Li-Fraumeni syndrome (LFS) is a highly penetrant, autosomal dominant, human 
familial cancer predisposition. Although a key role for the tumor suppressor p53 
has been implicated in LFS, the genetic and cellular mechanisms underpinning 
this disease remain unknown. Therefore, modeling LFS in a vertebrate system that 
is accessible to both large-scale genetic screens and in vivo cell biological 
studies will facilitate the in vivo dissection of disease mechanisms, help 
identify candidate genes, and spur the discovery of therapeutic compounds. Here, 
we describe a forward genetic screen in zebrafish embryos that was used to 
identify LFS candidate genes, which yielded a p53 mutant (p53(I166T)) that as an 
adult develops tumors, predominantly sarcomas, with 100% penetrance. As in 
humans with LFS, tumors arise in heterozygotes and display loss of 
heterozygosity (LOH). This report of LOH indicates that Knudson's two-hit 
hypothesis, a hallmark of human autosomal dominant cancer syndromes, can be 
modeled in zebrafish. Furthermore, as with some LFS mutations, the zebrafish 
p53(I166T) allele is a loss-of-function allele with dominant-negative activity 
in vivo. Additionally, we demonstrate that the p53 regulatory pathway, including 
Mdm2 regulation, is evolutionarily conserved in zebrafish, providing a bona fide 
biological context in which to systematically uncover novel modifier genes and 
therapeutic agents for human LFS.