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Caspase-3 feeds bac...
Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes
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- Sa Ferreira, Karine (författare)
- University of Freiburg
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- Kreutz, Clemens (författare)
- University of Freiburg
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- MacNelly, Sabine (författare)
- University Hospital Freiburg
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- Neubert, Karin (författare)
- University of Freiburg
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- Haber, Angelika (författare)
- University of Freiburg
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- Bogyo, Matthew (författare)
- Stanford University
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- Timmer, Jens (författare)
- Linköpings universitet,Institutionen för klinisk och experimentell medicin,Hälsouniversitetet
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- Borner, Christoph (författare)
- University of Freiburg
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(creator_code:org_t)
- 2012-01-13
- 2012
- Engelska.
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Ingår i: Apoptosis (London). - : Springer Verlag (Germany). - 1360-8185 .- 1573-675X. ; 17:5, s. 503-515
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- Type I apoptosis
- Caspase-3
- Caspase-8
- Caspase inhibitor
- Feedback loop
- Bid
- XIAP
- MEDICINE
- MEDICIN
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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