Pdx-1 enables insulin secretion by regulating synaptotagmin 1 gene expression.
Pdx-1 plays important roles both in the development of the pancreas and in maintaining pancreatic beta cell function. However, the role of Pdx-1 in the regulation of insulin release is not well established. We previously demonstrated that Pdx-1 overcomes the defect in insulin release from the insulin-producing cells derived from small hepatocytes (SHCs). Insulin secretion is regulated in vivo by the sequential events triggered by the increase of intracellular Ca(2+)-concentration in response to high glucose concentration. In the present study, we identified a new target of Pdx-1 involved in insulin release. Pdx-1 positively regulates the transcription of the gene encoding synaptotagmin 1 (Syt1) (a Ca(2+)-sensor that plays a central role in insulin release) through Pdx-1-binding sites within the 3' regulatory region of the Syt1 gene. We further demonstrated the essential role of Pdx-1 in insulin secretion by the gene knock-down strategy. Small interfering RNA (siRNA) directed against Pdx-1 specifically reduced the levels of Pdx-1 protein and Syt1 transcript in insulinoma lines. Our data indicate that Pdx-1 might contribute to the regulation of insulin release by promoting Syt1 expression in vivo, and provide useful information for future therapy of diabetes mellitus.
Nakajima-Nagata
Natsuki
N
Center for Molecular Biology and Genetics, Kyoto University, 53 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Sugai
Manabu
M
Sakurai
Tomonori
T
Miyazaki
Jun-ichi
J
Tabata
Yasuhiko
Y
Shimizu
Akira
A
D000818:Animals; D019556:COS Cells; D002135:Calcium-Binding Proteins; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter; D005822:Genetic Vectors; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D050863:Synaptotagmin I; C494311:Syt1 protein, mouse; C494312:Syt1 protein, rat; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D050857:Synaptotagmins; D008156:Luciferases