Wang C Y, Mayo M W, Korneluk R G, Goeddel D V, Baldwin A S
Department of Endodontics, School of Dentistry, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Science. 1998 Sep 11;281(5383):1680-3. doi: 10.1126/science.281.5383.1680.
Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) potentially initiates apoptosis and activates the transcription factor nuclear factor kappa B (NF-kappaB), which suppresses apoptosis by an unknown mechanism. The activation of NF-kappaB was found to block the activation of caspase-8. TRAF1 (TNFR-associated factor 1), TRAF2, and the inhibitor-of-apoptosis (IAP) proteins c-IAP1 and c-IAP2 were identified as gene targets of NF-kappaB transcriptional activity. In cells in which NF-kappaB was inactive, all of these proteins were required to fully suppress TNF-induced apoptosis, whereas c-IAP1 and c-IAP2 were sufficient to suppress etoposide-induced apoptosis. Thus, NF-kappaB activates a group of gene products that function cooperatively at the earliest checkpoint to suppress TNF-alpha-mediated apoptosis and that function more distally to suppress genotoxic agent-mediated apoptosis.
肿瘤坏死因子α（TNF-α）与肿瘤坏死因子受体（TNFR）结合可能启动细胞凋亡并激活转录因子核因子κB（NF-κB），而NF-κB通过未知机制抑制细胞凋亡。研究发现，NF-κB的激活会阻断半胱天冬酶-8的激活。TRAF1（肿瘤坏死因子受体相关因子1）、TRAF2以及凋亡抑制蛋白（IAP）c-IAP1和c-IAP2被确定为NF-κB转录活性的基因靶点。在NF-κB无活性的细胞中，所有这些蛋白都是完全抑制TNF诱导的细胞凋亡所必需的，而c-IAP1和c-IAP2足以抑制依托泊苷诱导的细胞凋亡。因此，NF-κB激活了一组基因产物，这些基因产物在最早的检查点协同发挥作用以抑制TNF-α介导的细胞凋亡，并在更远端发挥作用以抑制基因毒性剂介导的细胞凋亡。
