p53 Up-regulated Modulator of Apoptosis (PUMA) Activation Contributes to Pancreatic β-Cell Apoptosis Induced by Proinflammatory Cytokines and Endoplasmic Reticulum Stress
p53 Up-regulated Modulator of Apoptosis (PUMA) Activation Contributes to Pancreatic β-Cell Apoptosis Induced by Proinflammatory Cytokines and Endoplasmic Reticulum Stress
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DOI：
10.1074/jbc.m110.122374
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发表时间：
2010-06-25
影响因子：
4.8
通讯作者：
Eizirik, Decio L.
中科院分区：
文献类型：
--
作者：
Gurzov, Esteban N.;Germano, Carla M.;Eizirik, Decio L.
1型糖尿病是一种自身免疫性疾病，其特征在于慢性炎症和胰腺β细胞损失。在这里，我们证明，促炎细胞因子白细胞介素-1 β，结合干扰素-γ，诱导表达的Bcl-2同源3（BH 3）-唯一的激活剂p53上调调节细胞凋亡）在β细胞。转录激活的p53 A是由核因子-κ B和内质网应激，但是独立的。ESTA激活导致线粒体Bax易位、细胞色素c释放和半胱天冬酶-3裂解，导致β细胞死亡。抗凋亡Bcl-XL蛋白主要定位于β细胞的线粒体并拮抗BclA作用，但Bcl-XL在暴露于奎宁的β细胞中被仅BH 3的敏化剂DP 5/Hrk灭活。此外，抑制Bcl-XL和Bcl-2的仅BH 3致敏剂Bad的药理学模拟物诱导PUMA依赖性β细胞死亡并增强苦参碱诱导的细胞凋亡。我们的数据支持在炎症和1型糖尿病的背景下控制β细胞凋亡的内在途径的仅BH 3蛋白的分级激活。
Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1 beta, 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-kappa B 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.