We have further examined the mechanism by which phorbol ester-mediated @entity7131 ( @entity7131 ) activation protects against @entity5 @entity39 factor ( @entity310 )-related apoptosis-inducing ligand ( @entity2205 )-induced @entity137 . We now report that activation of @entity7131 targets death receptor signaling complex formation. Pre-treatment with 12-O-tetradecanoylphorbol-13-acetate (PMA) led to inhibition of @entity2205 -induced apoptosis in HeLa cells, which was characterized by a reduction in phosphatidylserine (PS) externalization, decreased @entity8186 processing, and incomplete maturation and activation of @entity522 . These effects of PMA were completely abrogated by the @entity7131 inhibitor, bisindolylmaleimide I (Bis I), clearly implicating @entity7131 in the protective effect of PMA. @entity2205 -induced mitochondrial release of the apoptosis mediators @entity4674 and @entity17205 was blocked by PMA. This, together with the observed decrease in Bid cleavage, suggested that @entity7131 activation modulates apical events in @entity2205 signaling upstream of mitochondria. This was confirmed by analysis of @entity2205 death-inducing signaling complex formation, which was disrupted in PMA-treated cells as evidenced by a marked reduction in @entity23903 ( @entity23903 ) recruitment, an effect that could not be explained by any change in @entity23903 phosphorylation state. In an in vitro binding assay, the intracellular domains of both @entity3048 and @entity3049 bound @entity23903 : activation of @entity7131 significantly inhibited this interaction suggesting that @entity7131 may be targeting key apical components of death receptor signaling. Significantly, this effect was not confined to @entity2205 , because isolation of the native @entity310 receptor signaling complex revealed that @entity7131 activation also inhibited @entity310 receptor-associated death domain protein recruitment to @entity10736 and @entity310 -induced phosphorylation of @entity4284 . Taken together, these results show that @entity7131 activation specifically inhibits the recruitment of key obligatory death domain-containing adaptor proteins to their respective membrane-associated signaling complexes, thereby modulating @entity2205 -induced apoptosis and @entity310 -induced NF-kappaB activation, respectively.

Protein kinase C modulates @entity5 XXXX factor-related apoptosis-inducing ligand-induced apoptosis by targeting the apical events of death receptor signaling.

@entity137 :: ('MESH:D064420', 'Disease') :: ['cytotoxicity'] @entity522 :: ('836', 'Gene') :: ['caspase-3'] @entity17205 :: ('56616', 'Gene') :: ['Smac'] @entity39 :: ('MESH:D009336', 'Disease') :: ['necrosis'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity2205 :: ('8743', 'Gene') :: ['TRAIL'] @entity310 :: ('7124', 'Gene') :: ['TNF'] @entity4674 :: ('54205', 'Gene') :: ['cytochrome c'] @entity3048 :: ('8797', 'Gene') :: ['TRAIL-R1'] @entity8186 :: ('841', 'Gene') :: ['caspase-8'] @entity7131 :: ('MESH:D020151', 'Disease') :: ['protein kinase C', 'PKC'] @entity3049 :: ('8795', 'Gene') :: ['TRAIL-R2'] @entity4284 :: ('4792', 'Gene') :: ['IkappaB-alpha'] @entity23903 :: ('8772', 'Gene') :: ['FADD', 'Fas-associated death domain protein'] @entity10736 :: ('7132', 'Gene') :: ['TNF-R1']
@entity39 :: (MESH:D009336,Disease) :: ['necrosis']
