Peutz-Jeghers syndrome (PJS) is a unique autosomal dominant syndrome characterized by cutaneous hypermelanocytic macules and associated hamartomatous polyp develop in the small bowel and colon. These patients also have a dramatically increased risk for development of a variety of different neoplasias including those of the small bowel, colon, pancreas, stomach, breast, ovary and testicle. PJS is caused by germline mutations in the gene encoding the serine threonine kinase LKB1. Recent evidence that the LKB1 gene is a tumor suppressor in hamartomas and adenocarcinomas from PJS patients. Although the function of the gene is not known, the LKB1 mutations studied by Mehennni et al. (1998) all caused a loss of kinase activity when assayed by auto-phosphorylation. This is the first known protein kinase that predisposes to cancer because of a loss of the kinase activity. The overall goal of the proposal is to generate an animal model for PJS. This will allow us to conduct more long-term studies leading to the development of functional assays for the detection of patients with PJS, the development of early detection strategies for cancer arising via the PJS pathway, and the development of preventive strategies for PJS cancers. Studies of the proposed animal model will also lead to the elucidation of the normal function of LKB1 and the mechanism by which disruption of this gene increases risk for PJS associated cancers. A conditional knock-out transgene mouse line for the lkb1 gene will be generated. The phenotype resulting from disruption of one of the mouse LKB1 alleles will be examined. Mot humans with PJS have one null allele for LKB1, the second allele is lost or mutated in hamartomas and adenocarcinomas. It is hypothesized that mice with one null allele will have a phenotype similar to the PJS. The phenotype resulting from the homozygous disruption of the lkb1 gene will be determined. If homozygous knock-out mice are not viable, tissue-specific conditional knock-out mice will e created to allow the effects of the lkb1 gene in the gastrointestinal tissues (including pancreas) to be studied. If adenocarcinomas are not observed in mice as a result of carrying out the aims described above, viable mice carrying lkb1 null alleles will be crossed with mice carrying a p53 null allele. The phenotype of these mice will be examined to determine if knocking out lkb1 accelerates the pathway for tumorigenesis in the mice. Because mutations in p53 are known to occur frequently in adenocarcinomas of PJS patients, the combination of the p53 mutation and the lkb1 null allele would provide two hints in the PJS pathway of tumorigenesis.
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| Wei, Chongjuan; Amos, Christopher I; Rashid, Asif et al. (2003) Correlation of staining for LKB1 and COX-2 in hamartomatous polyps and carcinomas from patients with Peutz-Jeghers syndrome. J Histochem Cytochem 51:1665-72 |
