05月 16, 2008 at 11:46 am | 重点关注
- Posted by qixinming |
Cell, Vol 133, 681-692, 16 May 2008
The killer lymphocyte protease granzyme A (GzmA) triggers
caspase-independent target cell death with morphological features of
apoptosis. We previously showed that GzmA acts directly on mitochondria
to generate reactive oxygen species (ROS) and disrupt the transmembrane
potential (ΔΨm) but does not permeabilize the mitochondrial
outer membrane. Mitochondrial damage is critical to GzmA-induced cell
death since cells treated with superoxide scavengers are resistant to
GzmA. Here we find that GzmA accesses the mitochondrial matrix to
cleave the complex I protein NDUFS3, an iron-sulfur subunit of the
NADH:ubiquinone oxidoreductase complex I, after Lys56 to interfere with
NADH oxidation and generate superoxide anions. Target cells expressing
a cleavage site mutant of NDUFS3 are resistant to GzmA-mediated cell
death but remain sensitive to GzmB.
05月 16, 2008 at 11:46 am | 重点关注
- Posted by qixinming |
Cell
Volume 133, Issue 4,
16 May 2008,
Pages 693-703
Summary
The inflammatory response of mammalian cells to TNF-
can be switched to apoptosis either by cotreatment with a protein
synthesis inhibitor, cycloheximide, or Smac mimetic, a small molecule
mimic of Smac/Diablo protein. Cycloheximide promotes caspase-8
activation by eliminating endogenous caspase-8 inhibitor, c-FLIP, while
Smac mimetic does so by triggering autodegradation of cIAP1 and cIAP2
(cIAP1/2), leading to the release of receptor interacting protein
kinase (RIPK1) from the activated TNF receptor complex to form a
caspase-8-activating complex consisting of RIPK1, FADD, and caspase-8.
This process also requires the action of CYLD, a RIPK1 K63
deubiquitinating enzyme. RIPK1 is critical for caspase-8
activation-induced by Smac mimetic but dispensable for that triggered
by cycloheximide. Moreover, Smac mimetic-induced caspase-8 activation
is not blocked by endogenous c-FLIP. These findings revealed that TNF-
is able to induce apoptosis via two distinct caspase-8 activation
pathways that are differentially regulated by cIAP1/2 and c-FLIP.
12月 28, 2007 at 4:21 pm | 重点关注
- Posted by qixinming |
Cell, Vol 131, 1248-1259, 28 December 2007
We report an unexpected role for Tel2 in the expression of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Although Tel2 was identified as a budding yeast gene required for the telomere length maintenance, we found no obvious telomeric function for mammalian Tel2. Targeted gene deletion showed that mouse Tel2 is essential in embryonic development, embryonic stem (ES) cells, and embryonic fibroblasts. Conditional deletion of Tel2 from embryonic fibroblasts compromised their response to IR and UV, diminishing the activation of checkpoint kinases and their downstream effectors. The effects of Tel2 deletion correlated with significantly reduced protein levels for the PI3K-related kinases ataxia telangiectasia mutated (ATM), ATM and Rad3 related (ATR), DNA-dependent protein kinase catalytic subunit ataxia (DNA-PKcs). Tel2 deletion also elicited specific depletion of the mammalian target of rapamycin (mTOR), suppressor with morphological effect on genitalia 1 (SMG1), and transformation/transcription domain-associated protein (TRRAP), and curbed mTOR signaling, indicating that Tel2 affects all six mammalian PIKKs. While Tel2 deletion did not alter PIKK mRNA levels, in vivo pulse labeling experiments showed that Tel2 controls the stability of ATM and mTOR. Each of the PIKK family members associated with Tel2 in vivo and in vitro experiments indicated that Tel2 binds to part of the HEAT repeat segments of ATM and mTOR. These data identify Tel2 as a highly conserved regulator of PIKK stability.
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