Antti Ylikorkala

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.

Expression of LKB1 and PTEN tumor suppressor genes during mouse embryonic development.

Germ-line mutations of LKB1 and PTEN tumor suppressor genes underlie the phenotypically related Peutz-Jeghers syndrome (PJS) and Cowden disease (CD), respectively. To analyze possible developmental roles of PTEN and LKB1, we have studied their mRNA expression during mouse embryonic development (E7-17.5) by in situ hybridization. Ubiquitous expression of both genes during early stages (E7-11) became more restricted in later embryonic development (E15-19) where LKB1 and PTEN showed prominent overlapping expression in e.g. gastrointestinal tract and lung. In contrast, LKB1 was selectively expressed at high levels in testis and PTEN was prominently expressed in skin epithelium and underlying mesenchyme. These results indicate that LKB1 and PTEN display largely overlapping expression patterns during embryonic development. Moreover, a high expression of these genes was observed in the tissues and organs affected in PJS and CD patients and in PTEN+/- mice.

Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-beta signaling.

Transforming growth factor-beta (TGF-beta) signaling is mediated from serine/threonine kinase receptors to transcriptional responses via Smad proteins. Here comparison of mRNA expression of Smad3-7 in mouse embryos (E9-E15) revealed developmentally regulated distinct expression patterns for Smad3, 4, 6, and 7. Smad3 was prominently expressed in the differentiating (from E10) central nervous system, but also in developing bones, branchial arches and epithelium of various tissues. Smad4 mostly showed ubiquitous expression, but in E15 embryos, a pronounced signal appeared in epithelial crypts of the gut. Inhibitory Smad6 and Smad7 were coexpressed at high levels in developing cardiovascular system from the earliest stages studied. In contrast, Smad6 was selectively expressed at high levels, e.g. in intramembranous bone whereas Smad7 was prominent in seminiferous tubules of the testis, demonstrating distinct expression of these genes in non-cardiovascular tissues.