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Peutz-Jeghers Syndrome: LBK1/STK11

Peutz-Jeghers Syndrome: LBK1/STK11. By Matt Wheeler. Peutz-Jeghers Syndrome. Rare autosomal dominant disorder formation of benign hamartomatous polyps throughout the gastrointestinal track melanin deposits. Jishage, K et al (2002) PNAS 89: 8903-8908.

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Peutz-Jeghers Syndrome: LBK1/STK11

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  1. Peutz-Jeghers Syndrome:LBK1/STK11 By Matt Wheeler

  2. Peutz-Jeghers Syndrome • Rare autosomal dominant disorder • formation of benign hamartomatous polyps throughout the gastrointestinal track • melanin deposits Jishage, K et al (2002) PNAS 89: 8903-8908 Choi, HS et al (1999) J Korean Med Sci 14: 2-7

  3. Clinical Characteristics of PJS • Abdominal pain, bowel obstruction, and bleeding • Increased lifetime risk of cancer

  4. LKB1/STK11 is mutated in PJS • Encodes a serine/threonine kinase • A tumor suppressor gene • Inherited mutation in LKB1/STK11

  5. Identification of the gene involved • Previously identified but unmapped gene • Gene mapped to short arm of chromosome 19 (19p13.3) Connolly, DC et al (2000) Am J Pathology 156: 339-345

  6. LKB1/STK11 is a serine-threonine protein kinase Boudeau, J et al (2003) FEBS letters 546:159-165

  7. Mutations in LKB1/STK11 • Mutations inactivate the protein • 75 mutations have been identified • Nearly all occur in the conserved kinase domain Yoo, YI et al (2002) Nature Reviews 2: 529-535

  8. Mouse Model of PJS • LKB1 -/- mice die by embryonic day 8 • Failure of embryo to turn, severe neural tube defects, and abnormal vasculature

  9. PJS Mouse model contd • LKB1 +/- mice develop normally and share characteristics of human PJS patients • Gastrointestinal polyps without neoplastic growths in other organs • 100% penetrance by week 40

  10. Cellular functions of LKB1/STK11 • Specific biological roles remain unclear • Regulates multiple cellular processes • These include: cell cycle arrest, apoptosis, Wnt signaling, TGF-ß signaling, Ras regulation, energy metabolism, and cell polarity

  11. Apoptosis regulation Yoo, YI et al (2002) Nature Reviews 2: 529-535

  12. Expression of WT LKB1 in fibrosarcoma cells leads to increased apoptosis zVAD and casp9DN = Caspase inhibitors KDA = version of LKB1 That only contains a Kinase domain K78M LKB1 = Mutant LKB1 with no kinase activity Karuman, P et al (2001) Molecular Cell 7: 1307-1319

  13. LKB1 and Cell Metabolism Kyriakis, JM (2003) Journal of Biology 2: 26

  14. Function in Cellular Growth Control: Inhibition of mTOR pathway Hardie, GD (2004) Journal of Cell Science 117: 5479-5487

  15. Cell polarity • Important during embryonic development • Assymetry necessary for proper cellular function • Loss of polarity is a key factor in cancer progression

  16. Cell polarity contd Epithelial Cell Diagram Muller, HJ (2000) Developmental Dynamics 218: 52-67

  17. LKB1 and Cell Polarity • Activation of LKB1 in single intestinal epithelial cells induces complete polarization Prior to LKB1 Activation After LKB1 activation Bass, AF et al (2004) Cell 116: 457-466

  18. Conclusions • Tumor Supressor • Serine threonine kinase • Biological roles unclear • Possible roles of LKB1 in cancer progression - Inactivation -> decreased apoptosis and increased cell proliferation - Loss of polarity promotes tumor metastasis

  19. Choi HS, Park YJ, Park JG. PeutzJeghers Syndrome: A New Understanding. J Korean Med Sci 1999; 14: 2-7 Yoo LI, Chung DC, Yuan J. LKB1- A Master Tumor Supressor of the Small Intestine and Beyond. Nature Reviews; 2: 529-535 Hardie GD. The AMP-activated protein kinase pathway-new players upstream and downstream. Journal of Cell Science2004; 117: 5479-5487 Kyriakis JM. At the crossroads: AMP activated kinase and the LKB1 tumor supressor link cell proliferation to metabolic regulation. Journal of Biology 2003; 2: 26 Shaw RJ, Bardeesy N, Manning BD et al. The LKB1 tumor supressor negatively regulated mTOR signaling. Cancer Cell 2004; 6: 91-99 Karuman P, Gozani O, Odze RD et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-Dependent cell death. Molecular Cell 2001; 7: 1307-1319 Muller HJ. Genetic control of epithelial cell polarity: Lessons from drosophila. Developmental Dynamics 2000; 218: 52-67 Bass AF, Kuipers J, Van Der Wel NN et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 2004; 116: 457-466 Bass AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in Cell Biology 2004; 14:312-319 Boudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS letters 2003; 546: 159-165 Ylikorkala A, Rossi DJ, Korsisaari N et al. Vascular abnormalities and deregulation of VEGF in LKB1- deficient mice. Science 2001; 1323-1326 References

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