TNF-INDUCED INTRACELLULAR SIGNALING LEADING TO GENE INDUCTION OR TO CYTOTOXICITY BY NECROSIS OR BY APOPTOSIS

TNF-induced apoptosis, e.g. in murine PC60 cells, requires the TNF rec eptor p55 (TNF-R55) and the TNF rceptor p75 (TNF-R75); the latter even does not have to be triggered. The intracellular domain of TNF-R55 ca n be activated in the cytosol by linking it to the trimeric CAT protei n; induction of this fusion protein leads to a full TNF response. A ne w MAP kinase, p38, has been shown to be also activated by TNF. This ac tivation is essential for gene induction, but not for cytotoxicity in L929 cells. TNF treatment of L929 leads to reactive oxygen formation i n the mitochondria, resulting in cell death by necrosis. TNF treatment of many other cell types results in apoptosis, and this process invol ves activation of one or more ICE homologs (IHO). In the mouse, seven cysteine proteases of the IHO family have been cloned and partially ch aracterized. One or more of these IHOs is involved in cell killing by proteolysis of critical substrate(s). One substrate, which may be a ke y effector molecule in the apoptotic process, is PITSLRE kinase. (C) 1 996 Wiley-Liss, Inc.