Atrial natriuretic peptide promotes pancreatic islet beta-cell growth and Akt/Foxo1a/cyclin D2 signaling.
The adult differentiated insulin-secreting pancreatic islet beta-cell experiences slow growth. This study shows that atrial natriuretic peptide (ANP) stimulates cell proliferation and [(3)H]thymidine incorporation in INS-1E glucose-sensitive rat beta-cell line cells and isolated rat islet DNA. In addition, cGMP, the second messenger of natriuretic peptide receptors (NPR) A and B, stimulated islet DNA biosynthesis. The NPR-A receptor was expressed in INS-1E cells and islets. ANP-stimulated INS-1E cell DNA biosynthesis was blocked by preincubation with LY294002 (50 microM), an inhibitor of phosphatidylinositol 3'-kinase (PI3K). An indicator of cell cycle progression, cyclin D2 mRNA was increased by 2- to 3-fold in ANP- or 8-Br-cGMP-treated INS-1E cells and islets, and these responses were inhibited by LY294002. ANP and 8-Br-cGMP stimulated the phosphorylation of Akt and Foxo1a in INS-1E cells and islets, and LY294002 inhibited these responses. In contrast, ANP reduced the levels of phospho-ERK in INS-1E cells. Pancreas duodenum homeobox-1 (PDX-1) is essential for pancreas development, insulin production, and glucose homeostasis, and ANP increased PDX-1 mRNA levels by 2- to 3-fold in INS-1E cells and islets. The levels of glucokinase mRNA in islets and INS-1E cells were also increased in response to ANP. The evidence suggests that pancreatic beta-cell NPR-A stimulation results in activation of a growth-promoting signaling pathway that includes PI3K/Akt/Foxo1a/cyclin D2. These data support the conclusion that the activation of Akt by ANP or 8-Br-cGMP promotes cyclin D2, PDX-1, and glucokinase transcription by phosphorylating and restricting Foxo1a activity.
You
Hui
H
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
Laychock
Suzanne G
SG
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099242:Atrial Natriuretic Factor Receptor B; D000071161:Forkhead Box Protein O1
D009320:Atrial Natriuretic Factor; D002867:Chromones; D006152:Cyclic GMP; D056742:Cyclin D2; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017461:Receptors, Atrial Natriuretic Factor; D015534:Trans-Activators; D000099242:Atrial Natriuretic Factor Receptor B; C084010:pancreatic and duodenal homeobox 1 protein; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C016276:8-bromocyclic GMP; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C091715:atrial natriuretic factor receptor A; C073616:atrial natriuretic factor receptor C