| Prostate Apoptosis Response-4 (Par-4): A Novel Substrate of Caspase-3 during Apoptosis Activation. | |
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MedLine Citation:
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PMID: 22184067 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Prostate apoptosis response-4 (Par-4) is a ubiquitously expressed pro-apoptotic tumor suppressor protein. Here, we show for the first time, that Par-4 is a novel substrate of caspase-3 during apoptosis. We found that Par-4 is cleaved during cisplatin-induced apoptosis in human normal and cancer cell lines. Par-4 cleavage generates a C-terminal fragment of ∼25kDa and the cleavage of Par-4 is completely inhibited by caspase-3 inhibitor suggesting that caspase-3 is directly involved in the cleavage of Par-4. Caspase-3-deficient MCF-7 cells does not show Par-4 cleavage in response to cisplatin treatment and restoration of caspase-3 in MCF-7 cells shows a decrease in Par-4 levels with the appearance of cleaved fragment. Additionally, knockdown of Par-4 reduces caspase-3 activation and apoptosis induction. Site-directed mutagenesis reveals that Par-4 cleavage by caspase-3 occurs at an unconventional site, EEPD(131)↓G. Interestingly, overexpression of wild type Par-4 and not Par-4 D131A mutant sensitizes cells to cisplatin-induced apoptosis. Upon caspase-3 cleavage, the cleaved fragment of Par-4 accumulates in the nucleus and displays increased apoptotic activity. Overexpression of the cleaved fragment of Par-4 inhibits IκBα phosphorylation and blocks NF-κB nuclear translocation. Together, we have identified a novel specific caspase-3 cleavage site in Par-4 and the cleaved fragment of Par-4 retains pro-apoptotic activity. |
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Authors:
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Parvesh Chaudhry; Mohan Singh; Sophie Parent; Eric Asselin |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-19 |
Journal Detail:
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Title: Molecular and cellular biology Volume: - ISSN: 1098-5549 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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From Research Group in Molecular Oncology and Endocrinology, Department of Chemistry-Biology, Université du Québec à Trois-Rivières, Trois-Rivières, Quebec, Canada. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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