| Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc. | |
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MedLine Citation:
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PMID: 20700104 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Apoptosis ensures tissue homeostasis in response to developmental cues or cellular damage. Recently reported genome-wide RNAi screens have suggested that several metabolic regulators can modulate caspase activation in Drosophila. Here, we establish a previously unrecognized link between metabolism and Drosophila apoptosis by showing that cellular NADPH levels modulate the initiator caspase Dronc through its phosphorylation at S130. Depletion of NADPH removed this inhibitory phosphorylation, resulting in the activation of Dronc and subsequent cell death. Conversely, upregulation of NADPH prevented Dronc-mediated apoptosis upon DIAP1 RNAi or cycloheximide treatment. Furthermore, this CaMKII-mediated phosphorylation of Dronc hindered Dronc activation, but not its catalytic activity. Blockade of NADPH production aggravated the death-inducing activity of Dronc in specific neurons, but not in the photoreceptor cells of the eyes of transgenic flies; similarly, non-phosphorylatable Dronc was more potent than wild type in triggering specific neuronal apoptosis. Our observations reveal a novel regulatory circuitry in Drosophila apoptosis, and, as NADPH levels are elevated in cancer cells, also provide a genetic model to understand aberrations in cancer cell apoptosis resulting from metabolic alterations. |
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Authors:
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Chih-Sheng Yang; Michael J Thomenius; Eugene C Gan; Wanli Tang; Christopher D Freel; Thomas J S Merritt; Leta K Nutt; Sally Kornbluth |
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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: 2010-08-10 |
Journal Detail:
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Title: The EMBO journal Volume: 29 ISSN: 1460-2075 ISO Abbreviation: EMBO J. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-15 Completed Date: 2010-10-07 Revised Date: 2012-04-26 |
Medline Journal Info:
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Nlm Unique ID: 8208664 Medline TA: EMBO J Country: England |
Other Details:
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Languages: eng Pagination: 3196-207 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Animals, Genetically Modified Apoptosis* Blotting, Western Caspases / metabolism* Cell Survival Cells, Cultured Drosophila Proteins / metabolism* Drosophila melanogaster / genetics, growth & development, metabolism* Enzyme Activation Immunoprecipitation Inhibitor of Apoptosis Proteins / metabolism* Malates / metabolism NADP / metabolism Neurons / cytology, metabolism* RNA, Small Interfering / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM 080333/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ark protein, Drosophila; 0/Drosophila Proteins; 0/Inhibitor of Apoptosis Proteins; 0/Malates; 0/RNA, Small Interfering; 0/thread protein, Drosophila; 53-59-8/NADP; 6915-15-7/malic acid; EC 3.4.22.-/Caspases; EC 3.4.22.-/Nc protein, Drosophila |
| Comments/Corrections | |
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