Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis

Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous melanin pigmentation. Germ line mutations in LKB1 cause PJS. We have generated mice carrying an Lkb1 exon 2 to 8 deletion by gene targeting in embryonic stem cells. Heterozygotes develop gastric hamartomas that are histologically similar to those found in humans with PJS. LKB1 is also reportedly a mediator of p53-dependent apoptosis. To explore the potential combined effects of p53 and Lkb1 alterations on tumorigenesis, we carried out a series of matings with Lkb1^+/- and p53 null mice to generate Lkb1^+/-/p53 ^-/- and Lkb1^+/-/p53^-/- mice. Similar to the Lkb1^+/- mice, gastrointestinal hamartomas have also been detected in the mice with these two genotypes. The Lkb1^+/-/p53^+/- mice displayed a dramatically reduced life span and increased tumor incidence compared to the mice with either Lkb1 or p53 single gene knockout. The time to onset of polyposis in Lkb1^+/-/p53^-/- mice is ∼2 months earlier than Lkb1^+/-/p53^+/- and Lkb1^+/- mice, whereas the latter two show a similar time to onset which is at ∼6 months of age. These results strongly suggested that mutations of p53 and Lkb1 gene cooperate in the acceleration of tumorigenesis.