Tumor spectrum analysis in p53-mutant mice.
BACKGROUND
The p53 tumor suppressor gene is mutated in a large percentage of human malignancies, including tumors of the colon, breast, lung and brain. Individuals who inherit one mutant allele of p53 are susceptible to a wide range of tumor types. The gene encodes a transcriptional regulator that may function in the cellular response to DNA damage. The construction of mouse strains carrying germline mutations of p53 facilitates analysis of the function of p53 in normal cells and tumorigenesis.


RESULTS
In order to study the effects of p53 mutation in vivo, we have constructed a mouse strain carrying a germline disruption of the gene. This mutation removes approximately 40% of the coding capacity of p53 and completely eliminates synthesis of p53 protein. As observed previously for a different germline mutation of p53, animals homozygous for this p53 deletion mutation are viable but highly predisposed to malignancy. Heterozygous animals also have an increased cancer risk, although the distribution of tumor types in these animals differs from that in homozygous mutants. In most cases, tumorigenesis in heterozygous animals is accompanied by loss of the wild-type p53 allele.


CONCLUSIONS
We reaffirm that p53 function is not required for normal mouse development and conclude that p53 status can strongly influence tumor latency and tissue distribution.
Jacks
T
T
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139.
Remington
L
L
Williams
B O
BO
Schmitt
E M
EM
Halachmi
S
S
Bronson
R T
RT
Weinberg
R A
RA
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002678:Chimera; D002872:Chromosome Deletion; D003433:Crosses, Genetic; D004249:DNA Damage; D017931:DNA Primers; D005260:Female; D016158:Genes, p53; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics*; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000302:isolation & purification
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53