Ultraviolet B radiation-induced apoptosis in human keratinocytes: cytosolic activation of procaspase-8 and the role of Bcl-2.
In this study, we show that ultraviolet B radiation (UVB)-induced apoptosis of human keratinocytes involves mainly cytosolic signals with mitochondria playing a central role. Overexpression of Bcl-2 inhibited UVB-induced apoptosis by blocking the early generation of reactive oxygen species, mitochondrial cardiolipin degradation and cytochrome c release, without affecting Fas ligand (FasL)-induced cell death. It also prevented the subsequent activation of procaspase-3 and -8 as well as Bid cleavage in UVB-treated cells. Comparative analysis of UVB and FasL death pathways revealed a differential role and mechanism of caspase activation, with the UVB-induced activation of procaspase-8 only being a bystander cytosolic event rather than a major initiator mechanism, as is the case for the FasL-induced cell death. Our results suggest that Bcl-2 overexpression, by preventing reactive oxygen species production, helps indirectly to maintain the integrity of lysosomal membranes, and therefore inhibits the release of cathepsins, which contribute to the cytosolic activation of procaspase-8 in UVB-irradiated keratinocytes.
Assefa
Zerihun
Z
Division of Biochemistry, Faculty of Medicine, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Garmyn
Marjan
M
Vantieghem
Annelies
A
Declercq
Wim
W
Vandenabeele
Peter
P
Vandenheede
Jackie R
JR
Agostinis
Patrizia
P
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000528:radiation effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D014466:Ultraviolet Rays
D004792:Enzyme Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases