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p53 up-regulated modulator of apoptosis (PUMA) activation contributes to pancreatic beta-cell apoptosis induced by proinflammatory cytokines and endoplasmic reticulum stress.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2010 Jun 25; Vol. 285 (26), pp. 19910-20. Date of Electronic Publication: 2010 Apr 26. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Apoptosis Regulatory Proteins genetics
Binding Sites genetics
Biphenyl Compounds pharmacology
Blotting, Western
Cell Line, Tumor
Cells, Cultured
Gene Expression drug effects
Humans
Insulin-Secreting Cells cytology
Insulin-Secreting Cells drug effects
Insulin-Secreting Cells metabolism
Interferon-gamma pharmacology
Interleukin-1beta pharmacology
Mutation
NF-kappa B metabolism
Nitrophenols pharmacology
Piperazines pharmacology
Proto-Oncogene Proteins genetics
RNA Interference
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Sulfonamides pharmacology
bcl-X Protein genetics
bcl-X Protein metabolism
Apoptosis drug effects
Apoptosis Regulatory Proteins metabolism
Cytokines pharmacology
Endoplasmic Reticulum metabolism
Proto-Oncogene Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 285
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20421300
- Full Text :
- https://doi.org/10.1074/jbc.M110.122374