| Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. | |
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MedLine Citation:
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PMID: 22246639 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The TNF-R1 like receptor Fas is highly expressed on the plasma membrane of hepatocytes and plays an essential role in liver homeostasis. We recently showed that in collagen-cultured primary mouse hepatocytes, Fas stimulation triggers apoptosis via the so-called type I extrinsic signaling pathway. Central to this pathway is the direct caspase-8-mediated cleavage and activation of caspase-3 as compared to the type II pathway which first requires caspase-8-mediated Bid cleavage to trigger mitochondrial cytochrome c release for caspase-3 activation. Mathematical modeling can be used to understand complex signaling systems such as crosstalks and feedback or feedforward loops. A previously published model predicted a positive feedback loop between active caspases-3 and -8 in both type I and type II FasL signaling in lymphocytes and Hela cells, respectively. Here we experimentally tested this hypothesis in our hepatocytic type I Fas signaling pathway by using wild-type and XIAP-deficient primary hepatocytes and two recently characterized, selective caspase-3/-7 inhibitors (AB06 and AB13). Caspase-3/-7 activity assays and quantitative western blotting confirmed that fully processed, active p17 caspase-3 feeds back on caspase-8 by cleaving its partially processed p43 form into the fully processed p18 species. Our data do not discriminate if p18 positively or negatively influences FasL-induced apoptosis or is responsible for non-apoptotic aspects of FasL signaling. However, we found that caspase-3 also feeds back on Bid and degrades its own inhibitor XIAP, both events that may enhance caspase-3 activity and apoptosis. Thus, potent, selective caspase-3 inhibitors are useful tools to understand complex signaling circuitries in apoptosis. |
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Authors:
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Karine Sá Ferreira; Clemens Kreutz; Sabine Macnelly; Karin Neubert; Angelika Haber; Matthew Bogyo; Jens Timmer; Christoph Borner |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-13 |
Journal Detail:
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Title: Apoptosis : an international journal on programmed cell death Volume: - ISSN: 1573-675X ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9712129 Medline TA: Apoptosis Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Institute of Molecular Medicine and Cell Research, University of Freiburg, Stefan-Meier-Str. 17, 79104, Freiburg, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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