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p53 Up-regulated Modulator of Apoptosis (PUMA) Activation Contributes to Pancreatic β-Cell Apoptosis Induced by Proinflammatory Cytokines and Endoplasmic Reticulum Stress

2010; Elsevier BV; Volume: 285; Issue: 26 Linguagem: Inglês

10.1074/jbc.m110.122374

1083-351X

Esteban N. Gurzov, Carla Maria Ramos Germano, Daniel A. Cunha, Fernanda Ortis, Jean‐Marie Vanderwinden, Piero Marchetti, Lin Zhang, Décio L. Eizirik,

Endoplasmic Reticulum Stress and Disease

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.