| Clostridium difficile toxin A-induced apoptosis is p53-independent but depends on glucosylation of Rho GTPases. | |
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MedLine Citation:
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PMID: 17437185 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Clostridium difficile toxin A (TcdA) is one of two homologous glucosyltransferases that mono-glucosylate Rho GTPases. HT29 cells were challenged with wild-type and mutant TcdA to investigate the mechanism by which apoptosis is induced. The TcdA-induced re-organization of the actin cytoskeleton led to an increased number of cells within the G2/M phase. Depolymerization of the actin filaments with subsequent G2/M arrest, however, was not causative for apoptosis, as shown in a comparative study using latrunculin B. The activation of caspase-3, -8, and -9 strictly depended on the glucosylation of Rho GTPases. Apoptosis measured by flow cytometry was completely abolished by a pan-caspase inhibitor (z-VAD-fmk). Interestingly, cleavage of procaspase-3 and Bid was not inhibited by z-VAD-fmk, but was inhibited by the calpain/cathepsin inhibitor ALLM. Cleavage of procaspase-8 was susceptible to inhibition by z-VAD-fmk and to the caspase-3 inhibitor Ac-DMQD-CHO, indicating a contribution to the activation of caspase-3 in an amplifying manner. Although TcdA induced mitochondrial damage and cytochrome c release, p53 was not activated or up-regulated. A p53-independent apoptotic effect was also checked by treatment of HCT 116 p53(-/-) cells. In summary, TcdA-induced apoptosis in HT29 cells depends on glucosylation of Rho GTPases leading to activation of cathepsins and caspase-3. |
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Authors:
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Stefanie Nottrott; Janett Schoentaube; Harald Genth; Ingo Just; Ralf Gerhard |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Apoptosis : an international journal on programmed cell death Volume: 12 ISSN: 1360-8185 ISO Abbreviation: Apoptosis Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-06-25 Completed Date: 2007-11-08 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9712129 Medline TA: Apoptosis Country: United States |
Other Details:
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Languages: eng Pagination: 1443-53 Citation Subset: IM |
Affiliation:
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Institute of Toxicology, Hannover Medical School, 30625 Hannover, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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metabolism Apoptosis / drug effects* Bacterial Toxins / metabolism*, pharmacology* Caspases / metabolism Cathepsins / antagonists & inhibitors Cell Cycle / drug effects Enterotoxins / metabolism*, pharmacology* Enzyme Activation / drug effects Glucosides / metabolism* Glycosyltransferases / metabolism, physiology HT29 Cells Humans Leupeptins / pharmacology Models, Biological Protein Processing, Post-Translational / drug effects Tumor Suppressor Protein p53 / physiology* rho GTP-Binding Proteins / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/Bacterial Toxins; 0/Enterotoxins; 0/Glucosides; 0/Leupeptins; 0/Tumor Suppressor Protein p53; 0/tcdA protein, Clostridium difficile; 110044-82-1/acetylleucyl-leucyl-norleucinal; EC 2.4.-/Glycosyltransferases; EC 3.4.-/Cathepsins; EC 3.4.22.-/Caspases; EC 3.6.5.2/rho GTP-Binding Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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