Role of BH3-only molecules Bim and Puma in β-cell death in Pdx1 deficiency

Diabetes. 2014 Aug;63(8):2744-50. doi: 10.2337/db13-1513. Epub 2014 Mar 21.

Abstract

Mutations in pancreatic duodenal homeobox-1 (PDX1) are associated with diabetes in humans. Pdx1-haploinsufficient mice develop diabetes due to an increase in β-cell death leading to reduced β-cell mass. For definition of the molecular link between Pdx1 deficiency and β-cell death, Pdx1-haploinsufficient mice in which the genes for the BH3-only molecules Bim and Puma had been ablated were studied on a high-fat diet. Compared with Pdx1(+/-) mice, animals haploinsufficient for both Pdx1 and Bim or Puma genes showed improved glucose tolerance, enhanced β-cell mass, and reduction in the number of TUNEL-positive cells in islets. These results suggest that Bim and Puma ablation improves β-cell survival in Pdx1(+/-) mice. For exploration of the mechanisms responsible for these findings, Pdx1 gene expression was knocked down in mouse MIN6 insulinoma cells resulting in apoptotic cell death that was found to be associated with increased expression of BH3-only molecules Bim and Puma. If the upregulation of Bim and Puma that occurs during Pdx1 suppression was prevented, apoptotic β-cell death was reduced in vitro. These results suggest that Bim and Puma play an important role in β-cell apoptosis in Pdx1-deficient diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Bcl-2-Like Protein 11
  • Cell Line
  • Gene Knockdown Techniques
  • Haplotypes
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / metabolism*
  • Lentivirus
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptome
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Homeodomain Proteins
  • Membrane Proteins
  • PUMA protein, mouse
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Trans-Activators
  • Tumor Suppressor Proteins
  • pancreatic and duodenal homeobox 1 protein