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Cited by 463Cell death mechanisms and regulationSkin Protection and AgingCancer-related Molecular Pathways

Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L

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Aragane, Yoshinori, Kulms, Dagmar, Metze, Dieter, Wilkes, Gabriele, Pöppelmann, Birgit, Luger, Thomas A., Schwarz, Thomas·1998·The Journal of Cell Biology
DOI 10.1083/jcb.140.1.171PMC PMC2132609
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Abstract

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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  • Apoptosis cannot be totally attributed to the extrinsic pathway because a neutralizing anti-CD95 antibody blocks CD95L-induced apoptosis but fails to prevent UV-induced apoptosis.

    “However, apoptosis cannot be totally attributed to this extrinsic pathway because a neutralizing anti-CD95 antibody blocks CD95L-induced apoptosis but fails to prevent UV-induced apoptosis [35].”

    From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [35]

    The Results section reports that a neutralizing anti-CD95 antibody completely prevented CD95L-induced killing of HaCaT cells but did not affect UV-induced killing. The Discussion cautions against inferring from this result that the CD95 pathway is uninvolved: it concludes that UV directly activates CD95 independently of CD95L. The antibody result is supported, but the claim’s inference about the extrinsic pathway does not reflect the paper’s conclusion. (LLM, conf=0.88)

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  • In transformed HaCaT cells, the extrinsic pathway appears to be important in apoptosis since HaCaT cells lack a functional p53.

    “In transformed HaCaT cells, one of the commonly used human keratinocytes, this extrinsic pathway appears to be important in apoptosis since HaCaT cells lack a functional p53 [35].”

    From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [35]

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Authors
Aragane, Y., Kulms, D., Metze, D., Wilkes, G., Pöppelmann, B., Luger, T. A., & Schwarz, T.
Affiliations
  • University of Münster (DE)
  • Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University of Münster, D-48149 Münster, Germany
Corresponding author
Schwarz, Thomas
ORCID
Venue
The Journal of Cell Biology
Publisher
Rockefeller University Press
Published
1998-01-12
Volume
140
Issue
1
Pages
171-182
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.140.1.171
PMC
PMC2132609
OpenAlex
W2012587770
Cited by
463
References
3
Citations by year
2025: 3 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 10 · 2016: 9 · 2015: 4 · 2014: 7 · 2013: 14 · 2012: 5
FWCI
14.33
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Dermatology › Skin Protection and Aging
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
ultraviolet radiation, apoptosis, Fas, Fas/APO-1, Fas ligand, keratinocytes, HaCaT keratinocytes, photocarcinogenesis, CPP32, FADD, receptor clustering, temperature dependence, p53-independent pathway
MeSH terms
Antibodies, beta-Galactosidase, Cell Line, Transformed, Cysteine Endopeptidases, Humans, Kinetics, Membrane Glycoproteins, Plant Proteins, Proteins, Recombinant Proteins, Transfection, Ultraviolet Rays, Keratinocytes, Apoptosis, fas Receptor, Caspases, Arabidopsis Proteins, Fatty Acid Desaturases, Caspase 3, Fas Ligand Protein

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