Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis.
Inactivating germ-line mutations of LKB1 lead to Peutz-Jeghers syndrome (PJS). We have generated mice heterozygous for a targeted inactivating allele of Lkb1 and found that they develop severe gastrointestinal polyposis. In all cases, the polyps arising in the Lkb1+/- mice were found to be hamartomas that were histologically indistinguishable from polyps resected from PJS patients, indicating that Lkb1+/- mice model human PJS polyposis. No evidence for inactivation of the remaining wild-type Lkb1 allele in Lkb1+/- -associated polyps was observed. Moreover, polyps and other tissues in heterozygote animals exhibited reduced Lkb1 levels and activity, indicating that Lkb1 was haploinsufficient for tumor suppression. Analysis of the molecular mechanisms characterizing Lkb1+/- polyposis revealed that cyclooxygenase-2 (COX-2) was highly up-regulated in murine polyps concomitantly with activation of the extracellular signal-regulated kinases 1 and 2 (Erk1/2). Subsequent examination of a large series of human PJS polyps revealed that COX-2 was also highly up-regulated in the majority of these polyps. These findings thereby identify COX-2 as a potential target for chemoprevention in PJS patients.
Rossi
Derrick J
DJ
Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, 00014 Helsinki, Finland.
Ylikorkala
Antti
A
Korsisaari
Nina
N
Salovaara
Reijo
R
Luukko
Keijo
K
Launonen
Virpi
V
Henkemeyer
Mark
M
Ristimaki
Ari
A
Aaltonen
Lauri A
LA
Makela
Tomi P
TP
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000378:metabolism; D004790:Enzyme Induction; D016147:Genes, Tumor Suppressor; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000096:biosynthesis*; D008222:Lymphokines / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010580:Peutz-Jeghers Syndrome / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; C491655:Stk11ip protein, mouse; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases