Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.22.61 (
caspase-8
)
6,833
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Autophagy and apoptosis regulate cancer cell viability in response to cytotoxic stress; however, their functional relationship remains unclear. p62/sequestosome 1 is a multifunctional protein and a signaling hub that shuttles ubiquitinated proteins to the lysosome during autophagy. Autophagy inhibition up-regulates p62, and prior data suggest that p62 may mediate apoptosis. Here, we demonstrate that p62 can regulate a
caspase-8
-dependent apoptosis in response to the BH3 mimetic agent, ABT-263. Up-regulation of p62 was shown to enhance ABT-263-induced
caspase-8
activation that was Bax-dependent and resulted from mitochondrial amplification.
Dependence
upon
caspase-8
was confirmed using
caspase-8
-deficient cells and by
caspase-8
siRNA. Ectopic wild-type p62, but not p62 mutants with loss of ability to promote apoptosis, was shown to co-localize with
caspase-8
and to promote its self-aggregation in ABT-263-treated cells, shown using a bimolecular fluorescence complementation assay. Endogenous p62 co-localized with
caspase-8
in the presence of ABT-263 plus an autophagy inhibitor. Caspase-8 was shown to interact and co-localize with the autophagosome marker, LC3II. Knockdown of p62 attenuated binding between
caspase-8
and LC3II, whereas p62 overexpression enhanced the co-localization of
caspase-8
aggregates with LC3. LC3 knockdown did not affect interaction between
caspase-8
and p62, suggesting that p62 may facilitate
caspase-8
translocation to the autophagosomal membrane. A direct activator of
caspase-8
, i.e., TRAIL, alone or combined with ABT-263, induced
caspase-8
aggregation and co-localization with p62 that was associated with a synergistic drug interaction. Together, these results demonstrate that up-regulation of p62 can mediate apoptosis via
caspase-8
in the setting of autophagy inhibition.
...
PMID:p62/sequestosome-1 up-regulation promotes ABT-263-induced caspase-8 aggregation/activation on the autophagosome. 2412 7
