Pdx-1 Activates Islet α- and β-Cell Proliferation via a Mechanism Regulated by Transient Receptor Potential Cation Channels 3 and 6 and Extracellular Signal-Regulated Kinases 1 and 2

Author:

Hayes Heather L.12,Moss Larry G.13,Schisler Jonathan C.1,Haldeman Jonathan M.12,Zhang Zhushan3,Rosenberg Paul B.13,Newgard Christopher B.123,Hohmeier Hans E.13

Affiliation:

1. Sarah W. Stedman Nutrition and Metabolism Center and Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina, USA

2. Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA

3. Medicine, Duke University Medical Center, Durham, North Carolina, USA

Abstract

ABSTRACT The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and β-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, cooverexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly β-cell proliferation, whereas Pdx-1 stimulates both α- and β-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1-stimulated but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 but not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and small interfering RNA (siRNA)-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1-stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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