Pancreatic β-Cell Death due to Pdx-1 Deficiency Requires Multi-BH Domain Protein Bax but Not Bak

Juan Sun,Li-Qun Mao,Kenneth S Polonsky,De-Cheng Ren

doi:10.1074/jbc.m115.705293

Abstract

Diabetes develops in Pdx1-haploinsufficient mice due to an increase in β-cell death leading to reduced β-cell mass and decreased insulin secretion. Knockdown of Pdx1 gene expression in mouse MIN6 insulinoma cells induced apoptotic cell death with an increase in Bax activation and knockdown of Bax reduced apoptotic β-cell death. In Pdx1 haploinsufficient mice, Bax ablation in β-cells increased β-cell mass, decreased the number of TUNEL positive cells and improved glucose tolerance after glucose challenge. These changes were not observed with Bak ablation in Pdx1-haploinsufficient mice. These results suggest that Bax mediates β-cell apoptosis in Pdx1-deficient diabetes.

Highlights

Membrane of mitochondria, and both Bax and Bak can convert from the non-activated to the activated conformation [5]
The results showed that the amount of Bax precipitated by 6A7 anti-Bax antibody was increased in Pdx1 KD cells (Fig. 1D)
We have previously demonstrated that reduced ␤-cell mass is an essential component of the diabetic phenotype in the Pdx1-deficient mouse [2], and Bim and Puma mediate ␤-cell death induced by Pdx1-deficiency [6]

Summary

Introduction

Membrane of mitochondria, and both Bax and Bak can convert from the non-activated to the activated conformation [5]. Results are presented as mean Ϯ S.E. Pdx1 Suppression Activates Bax in MIN6 Cells—Pdx1 KD MIN6 cells did not demonstrate a significant increase in Bax and Bak mRNA (Fig. 1A) or protein levels when compared with control cells (Fig. 1B). MRNA levels of Bax were increased in islets from Pdx1ϩ/Ϫ mice (p Ͻ 0.05) (Fig. 1F).

Results

Conclusion