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

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Abstract

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.

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APA

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

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