A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

Heather L Hayes; Lu Zhang; Thomas C Becker; Jonathan M Haldeman; Samuel B Stephens; Michelle Arlotto; Larry G Moss; Christopher B Newgard; Hans E Hohmeier

doi:10.1128/MCB.00103-16

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A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

Journal article

Peer reviewed

A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation

Heather L Hayes, Lu Zhang, Thomas C Becker, Jonathan M Haldeman, Samuel B Stephens, Michelle Arlotto, Larry G Moss, Christopher B Newgard and Hans E Hohmeier

Molecular and cellular biology, Vol.36(23), pp.2918-2930

12/01/2016

DOI: 10.1128/MCB.00103-16

PMCID: PMC5108880

PMID: 27620967

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Abstract

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.

Animals

Cell Proliferation

Cells, Cultured

Gene Expression Profiling

Glucagon-Secreting Cells - cytology

Glucagon-Secreting Cells - metabolism

Homeodomain Proteins - metabolism

Humans

Inhibin-beta Subunits - genetics

Insulin - genetics

Insulin-Secreting Cells - cytology

Insulin-Secreting Cells - metabolism

Islets of Langerhans - cytology

Islets of Langerhans - metabolism

Oligonucleotide Array Sequence Analysis

Promoter Regions, Genetic

Rats

Trans-Activators - metabolism

Details

Title: Subtitle: A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation
Creators: Heather L Hayes - Duke University
Lu Zhang - Duke University
Thomas C Becker - Duke University
Jonathan M Haldeman - Duke University
Samuel B Stephens - Duke University
Michelle Arlotto - Duke University
Larry G Moss - Duke University
Christopher B Newgard - Duke University
Hans E Hohmeier - Duke University
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.36(23), pp.2918-2930
DOI: 10.1128/MCB.00103-16
PMID: 27620967
PMCID: PMC5108880
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Grant note: T32 GM007184 / NIGMS NIH HHS U01 DK089538 / NIDDK NIH HHS
Language: English
Date published: 12/01/2016
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984359669602771

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