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. ©2005 American Association for Cancer Research.
Mendeley helps you to discover research relevant for your work.
CITATION STYLE
Wei, C., Amos, C. I., Stephens, L. C., Campos, I., Deng, J. M., Behringer, R. R., … Frazier, M. L. (2005). Mutation of Lkb1 and p53 genes exert a cooperative effect on tumorigenesis. Cancer Research, 65(24), 11297–11303. https://doi.org/10.1158/0008-5472.CAN-05-0716