A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation.
The homeodomain transcription factor Pdx-1 has important roles in pancreas and islet development as well as in β-cell function and survival. We previously reported that Pdx-1 overexpression stimulates islet cell proliferation, but the mechanism remains unclear. Here, we demonstrate that overexpression of Pdx-1 triggers proliferation largely by a non-cell-autonomous mechanism mediated by soluble factors. Consistent with this idea, overexpression of Pdx-1 under the control of a β-cell-specific promoter (rat insulin promoter [RIP]) stimulates proliferation of both α and β cells, and overexpression of Pdx-1 in islets separated by a Transwell membrane from islets lacking Pdx-1 overexpression activates proliferation in the untreated islets. Microarray and gene ontology (GO) analysis identified inhibin beta-B (Inhbb), an activin subunit and member of the transforming growth factor β (TGF-β) superfamily, as a Pdx-1-responsive gene. Overexpression of Inhbb or addition of activin B stimulates rat islet cell and β-cell proliferation, and the activin receptors RIIA and RIIB are required for the full proliferative effects of Pdx-1 in rat islets. In human islets, Inhbb overexpression stimulates total islet cell proliferation and potentiates Pdx-1-stimulated proliferation of total islet cells and β cells. In sum, this study identifies a mechanism by which Pdx-1 induces a soluble factor that is sufficient to stimulate both rat and human islet cell proliferation.
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Heather L
HL
Hayes
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Lu
L
Zhang
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Thomas C
TC
Becker
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Jonathan M
JM
Haldeman
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Samuel B
SB
Stephens
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
Michelle
M
Arlotto
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Larry G
LG
Moss
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Christopher B
CB
Newgard
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA Hans.Hohmeier@duke.edu.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Hans E
HE
Hohmeier
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics*; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*
D018398:Homeodomain Proteins; C422402:INHBB protein, human; C498906:Inhbb protein, rat; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D028322:Inhibin-beta Subunits