Unknown

Dataset Information

0

P53 up-regulated modulator of apoptosis (PUMA) activation contributes to pancreatic beta-cell apoptosis induced by proinflammatory cytokines and endoplasmic reticulum stress.


ABSTRACT: Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1beta, combined with interferon-gamma, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in beta-cells. Transcriptional activation of PUMA is regulated by nuclear factor-kappaB and endoplasmic reticulum stress but is independent of p53. PUMA activation leads to mitochondrial Bax translocation, cytochrome c release, and caspase-3 cleavage resulting in beta-cell demise. The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action, but Bcl-XL is inactivated by the BH3-only sensitizer DP5/Hrk in cytokine-exposed beta-cells. Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA-dependent beta-cell death and potentiates cytokine-induced apoptosis. Our data support a hierarchical activation of BH3-only proteins controlling the intrinsic pathway of beta-cell apoptosis in the context of inflammation and type 1 diabetes.

SUBMITTER: Gurzov EN 

PROVIDER: S-EPMC2888402 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

p53 up-regulated modulator of apoptosis (PUMA) activation contributes to pancreatic beta-cell apoptosis induced by proinflammatory cytokines and endoplasmic reticulum stress.

Gurzov Esteban N EN   Germano Carla M CM   Cunha Daniel A DA   Ortis Fernanda F   Vanderwinden Jean-Marie JM   Marchetti Piero P   Zhang Lin L   Eizirik Decio L DL  

The Journal of biological chemistry 20100426 26


Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1beta, combined with interferon-gamma, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in beta-cells. Transcriptional activation of PUMA is regulated by nuclear factor-kappaB and endoplasmic reticulum stress but is independent of p53. PUMA activation lead  ...[more]

Similar Datasets

| S-EPMC1832123 | biostudies-literature
| S-EPMC3862672 | biostudies-literature
| S-EPMC4330769 | biostudies-literature
| S-EPMC1142564 | biostudies-literature
| S-EPMC2711052 | biostudies-literature
| S-EPMC5596431 | biostudies-literature
| S-EPMC3823684 | biostudies-literature
| S-EPMC8327139 | biostudies-literature
| S-EPMC6461480 | biostudies-literature
| S-EPMC8245518 | biostudies-literature