| Loss of soluble N-ethylmaleimide-sensitive factor attachment protein α (αSNAP) induces epithelial cell apoptosis via down-regulation of Bcl-2 expression and disruption of the Golgi. | |
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MedLine Citation:
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PMID: 22194596 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Intracellular trafficking represents a key mechanism that regulates cell fate by participating in either prodeath or prosurvival signaling. Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein α (αSNAP) is a well known component of vesicle trafficking machinery that mediates intermembrane fusion. αSNAP increases cell resistance to cytotoxic stimuli, although mechanisms of its prosurvival function are poorly understood. In this study, we found that either siRNA-mediated knockdown of αSNAP or expression of its dominant negative mutant induced epithelial cell apoptosis. Apoptosis was not caused by activation of the major prodeath regulators Bax and p53 and was independent of a key αSNAP binding partner, NSF. Instead, death of αSNAP-depleted cells was accompanied by down-regulation of the antiapoptotic Bcl-2 protein; it was mimicked by inhibition and attenuated by overexpression of Bcl-2. Knockdown of αSNAP resulted in impairment of Golgi to endoplasmic reticulum (ER) trafficking and fragmentation of the Golgi. Moreover, pharmacological disruption of ER-Golgi transport by brefeldin A and eeyarestatin 1 or siRNA-mediated depletion of an ER/Golgi-associated p97 ATPase recapitulated the effects of αSNAP inhibition by decreasing Bcl-2 level and triggering apoptosis. These results reveal a novel role for αSNAP in promoting epithelial cell survival by unique mechanisms involving regulation of Bcl-2 expression and Golgi biogenesis. |
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Authors:
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Nayden G Naydenov; Gianni Harris; Bryan Brown; Katherine L Schaefer; Swadesh K Das; Paul B Fisher; Andrei I Ivanov |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-12-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-02-21 Completed Date: 2012-04-09 Revised Date: 2012-04-10 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 5928-41 Citation Subset: IM |
Affiliation:
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Department of Medicine, University of Rochester, Rochester, New York 14642, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphatases
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antagonists & inhibitors Apoptosis / drug effects, genetics* Cell Survival / drug effects, genetics Down-Regulation / drug effects, genetics* Endoplasmic Reticulum / drug effects, metabolism Endoplasmic Reticulum Stress / drug effects, genetics Enzyme Inhibitors / pharmacology Epithelial Cells / cytology*, drug effects, metabolism Golgi Apparatus / drug effects, metabolism* HCT116 Cells Humans Nuclear Proteins / antagonists & inhibitors Protein Transport / drug effects, genetics Proto-Oncogene Proteins c-bcl-2 / genetics* RNA, Small Interfering / genetics Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / deficiency*, genetics*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P01 CA104177/CA/NCI NIH HHS; R01 CA097318-10/CA/NCI NIH HHS; R01 CA97318/CA/NCI NIH HHS; R01 DK083968/DK/NIDDK NIH HHS; R01 DK084953/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/p97 ATPase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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