¹Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto, Japan

Correspondence: Professor MM Taketo, Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: taketo@mfour.med.kyoto-u.ac.jp

Received 2 July 2005; Revised 6 September 2005; Accepted 26 September 2005; Published online 7 November 2005.

Abstract

Germline mutations in the LKB1 gene are responsible for Peutz–Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomas and increasing risk of cancer. Mice with Lkb1^+/- mutation develop gastric hamartomas after >20 weeks of age, and hepatocellular adenomas and carcinomas >30 weeks. It has been reported that, in PJS patients, carcinomas progressed from hamartomas contain p53 mutations, and that LKB1 regulates p53-dependent apoptosis. To investigate the roles of LKB1 and p53 mutations in tumorigenesis, we constructed compound mutant mice of Lkb1 and p53 genes. In the Lkb1^+/-p53^-/- mice, formation of gastric hamartomas and hepatic tumors was accelerated. However, histopathology of hamartomas was similar between Lkb1^+/-p53^-/- and Lkb1^+/- mice, and Lkb1 genotype remained heterozygous, suggesting that the p53 mutation affected hamartoma initiation. Contrary to the heterozygous hamartomas in the stomach and duodenum, the hepatic adenomas in Lkb1^+/-p53^-/- mice showed loss of Lkb1 heterozygosity (LOH), suggesting that lack of p53 stimulated Lkb1 LOH and tumor initiation in the liver. Taken together, these results indicate that lack of p53 causes earlier onsets of gastric hamartomas and hepatic tumors in Lkb1^+/-p53^-/- mice.