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 receptor p55 (TNF-R55) and the TNF receptor p75 (TNF-R75); the latter even does not have to be triggered. The intracellular domain of TNF-R55 can be activated in the cytosol by linking it to the trimeric CAT protein; induction of this fusion protein leads to a full TNF response. A new MAP kinase, p38, has been shown to be also activated by TNF. This activation is essential for gene induction, but not for cytotoxicity in L929 cells. TNF treatment of L929 leads to reactive oxygen formation in the mitochondria, resulting in cell death by necrosis. TNF treatment of many other cell types results in apoptosis, and this process involves activation of one or more ICE homologs (IHO). In the mouse, seven cysteine proteases of the IHO family have been cloned and partially characterized. One or more of these IHOs is involved in cell killing by proteolysis of critical substrate(s). One substrate, which may be a key effector molecule in the apoptotic process, is PITSLRE kinase.
Laboratory of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, Ghent, Belgium.
W
W
Fiers
R
R
Beyaert
E
E
Boone
S
S
Cornelis
W
W
Declercq
E
E
Decoster
G
G
Denecker
B
B
Depuydt
D
D
De Valck
G
G
De Wilde
V
V
Goossens
J
J
Grooten
G
G
Haegeman
K
K
Heyninck
L
L
Penning
S
S
Plaisance
K
K
Vancompernolle
W
W
Van Criekinge
P
P
Vandenabeele
W
W
Vanden Berghe
M
M
Van de Craen
V
V
Vandevoorde
D
D
Vercammen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002415:Cats; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D009336:Necrosis; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha