Molecular mechanism of ultraviolet-induced keratinocyte apoptosis.
This article reviews advances in the study of the molecular mechanisms for ultraviolet (UV)-induced keratinocyte apoptosis, with particular reference to the cytokines tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL). TNF-alpha and FasL induce their respective receptors and then activate caspase enzymes that are critically involved in the apoptotic process. This activation is further amplified by intracellular mitochondria-associated mechanisms. Using gene-targeted knockout mice lacking either the TNF-Rp55 or the TNF-Rp75, we have shown that TNF-alpha plays an important role in UV-induced keratinocyte apoptosis via TNF-Rp55. TNF-Rp55 shares homology with Fas and contains an intracellular death domain. UV seems to directly stimulate cross-linking of Fas, resulting in the engagement of the death machinery. Fas-associated death domain protein (FADD) acts as an adapter protein in both the TNF-Rp55 and Fas death-inducing cascades and is responsible for downstream signal transduction by recruiting caspases. Moreover, signaling of p53 contributes to the induction of apoptosis by regulating Bcl-2 family expression and increasing surface Fas expression. In addition to induction mechanisms of apoptosis, there are numerous inhibitory molecules that play a role in restricting the apoptotic pathway. Thus, the ultimate determination of whether or not a cell undergoes apoptosis after UV radiation is based on the balance between agonist and antagonist pathways.
Zhuang
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Sunnybrook Health Science Centre, Department of Medical Biophysics and Immunology, University of Toronto, ON, Canada.
Wang
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B
Sauder
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D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology / Q000528:radiation effects*; D020169:Caspases / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology / Q000528:radiation effects*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D020169:Caspases