Female embryonic lethality in mice nullizygous for both Msh2 and p53

Abstract

The mutator hypothesis of tumorigenesis suggests that loss of chromosomal stability or maintenance functions results in elevated mutation rates, leading to the accumulation of the numerous mutations required for multistep carcinogenesis1. The human DNA mismatch repair (MMR) genes are highly conserved homologues of the Escherichia coli MutHLS system, which contribute to genomic stability by surveillance and repair of replication misincorporation errors and exogenous DNA damage2. Mutations in one of these MMR genes, HMSH2, account for about half of all cases of genetically linked hereditary non-polyposis colorectal cancer3,4. Loss of function of p53 has also been proposed to increase cellular hypermutability, thereby accelerating carcinogenesis5, although a clear role for p53 in genomic instability remains controversial2. p53 is mutated frequently in a wide range of human cancers, including colonic tumours6. Both Msh2- and p53-targeted knockout mice are viable and susceptible to cancer7–11. Here we demonstrate that combined Msh2 and p53 ablation (Msh2−/−p53−/−) results in developmental arrest of all female embryos at 9.5 days. In contrast, male Msh2−/−p53−/− mice are viable, but succumb to tumours significantly earlier (t1/2 is 73 days) than either Msh2−/− or p53−/− littermates. Furthermore, the frequency of microsatellite instability (MSI) in tumours from Msh2−/−p53−/− mice is not significantly different than in Msh2−/− mice. Synergism in tumorigenesis and independent segregation of the MSI phenotype suggest that Msh2 and p53 are not genetically epistatic.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Loeb, L.A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Fishel, R. & Wilson, T. MutS homologs in mammalian cells. Curr. Opin. Genet. Dev. 7, 105–113 (1997).

    CAS  Article  Google Scholar 

  3. 3

    Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer [published erratum appears in Cell 77, 1994]. Cell 75, 1027–1038 (1993).

    CAS  Article  Google Scholar 

  4. 4

    Nyström Lahti, M. et al. Mismatch repair genes on chromosomes 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families evaluable by linkage. Am. J. Hum. Genet. 55, 659–665 (1994).

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Kastan, M.B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

    CAS  Article  Google Scholar 

  6. 6

    Fearon, E. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    CAS  Article  Google Scholar 

  7. 7

    De Wind, N., Dekker, M., Berns, A., Radman, M. & te Riele, H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Reitmair, A.M. et al. MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nature Genet. 11, 64–70 (1995).

    CAS  Article  Google Scholar 

  9. 9

    Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    CAS  Article  Google Scholar 

  10. 10

    Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Purdie, C.A. et al. Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9, 603–609 (1994).

    CAS  Google Scholar 

  12. 12

    Sah, V.P. et al. A subset of p53-deficient embryos exhibit exencephaly. Nature Genet. 10, 175–180 (1995).

    CAS  Article  Google Scholar 

  13. 13

    Nicol, C.J., Harrison, M.L., Laposa, R.R., Gimelshtein, I.L. & Wells, P.G. A teratologic suppressor role for p53 in benzo[a]pyrene-treated transgenic p53-deficient mice. Nature Genet. 10, 181–187 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Blyth, K. et al. Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. Oncogene 10, 1717–1723 (1995).

    CAS  PubMed  Google Scholar 

  15. 15

    Williams, B.O., Morgenbesser, S.D., DePinho, R.A. & Jacks, T. Tumorigenic and developmental effects of combined germ-line mutations in Rb and p53. Cold Spring Harbor Symp. Quant. Biol. 59, 449–457 (1994).

    CAS  Article  Google Scholar 

  16. 16

    Williams, B.O. et al. Cooperative tumorigenic effects of germline mutations in Rb and p53. Cell 79, 329–339 (1994).

    Article  Google Scholar 

  17. 17

    Donehower, L.A. et al. Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes Dev. 9, 882–895 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Nacht, M. et al. Mutations in the p53 and SC/D genes cooperate in tumorigenesis. Genes Dev. 10, 2055–2066 (1996).

    CAS  Article  Google Scholar 

  19. 19

    Lyon, M.F. Gene action in the X chromosome of the mouse (Mus musculus L). Nature 190, 372–373 (1961).

    CAS  Article  Google Scholar 

  20. 20

    Rastan, S. X chromosome inactivation and the Xist gene. Curr. Opin. Genet. Dev. 4, 292–297 (1994).

    CAS  Article  Google Scholar 

  21. 21

    Theiler, K., The House Mouse Development and Normal Stages from Fertilization to 4 Weeks of Age, 168 (Springer-Verlag, New York, 1972).

  22. 22

    Taylor, J.H. Asynchronous replication of chromosomes in cultured cells of Chinese hamster. J. Biophys. Biochem. Cytol. 7, 455–464 (1960).

    CAS  Article  Google Scholar 

  23. 23

    Tagaki, N. Differentiation of the X chromosomes in early female mouse embryos.. Exp. Cell Res. 86, 127–135 (1974).

    Article  Google Scholar 

  24. 24

    Baker, S.J., Markowitz, S., Fearon, E.R., Willson, J.K. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).

    CAS  Article  Google Scholar 

  25. 25

    Diller, L. et al. p53 functions as a cell cycle control protein in osteosarcomas. Mol. Cell. Biol. 10, 5772–5781 (1990).

    CAS  Article  Google Scholar 

  26. 26

    Lin, D., Shields, M.T., Ullrich, S.J., Appella, E. & Mercer, W.E. Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. Proc. Natl. Acad. Sci. USA 89, 9210–9214 (1992).

    CAS  Article  Google Scholar 

  27. 27

    Hawn, M.T. et al. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 55, 3721–3725 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Marra, G. et al. Expression of human MutS homolog 2 (hMSH2) protein in resting and proliferating cells. Oncogene 13, 2189–2196 (1996).

    CAS  PubMed  Google Scholar 

  29. 29

    Rogel, A., Popliker, M., Webb, C.G. & Oren, M. p53 cellular tumor antigen: analysis of mRNA levels in normal adult tissues, embryos, and tumors. Mol. Cell. Biol. 5, 2851–2855 (1985).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cranston, A., Bocker, T., Reitmair, A. et al. Female embryonic lethality in mice nullizygous for both Msh2 and p53. Nat Genet 17, 114–118 (1997). https://doi.org/10.1038/ng0997-114

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing