle9207798

    Article  CAS  PubMed  Google Scholar 

  • M Harvey MJ McArthur CA Montgomery SuffixJr. A Bradley Donehower LA (1993) ArticleTitleGenetic background alters the spectrum of tumors that develop in p53-deficient mice Faseb J 7 938–943 Occurrence Handle10.1096/fasebj.7.10.8344491 Occurrence Handle1:CAS:528:DyaK3sXmt1ejtro%3D Occurrence Handle8344491

    Article  CAS  PubMed  Google Scholar 

  • WE Heston (1963) Genetics of neoplasia WJ Burdette (Eds) Methodology in mammalian genetics Holden-Day San Francisco 247–268

    Google Scholar 

  • SE Hodge RC Elston (1994) ArticleTitleLods, wrods, and mods: the interpretation of lod scores calculated under different models Genet Epidemiol 11 329–342 Occurrence Handle10.1002/gepi.1370110403 Occurrence Handle1:STN:280:DyaK2M7htlejsA%3D%3D Occurrence Handle7813895

    Article  CAS  PubMed  Google Scholar 

  • S-J Hwang G Lozano CI Amos LC Strong (2003) ArticleTitleGermline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk Am J Hum Genet 72 975 Occurrence Handle10.1086/374567 Occurrence Handle1:CAS:528:DC%2BD3sXivFWgurs%3D Occurrence Handle12610779 Occurrence Handle1180359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • T Jacks L Remington BO Williams EM Schmitt S Halachmi RT Bronson RA Weinberg (1994) ArticleTitleTumor spectrum analysis in p53-mutant mice Curr Biol 4 1–7 Occurrence Handle10.1016/S0960-9822(00)00002-6 Occurrence Handle1:CAS:528:DyaK2cXhvVygu7k%3D Occurrence Handle7922305

    Article  CAS  PubMed  Google Scholar 

  • SN Jones AE Roe LA Donehower A Bradley (1995) ArticleTitleRescue of embryonic lethality in Mdm2-deficient mice by absence of p53 Nature 378 206–208 Occurrence Handle10.1038/378206a0 Occurrence Handle1:CAS:528:DyaK2MXptlSmtb0%3D Occurrence Handle7477327

    Article  CAS  PubMed  Google Scholar 

  • P Kleihues B Schauble A zur Hausen J Esteve H Ohgaki (1997) ArticleTitleTumors associated with p53 germline mutations: a synopsis of 91 families Am J Pathol 150 1–13 Occurrence Handle9006316 Occurrence Handle1858532 Occurrence Handle1:STN:280:DyaK2s7lvV2ktw%3D%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • DS Lim P Hasty (1996) ArticleTitleA mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53 Mol Cell Biol 16 7133–7143 Occurrence Handle10.1128/MCB.16.12.7133 Occurrence Handle1:CAS:528:DyaK28XntVyrtLY%3D Occurrence Handle8943369 Occurrence Handle231717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • T Ludwig DL Chapman VE Papaioannou A Efstratiadis (1997) ArticleTitleTargeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos Genes Dev 11 1226–1241 Occurrence Handle10.1101/gad.11.10.1226 Occurrence Handle1:CAS:528:DyaK2sXjsFahs7g%3D Occurrence Handle9171368

    Article  CAS  PubMed  Google Scholar 

  • CJ MacLean DT Bishop SL Sherman SR Diehl (1993) ArticleTitleDistribution of lod scores under uncertain mode of inheritance Am J Hum Genet 52 354–361 Occurrence Handle8430696 Occurrence Handle1682196 Occurrence Handle1:STN:280:DyaK3s7lvVKisw%3D%3D

    PubMed  PubMed Central  CAS  Google Scholar 

  • R MontesOca Luna Particlede DS Wagner G Lozano (1995) ArticleTitleRescue of early embryonic lethality in mdm2-deficient mice by deletion of p53 Nature 378 203–206 Occurrence Handle10.1038/378203a0

    Article  Google Scholar 

  • ED Murphy (1966) Characteristic tumors EL Green (Eds) Biology of the laboratory mouse EditionNumber2 McGraw-Hill New York 521–562

    Google Scholar 

  • CJ Nicol ML Harrison RR Laposa IL Gimelshtein PG Wells (1995) ArticleTitleA teratologic suppressor role for p53 in benzo[a]pyrene-treated transgenic p53-deficient mice Nat Genet 10 181–187 Occurrence Handle10.1038/ng0695-181 Occurrence Handle1:CAS:528:DyaK2MXmtFCqt74%3D Occurrence Handle7663513

    Article  CAS  PubMed  Google Scholar 

  • J Ott (1999) Analysis of Human Genetic Linkage EditionNumber3 Johns Hopkins University Press Baltimore

    Google Scholar 

  • L Pani M Horal MR Loeken (2002) ArticleTitleRescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3-dependent development and tumorigenesis Genes Dev 16 676–80 Occurrence Handle10.1101/gad.969302 Occurrence Handle1:CAS:528:DC%2BD38XisVaju7o%3D Occurrence Handle11914272 Occurrence Handle155364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • VP Sah LD Attardi GJ Mulligan BO Williams RT Bronson T Jacks (1995) ArticleTitleA subset of p53-deficient embryos exhibit exencephaly Nat Genet 10 175–80 Occurrence Handle10.1038/ng0695-175 Occurrence Handle1:CAS:528:DyaK2MXmtFCqtrc%3D Occurrence Handle7663512

    Article  CAS  PubMed  Google Scholar 

  • LC Strong M Stine TL Norsted (1987) ArticleTitleCancer in survivors of childhood soft tissue sarcoma and their relatives J Natl Cancer Inst 79 1213–20 Occurrence Handle3480372 Occurrence Handle1:STN:280:DyaL1c%2FptFOisA%3D%3D

    PubMed  CAS  Google Scholar 

  • JM Varley G McGown M Thorncroft MF Santibanez-Koref AM Kelsey KJ Tricker DG Evans JM Birch (1997) ArticleTitleGerm-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families Cancer Res 57 3245–52 Occurrence Handle9242456 Occurrence Handle1:CAS:528:DyaK2sXkvFKqsLs%3D

    PubMed  CAS  Google Scholar 

  • KS Vogel LF Parada (1998) ArticleTitleSympathetic neuron survival and proliferation are prolonged by loss of p53 and neurofibromin Mol Cell Neurosci 11 19–28 Occurrence Handle10.1006/mcne.1998.0670 Occurrence Handle1:CAS:528:DyaK1cXjsFWgsbs%3D Occurrence Handle9608530

    Article  CAS  PubMed  Google Scholar 

  • BS Weir (1996) Genetic Data Analysis II Sinauer Associates, Inc. Sunderland

    Google Scholar 

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Acknowledgments

We thank Louise Strong for her scientific discussions and Carolyn Foster and Meera Narayana for their technical help. This work was supported by NIH grant CA79743, HG02275, and CA34936.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA

    Susan C. Evans & Min Liang

  2. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Christopher Amos & Xiangjun Gu

  3. Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Guillermina Lozano

Authors
  1. Susan C. Evans
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  2. Min Liang
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  3. Christopher Amos
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  4. Xiangjun Gu
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  5. Guillermina Lozano
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Correspondence to Susan C. Evans.

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Evans, S., Liang, M., Amos, C. et al. A novel genetic modifier of p53, mop1, results in embryonic lethality. Mamm Genome 15, 415–423 (2004). https://doi.org/10.1007/s00335-004-2327-y

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  • DOI: https://doi.org/10.1007/s00335-004-2327-y

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