Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice.
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.
Takeda
H
H
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Miyoshi
H
H
Kojima
Y
Y
Oshima
M
M
Taketo
M M
MM
D055372:AMP-Activated Protein Kinases; D000236:Adenoma / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D006222:Hamartoma / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010580:Peutz-Jeghers Syndrome / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013272:Stomach Diseases / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases