Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment.
After partial pancreatectomy (Ppx), substantial regeneration of the endocrine and exocrine pancreatic compartments has been shown in adult rodents. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments endocrine beta-cell mass by stimulating neogenesis, proliferation, and cell survival. After Ppx, treatment with Ex-4 ameliorates hyperglycemia by stimulating beta-cell mass recovery. We utilized a cDNA microarray approach to identify genes differentially regulated during pancreatic regeneration after Ppx and/or Ex-4 administration. The pancreatic remnant after Ppx showed a large number of differentially regulated genes. In contrast, Ex-4 treatment resulted in a smaller number of differentially regulated genes. Of note, a common subset of genes regulated by Ex-4 and after Ppx was identified, including three members of the mitogenic Reg gene family, Reg2, -3gamma, and -3beta, as well as fragilis, a gene that maintains pluripotency during germ cell specification, and Serpin b1a, a member of an intracellular protease inhibitor family involved in cell survival. These observations were confirmed by real-time PCR. We determined that Reg3beta protein is also induced in the acinar pancreas after Ppx, suggesting a novel role for this factor in pancreatic growth or response to injury. Finally, comparison of transcription factor-binding sites present in the proximal promoters of these genes identified potential common transcription factors that may regulate these genes. Chromatin immunoprecipitation analyses confirmed Reg3gamma as a novel transcriptional target of Foxa2 (HNF3beta). Our data suggest molecular pathways that may regulate pancreatic growth and offer a unique set of candidate genes to target in the development of therapies aimed at improving pancreatic growth and function.
De León
Diva D
DD
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Farzad
Cyrus
C
Crutchlow
Michael F
MF
Brestelli
John
J
Tobias
John
J
Kaestner
Klaus H
KH
Stoffers
Doris A
DA
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D000077270:Exenatide; D020869:Gene Expression Profiling; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D010180:Pancreatectomy; D010455:Peptides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D015843:Serpins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D014688:Venoms / Q000494:pharmacology*
C496503:Foxa2 protein, mouse; D008565:Membrane Proteins; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; C088549:RegIII protein, mouse; D015843:Serpins; D014157:Transcription Factors; D014688:Venoms; C462181:fragilis protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; D000077270:Exenatide