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J. Cell Biol.,
Volume 140, Number 1, January 12, 1998 171-182
Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of
Münster, D-48149 Münster, Germany
Induction of apoptosis in keratinocytes by
UV light is a critical event in photocarcinogenesis. Although p53 is of importance in this process, evidence
exists that other pathways play a role as well. Therefore, we studied whether the apoptosis-related surface molecule CD95 (Fas/APO-1) is involved. The human
keratinocyte cell line HaCaT expresses CD95 and undergoes apoptosis after treatment with UV light or with
the ligand of CD95 (CD95L). Incubation with a neutralizing CD95 antibody completely prevented CD95L-induced apoptosis but not UV-induced apoptosis, initially suggesting that the CD95 pathway may not be
involved. However, the protease CPP32, a downstream
molecule of the CD95 pathway, was activated in UV-exposed HaCaT cells, and UV-induced apoptosis was
blocked by the ICE protease inhibitor zVAD, implying
that at least similar downstream events are involved in
CD95- and UV-induced apoptosis. Activation of CD95
results in recruitment of the Fas-associated protein with death domain (FADD) that activates ICE proteases.
Immunoprecipitation of UV-exposed HaCaT cells revealed that UV light also induces recruitment of
FADD to CD95. Since neutralizing anti-CD95 antibodies failed to prevent UV-induced apoptosis, this suggested that UV light directly activates CD95 independently of the ligand CD95L. Confocal laser scanning
microscopy showed that UV light induced clustering of
CD95 in the same fashion as CD95L. Prevention of UV-induced CD95 clustering by irradiating cells at
10°C was associated with a significantly reduced death
rate. Together, these data indicate that UV light directly stimulates CD95 and thereby activates the CD95
pathway to induce apoptosis independently of the natural ligand CD95L. These findings further support the
concept that UV light can affect targets at the plasma
membrane, thereby even inducing apoptosis.
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