| Hsp90 cleavage by an oxidative stress leads to its client proteins degradation and cancer cell death. | |
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MedLine Citation:
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PMID: 19014912 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The heat shock protein 90 (Hsp90) plays a crucial role in the stability of several proteins that are essential for malignant transformation. Hsp90 is therefore an interesting therapeutic target for cancer therapy. In this paper, we investigated whether an oxidative stress generated during ascorbate-driven menadione redox cycling (ascorbate/menadione), affects Hsp90 leading to the degradation of some critical proteins and cell death. Unlike 17-AAG, which inhibits Hsp90 but enhances Hsp70 levels, ascorbate/menadione-treated cells present an additional Hsp90 protein band of about 70kDa as shown by Western blot analysis, suggesting Hsp90 cleavage. This Hsp90 cleavage seems to be a selective phenomenon since it was observed in a large panel of cancer cell lines but not in non-transformed cells. Antibodies raised against either the N-terminus or the C-terminus domains of Hsp90 suggest that the site of cleavage should be located at its N-terminal part. Furthermore, antibodies raised against either the alpha- or the beta-Hsp90 isoform show that Hsp90beta is cleaved while the alpha isoform is down-regulated. We have further shown that different Hsp90 client proteins like Bcr-Abl (a chimerical protein expressed in K562 leukemia cells), RIP and Akt, were degraded when K562 cells were exposed to an oxidative stress. Both Hsp90 cleavage and Bcr-Abl degradation were observed by incubating K562 cells with another H(2)O(2)-generating system (glucose/glucose oxidase) and by incubating KU812 cells (another leukemia cell line) with ascorbate/menadione. Due to the major role of Hsp90 in stabilizing oncogenic and mutated proteins, these results may have potential clinical applications. |
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Authors:
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Raphael Beck; Julien Verrax; Thomas Gonze; Marianne Zappone; Rozangela Curi Pedrosa; Henryk Taper; Olivier Feron; Pedro Buc Calderon |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-10-28 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 77 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2009 Feb |
Date Detail:
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Created Date: 2009-01-26 Completed Date: 2009-02-12 Revised Date: 2009-05-21 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 375-83 Citation Subset: IM |
Affiliation:
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Unité de Pharmacocinétique, Métabolisme, Nutrition, et Toxicologie, Département des sciences pharmaceutiques, Université Catholique de Louvain, avenue E. Mounier 73, 1200 Brussels, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis* Ascorbic Acid / pharmacology Blotting, Western HSP90 Heat-Shock Proteins / metabolism* Humans Hydrolysis K562 Cells Oxidative Stress* Vitamin K 3 / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/HSP90 Heat-Shock Proteins; 50-81-7/Ascorbic Acid; 58-27-5/Vitamin K 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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