Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells.
We have established a primary pancreatic duct epithelial cell culture (PDEC) system to investigate the relationship between oncogenic activation of K-ras and pancreatic ductal tumorigenesis. We have found that the acute introduction of physiological levels of oncogenic K-ras (K-rasV12) into quiescent PDECs stimulates S-phase entry and induces a pronounced increase in cell size. Both effects are dependent on the functional integrity of the phosphatidylinositol 3'-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway. In addition, K-rasV12 promotes the loss of epithelial E-cadherin and the gain of mesenchymal N-cadherin in PDEC. Our observations indicate that the oncogenic activation of K-ras is sufficient to elicit mitogenic and morphogenic responses in pancreatic ductal cells and hence is likely to play an instructive role in the initiation of pancreatic ductal adenocarcinoma.
Graduate Program in Molecular and Cellular Biology, State University of New York at Stony Brook, Stony Brook, New York 11794-5222, USA.
Cristina
C
Agbunag
Dafna
D
Bar-Sagi
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D048429:Cell Size / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics*; D008297:Male; D009154:Mutation; D010183:Pancreatic Ducts / Q000473:pathology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344
D019869:Phosphatidylinositol 3-Kinases