Regulation of pancreatic duct cell differentiation by phosphatidylinositol-3 kinase.
We have previously demonstrated that the phosphatidylinositol-3 kinase (PI3K)/Akt signaling is essential for pancreatic regeneration after partial pancreatectomy in mice. In the present study, we examined a role of PI3K/Akt signaling for pancreatic duct cell differentiation into insulin-producing cells. Epithelial-like cells were isolated from mouse pancreas and confirmed to be positive for a duct cell marker cytokeratin-20 (CK-20) but negative for insulin. Incubation of these cells with epidermal growth factor, exhibited a gradual increase in Akt phosphorylation and expression of pancreatic duodenal homeobox-1 (PDX-1), a regulator of beta-cell differentiation. Three weeks later, these CK-20-positive cells were noted to express insulin as determined by immunofluorescent double-staining. Akt phosphorylation, PDX-1 expression, and insulin production were effectively reduced by blocking the PI3K/Akt pathway using siRNA to the p85alpha regulatory subunit of PI3K. Our results demonstrate that PI3K/Akt activation has a critical role for pancreatic duct cell differentiation into insulin-producing cells.
Watanabe
Hiroaki
H
Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0536, USA.
Saito
Hiroshi
H
Ueda
Junji
J
Evers
B Mark
BM
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000201:enzymology*; D053554:Keratin-20 / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010183:Pancreatic Ducts / Q000166:cytology* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism
D018398:Homeodomain Proteins; D007328:Insulin; D053554:Keratin-20; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein