Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis

Derrick J Rossi; Antti Ylikorkala; Nina Korsisaari; Reijo Salovaara; Keijo Luukko; Virpi Launonen; Mark Henkemeyer; Ari Ristimaki; Lauri A Aaltonen; Tomi P Makela

doi:10.1073/pnas.192301399

Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis

Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12327-32. doi: 10.1073/pnas.192301399. Epub 2002 Sep 6.

Authors

Derrick J Rossi¹, Antti Ylikorkala, Nina Korsisaari, Reijo Salovaara, Keijo Luukko, Virpi Launonen, Mark Henkemeyer, Ari Ristimaki, Lauri A Aaltonen, Tomi P Makela

Affiliation

¹ Haartman Institute and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. Box 63, University of Helsinki, 00014 Helsinki, Finland.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases
Adaptor Proteins, Signal Transducing
Animals
Carrier Proteins*
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / pharmacology
Disease Models, Animal
Endothelial Growth Factors / metabolism
Enzyme Induction
Genes, Tumor Suppressor
Heterozygote
Humans
Intracellular Signaling Peptides and Proteins
Isoenzymes / biosynthesis*
Lymphokines / metabolism
Membrane Proteins
Mice
Mice, Knockout
Peutz-Jeghers Syndrome / drug therapy
Peutz-Jeghers Syndrome / enzymology*
Peutz-Jeghers Syndrome / genetics*
Peutz-Jeghers Syndrome / pathology
Prostaglandin-Endoperoxide Synthases / biosynthesis*
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics
Signal Transduction
Up-Regulation
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Endothelial Growth Factors
Intracellular Signaling Peptides and Proteins
Isoenzymes
Lymphokines
Membrane Proteins
Stk11ip protein, mouse
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Cyclooxygenase 2
PTGS2 protein, human
Prostaglandin-Endoperoxide Synthases
Protein Serine-Threonine Kinases
Stk11 protein, mouse
AMP-Activated Protein Kinases