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Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death.
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- Author(s): Hu P;Hu P; Han Z; Couvillon AD; Exton JH
- Source:
The Journal of biological chemistry [J Biol Chem] 2004 Nov 19; Vol. 279 (47), pp. 49420-9. Date of Electronic Publication: 2004 Aug 31.
- Publication Type:
Journal Article
- Language:
English
- Additional Information
- Source:
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Print ISSN: 0021-9258 (Print) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
- Publication Information:
Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology
Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology
- Subject Terms:
- Abstract:
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of many diseases and in cancer therapy. Although the unfolded protein response is known to alleviate ER stress by reducing the accumulation of misfolded proteins, the exact survival elements and their downstream signaling pathways that directly counteract ER stress-stimulated apoptotic signaling remain elusive. Here, we have shown that endogenous Akt and ERK are rapidly activated and act as downstream effectors of phosphatidylinositol 3-kinase in thapsigargin- or tunicamycin-induced ER stress. Introduction of either dominant-negative Akt or MEK1 or the inhibitors LY294002 and U0126 sensitized cells to ER stress-induced cell death in different cell types. Reverse transcription-PCR analysis of gene expression during ER stress revealed that cIAP-2 and XIAP, members of the IAP family of potent caspase suppressors, were strongly induced. Transcription of cIAP-2 and XIAP was up-regulated by the phosphatidylinositol 3-kinase/Akt pathway as shown by its reversal by dominant-negative Akt or LY294002. Ablation of these IAPs by RNA interference sensitized cells to ER stress-induced death, which was reversed by the caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone. The protective role of IAPs in ER stress coincided with Smac release from mitochondria to the cytosol. Furthermore, it was shown that mTOR was not required for Akt-mediated survival. These results represent the first demonstration that activation of endogenous Akt/IAPs and MEK/ERK plays a critical role in controlling cell survival by resisting ER stress-induced cell death signaling.
- Accession Number:
0 (Amino Acid Chloromethyl Ketones)
0 (Enzyme Inhibitors)
0 (Proteins)
0 (Proto-Oncogene Proteins)
0 (Tetrazolium Salts)
0 (Thiazoles)
0 (X-Linked Inhibitor of Apoptosis Protein)
0 (XIAP protein, human)
0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
11089-65-9 (Tunicamycin)
67526-95-8 (Thapsigargin)
EC 2.7.- (Protein Kinases)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.11.1 (AKT1 protein, human)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EUY85H477I (thiazolyl blue)
- Publication Date:
Date Created: 20040902 Date Completed: 20050111 Latest Revision: 20240109
- Publication Date:
20250114
- Accession Number:
10.1074/jbc.M407700200
- Accession Number:
15339911
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