| First Author | Shikama Y | Year | 2003 |
| Journal | Eur J Immunol | Volume | 33 |
| Issue | 7 | Pages | 1998-2006 |
| PubMed ID | 12884866 | Mgi Jnum | J:203409 |
| Mgi Id | MGI:5526940 | Doi | 10.1002/eji.200324013 |
| Citation | Shikama Y, et al. (2003) Caspase-8 and caspase-10 activate NF-kappaB through RIP, NIK and IKKalpha kinases. Eur J Immunol 33(7):1998-2006 |
| abstractText | NF-kappaB regulates the expression of various genes involved in cell growth and differentiation, immune response and inhibition of apoptosis. Recently, some death effector domain (DED)-containing proteins, such as FADD and c-FLIP were reported to activate NF-kappaB. We previously reported that the prodomain-only isoforms of caspase-8 and -10 (PDCasp8/10), containing two DED motifs, could inhibit Fas-mediated apoptosis. Here, we demonstrate that these isoforms also activate NF-kappaB, implying this to be one of the mechanisms by which these polypeptides inhibit apoptosis. The GST pull-down assay revealed that, among upstream kinases that activate NF-kappaB, only NIK and RIP, but not RICK or IKKalpha/beta, could directly bind to PDCasp8/10. In addition, both modules ofDED in PDCasp8/10 were required for these interactions as well as NF-kappaB activation. Experiments using a kinase-dead mutant of IKKalpha and an RIP mutant lacking a kinase domain, both of which function as dominant-negative mutants for their wild-type counterparts, blocked PDCasp8/10-mediated NF-kappaB activation. Using small interfering RNA technology, we further demonstrate that the down-regulation of IKKalpha but not IKKbeta significantly inhibits PDCasp8-mediated NF-kappaB activation. Taken together, these results suggest that caspase-8 and -10 have roles in a non- or anti-apoptotic signaling pathway leading to NF-kappaB activation through RIP, NIK and IKKalpha. |
