Activation of phosphatidylinositol-3 kinase regulates pancreatic duodenal homeobox-1 in duct cells during pancreatic regeneration.
OBJECTIVE
The purpose of our study was to determine whether the phosphatidylinositol 3-kinase (PI3K)/Akt pathway contributes to expression of pancreatic duodenal homeobox-1 (PDX-1) in duct cells and the cell differentiation during pancreatic regeneration.


METHODS
The role of PI3K in PDX-1 expression and duct cell differentiation with pancreatic regeneration in mice after partial pancreatectomy (Px) was examined using either wortmannin, a pharmacological PI3K inhibitor, or small-interfering RNA directed to the p85alpha regulatory subunit of PI3K. Akt phosphorylation, a marker of PI3K activation, and PDX-1 expression were assessed by Western blot analysis and immunohistochemistry.


RESULTS
Both PDX-1 levels and Akt phosphorylation were concomitantly increased in pancreatic ducts after partial Px and, conversely, blocked by treatment with wortmannin or p85alpha small-interfering RNA. Pancreatic duct cell differentiation, as assessed by appearance of insulin-positive cells 3 days after partial Px, was effectively reduced by wortmannin.


CONCLUSIONS
The PI3K/Akt activation plays a critical role for both PDX-1 expression and pancreatic duct cell differentiation into insulin-producing cells during pancreatic regeneration.
Watanabe
Hiroaki
H
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0526, USA.
Saito
Hiroshi
H
Nishimura
Haruto
H
Ueda
Junji
J
Evers
B Mark
BM
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D004789:Enzyme Activation; D018398:Homeodomain Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000601:surgery; D010180:Pancreatectomy; D010183:Pancreatic Ducts / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D018398:Homeodomain Proteins; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000077191:Wortmannin; C084010:pancreatic and duodenal homeobox 1 protein