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Protein Kinase
C Functions Downstream of the Death Receptor Signaling Complex in Mediating
Inhibition of Singlet Oxygen-Induced Apoptosis
Zhuang, Shougang 1,
Demirs, John1 and Kochevar, Irene1
Massachusetts General Hospital1
Massachusetts General Hospital2
Massachusetts General Hospital3
Abstract-
Although activation of protein kinase C (PKC) inhibits apoptosis induced
by a variety of stimuli including singlet oxygen, whether PKC activation
interferes with apoptotic signaling is not well defined. In this study,
we investigated the role of PKC in the regulation of caspase pathway
initiated by singlet oxygen. Singlet oxygen induced the Fas clustering
and subsequent recruitment of FADD and caspase-8. However, treatment
of cells with the phorbol ester12-O-tetradecanoylphorbol-13-acetate
(TPA), a PKC activator, did not affect the caspase-8 binding to the
aggregated Fas. Surprisingly, PKC activation were still able to prevent
singlet oxygen-induced activation of caspase-8 and blocked its downstream
signaling events including cleavage of Bid and caspase-3, as well as
release of cytochrome c from mitochondria. In contrast, inhibition of
PKC by GF109203 or H7, counteracted the TPA-mediated effects on the
cleavage of caspase-3 and-8. These data not only suggest that PKC can
inhibit apoptosis by blocking caspase pathway and also places the site
of action downstream of Fas signaling complex. Although p38 is also
involved in the activation of caspase pathway and apoptosis in singlet
oxygen-treated cells, neither activation nor inhibition of PKC affected
p38 phosphorylation, indicating that role of PKC is not mediated by
this kinase.
Keywords: protein
kinase C, singlet oxygen, apoptosis, caspases
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