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LKB1 and Peutz-Jeghers Syndrome Josh Lawrimore Gene Specifics Location: 19p13.3 LKB1 http://www.lbl.gov/Publications/Currents/Archive/Apr-02-2004.html Protein Specifics LKB1 encodes a kinase 433 amino acids 48 kDa Serine-Threonine Kinase Activity Yoo L. I. et al. Nature. 2002 Other features of the protein suggest mechanisms of localization and regulation Phosphorylation Sites N-Terminal Nuclear Localization Sites Yoo L. I. et al. Nature. 2002 C-Terminal Prenylation Site Other features of the protein suggest mechanisms of localization and regulation Mainly cytoplasmic Can also be localized in the nucleus Yoo L. I. et al. Nature. 2002 LBK1 Protein’s Cellular Function “LKB1 Kinase: Master and Commander of Metabolism and Polarity” Spicer and Ashworth, Current Biology, 2004 The study of LKB1 homologs in model organisms suggest important roles in cell polarity C. elegans – Par-4 genes anterior-posterior axis in embryo Drosophila – lkb1 gene anterior-posterior polarity of oocyte and repolarization of the oocyte cytoskeleton LBK1 Activation can polarize individual cells Bass et al. TRENDS in cell Biology, 2004 LKB1 leaves the nucleus to form a heterotrimeric complex to regulate cell polarity Bass et al. TRENDS in cell Biology, 2004 LBK1 is an upstream regulator of AMPK and Cell Metabolism MO25 ? Spicer and Ashworth, Current Biology, 2004 Loss of LKB1 leads to loss of cell polarity and increased protein MO25 synthesis Spicer and Ashworth, Current Biology, 2004 LKB1 has other functions as well Apoptosis via p53 Cell cycle arrest via cyclin-dependent kinase inhibitor WAF1 (p21) Sensor of microtubule integrity Possible Apoptosis Model Yoo L. I. et al. Nature. 2002 LBK1 is Broadly expressed in Adults and Embryos Sanchez-Cespedes, Oncogene, 2007 Homozygous Knock-Outs Are Lethal KO mice die at mid-gestation Sever neural-tube defects Excessive mesenchymal cell death Abnormal vasculature Phenotype looks like Cowden’s disease (a PTEN KO mutation) Bass et al. TRENDS in cell Biology, 2004 LBK1 is expressed in differentiated cells in the Small Intestine Yoo L. I. et al. Nature. 2002 Peutz-Jeghers Syndrome First described in a Dutch Family by Peutz in 1921 and later by Jeghers Rare Autosomal-dominant polyposis disorder Yoo L. I. et al. Nature. 2002 http://home.megapass.co.kr/~faldo/diseases/peutzjeghers.html Symptoms http://www.surgical-tutor.org.uk/defaulthome.htm?system/abdomen/colonic_polyp.htm~right Symptoms The Johns Hopkins Guide for Patients and Families: Peutz-Jeghers Syndrome Figure 1 A typical Peutz–Jeghers syndrome polyp demonstrating the arborizing pattern of smooth-muscle proliferation Permission obtained from Macmillan Publishers Ltd © Bronner (2003)79 Modern Pathology 16: 359–365 Zbuk KM and Eng C (2007) Hamartomatous polyposis syndromes Nat Clin Pract Gastroenterol Hepatol 4: 492–502 doi:10.1038/ncpgasthep0902 PJS and LKB1 Mutations Mutation is loss of function PJS hamartomatous polyps have typically shown LOH at LKB1 But recently shown that as many as 60% of PJS polyps fails to show LOH Indicates Possible Halpoinsufficiency Yoo L. I. et al. Nature. 2002 The Johns Hopkins Guide for Patients and Families: Peutz-Jeghers Syndrome Inheritance and Cancer Germ line mutation in 70% of classic families Nearly 100% penetrance in inherited cases 93% risk of getting cancer Cancer around age 43 Yoo L. I. et al. Nature. 2002 PJS and Cancer Colon Cancer 84-fold increase Gastric Cancer Small-intestinal Cancer Yoo L. I. et al. Nature. 2002 213-fold increase 520-fold increase