Female embryonic lethality in mice nullizygous for both Msh2 and p53.
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 carcinogenesis. 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 damage. Mutations in one of these MMR genes, hMSH2, account for about half of all cases of genetically linked hereditary non-polyposis colorectal cancer. Loss of function of p53 has also been proposed to increase cellular hypermutability, thereby accelerating carcinogenesis, although a clear role for p53 in genomic instability remains controversial. p53 is mutated frequently in a wide range of human cancers, including colonic tumours. Both Msh2- and p53-targeted knockout mice are viable and susceptible to cancer. 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.
Cranston
A
A
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Bocker
T
T
Reitmair
A
A
Palazzo
J
J
Wilson
T
T
Mak
T
T
Fishel
R
R
D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D005327:Fetal Resorption / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D011247:Pregnancy; D011336:Probability; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D012727:Sex Characteristics; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein