| Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. | |
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MedLine Citation:
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PMID: 20724831 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptotic defects endow tumor cells with survival advantages. Such defects allow the cellular stress response to take the path of cytoprotective autophagy, which either precedes or effectively blocks an apoptotic cascade. Inhibition of the cytoprotective autophagic response shifts the cells toward apoptosis, by interfering with an underlying molecular mechanism of cytoprotection. The current study has identified such a mechanism that is centered on the regulation of caspase-8 activity. The study took advantage of Bax(-/-) Hct116 cells that are TRAIL-resistant despite significant DISC processing of caspase-8, and of the availability of a caspase-8-specific antibody that exclusively detects the caspase-8 large subunit or its processed precursor. Utilizing these biological tools, we investigated the expression pattern and subcellular localization of active caspase-8 in TRAIL-mediated autophagy and in the autophagy-to-apoptosis shift upon autophagy inhibition. Our results suggest that the TRAIL-mediated autophagic response counter-balances the TRAIL-mediated apoptotic response by the continuous sequestration of the large caspase-8 subunit in autophagosomes and its subsequent elimination in lysosomes. The current findings are the first to provide evidence for regulation of caspase activity by autophagy and thus broaden the molecular basis for the observed polarization between autophagy and apoptosis. |
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Authors:
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Wen Hou; Jie Han; Caisheng Lu; Leslie A Goldstein; Hannah Rabinowich |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-16 |
Journal Detail:
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Title: Autophagy Volume: 6 ISSN: 1554-8635 ISO Abbreviation: Autophagy Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-24 Completed Date: 2011-03-01 Revised Date: 2012-05-07 |
Medline Journal Info:
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Nlm Unique ID: 101265188 Medline TA: Autophagy Country: United States |
Other Details:
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Languages: eng Pagination: 891-900 Citation Subset: IM |
Affiliation:
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Department of Pathology, The University of Pittsburgh School of Medicine, and The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology Apoptosis / physiology* Apoptosis Regulatory Proteins / genetics, metabolism Autophagy / physiology* Caspase 8 / metabolism* Cell Line, Tumor Cisplatin / pharmacology Gene Knockdown Techniques Humans Membrane Proteins / genetics, metabolism Microtubule-Associated Proteins / genetics, metabolism Pepstatins / metabolism Protease Inhibitors / metabolism TNF-Related Apoptosis-Inducing Ligand / metabolism bcl-2-Associated X Protein / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA111786/CA/NCI NIH HHS; R01 CA134776/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Membrane Proteins; 0/Microtubule-Associated Proteins; 0/Pepstatins; 0/Protease Inhibitors; 0/TNF-Related Apoptosis-Inducing Ligand; 0/bcl-2-Associated X Protein; 0/light chain 3, human; 15663-27-1/Cisplatin; 39324-30-6/pepstatin; EC 3.4.22.-/Caspase 8 |
| Comments/Corrections | |
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