DNA damage, death receptor activation and reactive oxygen species contribute to ultraviolet radiation-induced apoptosis in an essential and independent way.
Nuclear DNA damage and death receptor (CD95) activation by ultraviolet-B radiation (UVB) play a major role in UVB-induced apoptosis. Removal of DNA damage combined with inhibition of death receptor activation resulted in pronounced but not complete suppression of apoptosis, indicating that a third independent pathway is involved. Since reactive oxygen species (ROS) cause apoptosis and are induced by UVB, the radical scavenger pyrrolidene-dithiocarbamate (PDTC) was used. PDTC prevented UVB-induced apoptosis partially, H(2)O(2)-induced cell death largely, but not CD95-mediated apoptosis. The same was observed for cytochrome c release from mitochondria, another important event during apoptosis. The proapoptotic protein Bid was cleaved upon exposure to UVB or to agonistic anti-CD95-antibodies, but not to H(2)O(2), indicating that H(2)O(2) uses a different pathway. The fact that PDTC neither inhibited CD95-mediated apoptosis nor affected UV-induced DNA damage indicated that ROS generated during UVB irradiation may directly trigger mitochondrial cytochrome c release, thereby contributing to apoptosis. Accordingly, complete inhibition of apoptosis was observed when in addition to DNA damage removal via photoreactivation and blockade of CD95 signaling by caspase-8 inhibitor zIETD, PDTC was added before UVB exposure. This indicates that DNA damage, death receptor activation and ROS formation contribute to UVB-induced apoptosis in an essential and independent way.
Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, Department of Dermatology, University Münster, Germany.
Dagmar
D
Kulms
Elke
E
Zeise
Birgit
B
Pöppelmann
Thomas
T
Schwarz
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair; D006367:HeLa Cells / Q000528:radiation effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000378:metabolism / Q000528:radiation effects*
D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D019014:fas Receptor; C066229:prolinedithiocarbamate; D011392:Proline; D006861:Hydrogen Peroxide