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pubmed-article:21402772pubmed:abstractTextActin cytoskeleton has been shown to play a regulating role in several signaling pathways, and disruption of actin filament has been reported to increase sTNF-?-induced cell death. However, whether actin is involved in tmTNF-?-mediated cytotoxicity remains unclear. Here, we demonstrated that pretreatment of HL-60 with CytD or LatA to depolymerize actin significantly suppressed tmTNF-?-mediated apoptosis. Interestingly, tmTNF-? increased the actin immunoprecipitated by anti-TNFR2 but not anti-TNFR1 antibody, and disruption of the actin filament totally blocked this effect. In addition, TNFR1 knockdown by siRNA did not affect tmTNF-?-mediated cytotoxicity and the inhibitory effect of CytD, suggesting that the involvement of actin in the tmTNF-?-induced apoptosis is linked to the TNFR2 pathway. Our results revealed further that tmTNF-? signaled the inhibition of I?B degradation and NF-?B activity by recruiting RIP1 to and uncoupling TRAF2 from the TNFR2 complex. Nevertheless, CytD totally reversed the tmTNF-? signaling and activated NF-?B by recruiting TRAF2 to and dissociating RIP1 from the TNFR2 complex. Furthermore, tmTNF-? led to activation of caspase-8 by dissociation of cFLIP from TNFR2 and inhibition of the cFLIP expression. Activated caspase-8 cleft RIP1 to suppress NF-?B activity and also mediated tmTNF-?-induced apoptosis. However, CytD blocked the tmTNF-?-induced uncoupling of cFLIP from TNFR2 and prevented caspase-8 activation and the resulting cleavage of RIP1, converting the signaling for tmTNF-?-mediated apoptosis into one for activating NF-?B to survive. These results suggest that the actin cytoskeleton functions in transmitting signals via TNFR2 to mediate tmTNF-?-induced apoptosis.lld:pubmed
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pubmed-article:21402772pubmed:articleTitleThe involvement of ?-actin in the signaling of transmembrane TNF-?-mediated cytotoxicity.lld:pubmed
pubmed-article:21402772pubmed:affiliationDepartment of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.lld:pubmed
pubmed-article:21402772pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:21402772pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed