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5th
EMBL/EMBO Joint Conference 2004 |
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Session II |
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| No life without death |
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CD95, a member of the
tumor necrosis factor [TNF] receptor superfamily,
induces apoptosis upon receptor oligomerization.
The receptor and its ligand are important for apoptosis
of peripheral T cells, for downregulation of an
immune response and most likely, at least in part,
also for peripheral T cell tolerance. In AIDS, apoptosis
mediated by this system might contribute to the
depletion of T helper lymphocytes. Likewise, in
diseases in which liver cells are destroyed, the
CD95 system might play a major role. In a search
to identify the intracellular signalling pathway
of CD95 several molecules coupling to oligomerized
CD95 were immunoprecipitated from apoptosis-sensitive
human leukemic T cell and lymphoblastoid B cell
lines. The following binding molecules were only
associated with aggregated and not with monomeric
CD95: phosphorylated FADD [MORT1] and caspase 8.
Thus, caspase 8 was identified as the most CD95
receptor proximal protease which starts the cascade
of protease reactions important for CD95-mediated
apoptosis. Association of FADD and caspase 8 with
CD95 was not observed with C-terminally truncated
non-signalling CD95. FADD and FLICE did also not
associate with a CD95 cytoplasmic tail carrying
the lprcg amino acid replacement. FADD and caspase
8 form a death-inducing signalling complex [DISC]
with the CD95 receptor and are, thus, the first
CD95 associating proteins of a signalling cascade
mediating apoptosis.The function of the DISC is
discussed in detail, particularly with respect to
its role in sensitivity and resistance to apoptosis.
The CD95 death system plays a role in destruction
of liver tissue. In hepatitis cytotoxic T lymphocytes
might use the CD95 system to kill infected hepatocytes.
In M. Wilson copper overload leads to upregulation
of the CD95 ligand that may finally contribute to
acute liver failure. In HCC from patients treated
with chemotherapeutic drugs the CD95 receptor and
ligand are upregulated and may contribute to apoptosis
of the tumor or, depending on the drug sensitivity
of the tumor, to the status of the tumor as an immunoprivileged
site.
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