ABSTRACT
The best-studied members of the death-receptor family are TNF receptor 1 (TNFRl), Fas (also known as CD95 or Apo-1), and the receptors for TNF-related apop tosis-inducing ligand (TRAIL). Whereas it has long been known that TNF-induced death can take the shape of either apoptosis or necrosis (Laster et al.y 1988), the ability of the Fas ligand (FasL) and TRAIL to induce necrosis-like PCD has been
Except for the dependence on reactive oxygen species (ROS) and, in some cases, serine protease activity, necrotic signaling pathways have remained ambiguous until recently (Denecker et al, 2001). Novel data demonstrate now that TNF, FasL, and TRAIL can trigger caspase-8-independent necrosis-like PCD that is dependent on the Fas-associated death domain (FADD) protein and the kinase activity of the receptor-interacting protein (RIP) (Holler et a l , 2000). The dependence of RIPmediated necrotic PCD on proteases remains to be studied. Interestingly, some TNF-resistant cells are sensitized to TNF-induced necrosis-like PCD upon inhibi tion of caspases, suggesting that caspases act as survival factors that directly inhibit the TNF-induced necrotic pathway (Khwaja and Tatton, 1999). Death receptors can also trigger caspase-independent apoptosis-like PCD. In immortalized epithe lial cells, activated Fas has been reported to recruit Daxx from the nucleus to the receptor complex, and to trigger its binding with apoptosis signal-regulating kinase 1 (Askl) (Charette et a l , 2000; Ko et a l , 2001). Others have, however, have failed to detect Daxx in the cytosol and have suggested that Daxx enhances Fas-induced caspase-dependent death from its nuclear localization (Torii et a l , 1999). Thus, Daxx may stimulate Fas-induced death by two independent mechanisms, the cas pase-independent pathway being evident only when caspase activation is defective (Charette etai, 2000) and enough Askl is available (Ko etai, 2001). In addition to a caspase-dependent proapoptotic function that depends on its kinase activity, Askl possesses a caspase-independent killing function that is independent of its kinase activity and is activated by interaction with Daxx (Charette et a l , 2001). Askl has also been found to be essential for TNF-triggered apoptosis of primary fibroblasts, but its activation by TNF appears to require ROS (Tobiume et al, 2001 ) instead of Daxx (Yang et a l , 1997). In TNF-treated fibrosarcoma cells cysteine cathepsins act as dominant execution proteases and bring about apoptosis-like morphologic changes (Foghsgaard et a l , 2001). Whether Askl and cathepsins act on the same signaling pathway is as yet unknown.
