Mammalian Genome

, Volume 15, Issue 6, pp 415–423 | Cite as

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

  • Susan C. EvansEmail author
  • Min Liang
  • Christopher Amos
  • Xiangjun Gu
  • Guillermina Lozano
Original Contributions


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.


Genetic Modifier Embryonic Lethality Congenic Mouse Simple Sequence Length Polymorphism Recessive Locus 



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.


  1. Almog, N, Rotter, V 1997Involvement of p53 in cell differentiation and developmentBiochim Biophys Acta1333F127PubMedGoogle Scholar
  2. Armstrong, JF, Kaufman, MH, Harrison, DJ, Clarke, AR 1995High-frequency developmental abnormalities in p53-deficient miceCurr Biol5931936CrossRefPubMedGoogle Scholar
  3. Barlow, C, Liyanage, M, Moens, PB, Deng, CX, Ried, T, Wynshaw-Boris, A 1997Partial rescue of the prophase I defects of Atm-deficient mice by p53 and p21 null allelesNat Genet17462466CrossRefPubMedGoogle Scholar
  4. Bascom-Slack, CA, Ross, LO, Dawson, DS 1997Chiasmata, crossovers, and meiotic chromosome segregationAdvances in Genetics35253PubMedGoogle Scholar
  5. Choi, J, Donehower, LA 1999p53 in embryonic development: maintaining a fine balanceCell Mol Life Sci553847CrossRefPubMedGoogle Scholar
  6. Cottingham, RW, Idury, Jr., RM, Schaffer, AA 1993Faster sequential genetic linkage computationsAm J Hum Genet53252263PubMedPubMedCentralGoogle Scholar
  7. Donehower, LA, Harvey, M, Slagle, BL, McArthur, MJ, Montgomery, CA, Butel, Jr., JS, Bradley, A 1992Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumoursNature356215221CrossRefPubMedGoogle Scholar
  8. Donehower, LA, Harvey, M, Vogel, H, McArthur, MJ, Montgomery, CA, Park, Jr., SH, Thompson, T, Ford, RJ, Bradley, A 1995Effects of genetic background on tumorigenesis in p53-deficient miceMol Carcinog141622CrossRefPubMedGoogle Scholar
  9. Eizenberg, O, Faber-Elman, A, Gottlieb, E, Oren, M, Rotter, V, Schwartz, M 1996p53 plays a regulatory role in differentiation and apoptosis of central nervous system-associated cellsMol Cell Biol165178185CrossRefPubMedPubMedCentralGoogle Scholar
  10. Evans, SC, Lozano, G 1997The Li-Fraumeni syndrome: an inherited susceptibility to cancerMol Med Today3390395CrossRefPubMedGoogle Scholar
  11. Evans, SC, Mims, B, McMasters, KM, Foster, CJ, deAndrade, M, Amos, CI, Strong, LC, Lozano, G 1998Exclusion of a p53 germline mutation in a classic Li-Fraumeni syndrome familyHum Genet102681686CrossRefPubMedGoogle Scholar
  12. Frebourg, T, Barbier, N, Yan, YX, Garber, JE, Dreyfus, M, Fraumeni, J,Jr., Li, FP, Friend, SH 1995Germ-line p53 mutations in 15 families with Li-Fraumeni syndromeAm J Hum Genet56608615PubMedPubMedCentralGoogle Scholar
  13. Hakem, R, Pompa, JL, Elia, A, Potter, J, Mak, TW 1997Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutationNat Genet16298302CrossRefPubMedGoogle Scholar
  14. Harvey, M, McArthur, MJ, Montgomery, CA,Jr., Bradley, A, Donehower, , LA,  1993Genetic background alters the spectrum of tumors that develop in p53-deficient miceFaseb J7938943CrossRefPubMedGoogle Scholar
  15. Heston, WE 1963Genetics of neoplasiaBurdette, WJ eds. Methodology in mammalian geneticsHolden-DaySan Francisco247268Google Scholar
  16. Hodge, SE, Elston, RC 1994Lods, wrods, and mods: the interpretation of lod scores calculated under different modelsGenet Epidemiol11329342CrossRefPubMedGoogle Scholar
  17. Hwang, S-J, Lozano, G, Amos, CI, Strong, LC 2003Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer riskAm J Hum Genet72975CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jacks, T, Remington, L, Williams, BO, Schmitt, EM, Halachmi, S, Bronson, RT, Weinberg, RA 1994Tumor spectrum analysis in p53-mutant miceCurr Biol417CrossRefPubMedGoogle Scholar
  19. Jones, SN, Roe, AE, Donehower, LA, Bradley, A 1995Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53Nature378206208CrossRefPubMedGoogle Scholar
  20. Kleihues, P, Schauble, B, zur Hausen, A, Esteve, J, Ohgaki, H 1997Tumors associated with p53 germline mutations: a synopsis of 91 familiesAm J Pathol150113PubMedPubMedCentralGoogle Scholar
  21. Lim, DS, Hasty, P 1996A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53Mol Cell Biol1671337143CrossRefPubMedPubMedCentralGoogle Scholar
  22. Ludwig, T, Chapman, DL, Papaioannou, VE, Efstratiadis, A 1997Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryosGenes Dev1112261241CrossRefPubMedGoogle Scholar
  23. MacLean, CJ, Bishop, DT, Sherman, SL, Diehl, SR 1993Distribution of lod scores under uncertain mode of inheritanceAm J Hum Genet52354361PubMedPubMedCentralGoogle Scholar
  24. MontesOca Luna, R, Wagner, DS, Lozano, G 1995Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53Nature378203206CrossRefGoogle Scholar
  25. Murphy, ED 1966Characteristic tumorsGreen, EL eds. Biology of the laboratory mouse2McGraw-HillNew York521562Google Scholar
  26. Nicol, CJ, Harrison, ML, Laposa, RR, Gimelshtein, IL, Wells, PG 1995A teratologic suppressor role for p53 in benzo[a]pyrene-treated transgenic p53-deficient miceNat Genet10181187CrossRefPubMedGoogle Scholar
  27. Ott, J 1999Analysis of Human Genetic Linkage3Johns Hopkins University PressBaltimoreGoogle Scholar
  28. Pani, L, Horal, M, Loeken, MR 2002Rescue of neural tube defects in Pax-3-deficient embryos by p53 loss of function: implications for Pax-3-dependent development and tumorigenesisGenes Dev1667680CrossRefPubMedPubMedCentralGoogle Scholar
  29. Sah, VP, Attardi, LD, Mulligan, GJ, Williams, BO, Bronson, RT, Jacks, T 1995A subset of p53-deficient embryos exhibit exencephalyNat Genet1017580CrossRefPubMedGoogle Scholar
  30. Strong, LC, Stine, M, Norsted, TL 1987Cancer in survivors of childhood soft tissue sarcoma and their relativesJ Natl Cancer Inst79121320PubMedGoogle Scholar
  31. Varley, JM, McGown, G, Thorncroft, M, Santibanez-Koref, MF, Kelsey, AM, Tricker, KJ, Evans, DG, Birch, JM 1997Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 familiesCancer Res57324552PubMedGoogle Scholar
  32. Vogel, KS, Parada, LF 1998Sympathetic neuron survival and proliferation are prolonged by loss of p53 and neurofibrominMol Cell Neurosci111928CrossRefPubMedGoogle Scholar
  33. Weir, BS 1996Genetic Data Analysis IISinauer Associates, Inc.SunderlandGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Susan C. Evans
    • 1
    Email author
  • Min Liang
    • 1
  • Christopher Amos
    • 2
  • Xiangjun Gu
    • 2
  • Guillermina Lozano
    • 3
  1. 1.Department of Chemistry and BiochemistryOhio UniversityAthensUSA
  2. 2.Department of EpidemiologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of Molecular GeneticsThe University of Texas M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations