Key Points
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Peutz–Jeghers syndrome (PJS) is an autosomal polyposis disorder that is characterized by cancer predisposition at a young age. It is associated with inactivating mutations in the LKB1 gene.
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Different hamartomatous polyposis syndromes are associated with different types of genetic defects. PJS is characterized by gastrointestinal hamartomas that have a smooth-muscle core.
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LKB1 is required for normal fetal development and is present in apoptotic intestinal cells. LKB1 has been shown to be involved in p53-mediated apoptosis. LKB1 phosphorylates p53 at low levels, which might be required for p53 activation.
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LKB1 has also been shown to control cell proliferation. It interacts with the chromatin remodelling protein brahma-related gene-1 (BRG1), and also with the cell-cycle regulatory proteins LKB1-interacting protein 1 (LIP1) and WAF1.
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LKB1 is therefore an important tumour suppressor that might be developed as a cancer therapeutic target.
Abstract
Peutz–Jeghers syndrome (PJS) is a rare, inherited intestinal polyposis syndrome that is associated with a significantly increased risk of several types of cancer — particularly those of the gastrointestinal and reproductive systems. Most cases of PJS have been associated with loss-of-function mutations in the ubiquitously expressed LKB1 gene, which encodes a serine/ threonine kinase. Recent studies have begun to illustrate the molecular mechanisms by which LKB1 functions as an important new tumour suppressor.
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Acknowledgements
J. Y. and D. C. C are supported in part by National Cancer Institute grants. L. I. Y. is supported by a fellowship from the American Cancer Society.
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Glossary
- HAMARTOMA
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A benign overgrowth of tissue that is composed of cells that are normally present at that site. In the gastrointestinal tract, hamartomas typically have a marked expansion of the muscular and fibrous tissue layer.
- LOSS OF HETEROZYGOSITY
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(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome that carries the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.
- FLUORESCENT IN SITU HYBRIDIZATION
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(FISH). A technique that is used to detect nucleic acids in cells or tissues by using probes that are coupled to a fluorescent dye.
- NON-CELL AUTONOMOUS
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Describes a signal that is is passed from one cell to another.
- PRENYLATION
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The covalent attachment of a hydrophobic prenyl group to a molecule. This can result in membrane localization.
- PYKNOTIC
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Describes a condensed, misshapen nucleus, that is characteristic of an apoptotic cell.
- DOMINANT-NEGATIVE MUTANT
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A non-functional mutant protein that competes with the normal, non-mutated protein, blocking its activity.
- FORSKOLIN
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A vasodilating drug that is produced by the Coleus forskohlii plant. It activates adenylate cyclase, leading to elevated cyclic AMP levels.
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Yoo, L., Chung, D. & Yuan, J. LKB1 — A master tumour suppressor of the small intestine and beyond. Nat Rev Cancer 2, 529–535 (2002). https://doi.org/10.1038/nrc843
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DOI: https://doi.org/10.1038/nrc843
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