| Autor: |
Li, Ming, Shillinglaw, Wendy, Henzel, William J., Beg, Amer A. |
| Zdroj: |
Journal of Biological Chemistry; January 2001, Vol. 276 Issue: 2 p1185-1194, 10p |
| Abstrakt: |
Double-stranded RNA (dsRNA) molecules generated during virus infection can initiate a host antiviral response to limit further infection. Such a response involves induction of antiviral gene expression by the dsRNA-activated protein kinase (PKR) and the NF-κB transcription factor. In addition, dsRNA can also induce apoptosis by an incompletely understood mechanism that may serve to further limit viral replication. Here we demonstrate a novel role for the RelA subunit of NF-κB in inhibiting dsRNA-induced cell death. dsRNA treatment resulted in caspase 3 activation and apoptotic morphological transformations in mouse embryonic fibroblasts (MEFs) derived from RelA−/− mice but not from RelA+/+ mice. Such dsRNA-induced killing could be inhibited by expression of either a dominant-negative mutant of PKR or wild-type RelA. Interestingly, caspase 3 activated following dsRNA treatment of RelA−/− MEFs was essential for apoptotic nuclear changes but dispensable for cytotoxicity. A broader specificity caspase inhibitor was also unable to inhibit dsRNA-induced cytotoxicity, suggesting that caspase activation is not essential for the induction of cell death by dsRNA in MEFs. However, combined inhibition of caspase 3 and reactive oxygen species production resulted in complete inhibition of dsRNA-induced cytotoxicity. These results demonstrate an essential role for NF-κB in protecting cells from dsRNA-induced apoptosis and suggest that NF-κB may inhibit both caspase-dependent and reactive oxygen species-dependent cytotoxic pathways. |
| Databáze: |
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