| Knockdown of Akt1 promotes Akt2 upregulation and resistance to oxidative-stress-induced apoptosis through control of multiple signaling pathways. | |
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MedLine Citation:
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PMID: 21303257 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The Akt signaling pathway plays a key role in promoting the survival of various types of cells from stress-induced apoptosis, and different members of the Akt family display distinct physiological roles. Previous studies have shown that in response to UV irradiation, Akt2 is sensitized to counteract the induced apoptosis. However, in response to oxidative stress such as hydrogen peroxide, it remains to be elucidated what member of the Akt family would be activated to initiate the signaling cascades leading to resistance of the induced apoptosis. In the present study, we present the first evidence that knockdown of Akt1 enhances cell survival under exposure to 50 μM H(2)O(2). This survival is derived from selective upregulation and activation of Akt2 but not Akt3, which initiates 3 major signaling cascades. First, murine double minute 2 (MDM2) is hyperphosphorylated, which promotes p53 degradation and attenuates its Ser-15 phosphorylation, significantly attenuating Bcl-2 homologous antagonist killer (Bak) upregulation. Second, Akt2 activation inactivates glycogen synthase kinase 3 beta (GSK-3β) to promote stability of myeloid leukemia cell differentiation protein 1 (MCL-1). Finally, Akt2 activation promotes phosphorylation of FOXO3A toward cytosolic export and thus downregulates Bim expression. Overexpression of Bim enhances H(2)O(2)-induced apoptosis. Together, our results demonstrate that among the Akt family members, Akt2 is an essential kinase in counteracting oxidative-stress-induced apoptosis through multiple signaling pathways. |
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Authors:
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Lan Zhang; Shuming Sun; Jie Zhou; Jiao Liu; Jia-Han Lv; Xiang-Qiang Yu; Chi Li; Lili Gong; Qin Yan; Mi Deng; Ling Xiao; Haili Ma; Jin-Ping Liu; Yun-Lei Peng; Dao Wang; Gao-Peng Liao; Li-Jun Zou; Wen-Bin Liu; Ya-Mei Xiao; David Wan-Cheng Li |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-04-26 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: 15 ISSN: 1557-7716 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-09 Completed Date: 2011-09-30 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: United States |
Other Details:
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Languages: eng Pagination: 1-17 Citation Subset: IM |
Affiliation:
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University of Nebraska Medical Center, Omaha, 68198-5870, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Cell Line Cell Survival / drug effects Female Forkhead Transcription Factors / genetics, metabolism Gene Knockdown Techniques Glycogen Synthase Kinase 3 Humans Mice Pregnancy Proteins / genetics, metabolism Proto-Oncogene Proteins c-akt / genetics*, metabolism* Proto-Oncogene Proteins c-mdm2 / genetics, metabolism Signal Transduction / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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1R01EY015765/EY/NEI NIH HHS; 1R01EY18380/EY/NEI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/FOXO3 protein, human; 0/Forkhead Transcription Factors; 0/MLF1 protein, human; 0/Proteins; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
| Comments/Corrections | |
Erratum In:
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Antioxid Redox Signal. 2011 Aug 1;15(3):854 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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