TWEAKing death.
Smac mimetics (inhibitor of apoptosis [IAP] antagonists) are synthetic reagents that kill susceptible tumor cells by inducing degradation of cellular IAP (cIAP) 1 and cIAP2, nuclear factor kappaB activation, tumor necrosis factor (TNF) alpha production, TNF receptor 1 occupancy, and caspase-8 activation. In this issue of The Journal of Cell Biology, Vince et al. (see p. 171) report remarkable similarities in the events leading to tumor cell death triggered by the cytokine TWEAK (TNF-like weak inducer of apoptosis) and IAP antagonists. Although the mechanistic details differ, a common and necessary feature that is also shared by TNF receptor 2 signaling is reduction in the level of cIAP1 and, in some cases, cIAP2 and TNF receptor-associated factor 2. These findings not only extend our appreciation of how cell death pathways are kept in check in tumors, they reinforce the possible utility of induced cIDE (cIAP deficiency) in the selective elimination of neoplastic cells.
Ashwell
Jonathan D
JD
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. jda@pop.nci.nih.gov
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D000074050:TWEAK Receptor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051034:Inhibitor of Apoptosis Proteins; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D000074050:TWEAK Receptor; D014409:Tumor Necrosis Factor-alpha