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 (Fa sL). TNF-alpha and FasL induce their respective receptors and then activate caspase enzymes that are critically involved in the apoptotic process. Thi s activation is further amplified by intracellular mitochondria-associated mechanisms. Using gene-targeted knockout mice lacking either the TNF-Rp55 o r 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 stimul ate cross-linking of Fas, resulting in the engagement of the death machiner y. 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 d ownstream signal transduction by recruiting caspases, Moreover, signaling o f 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 determinati on of whether or not a cell undergoes apoptosis after UV radiation is based on the balance between agonist and antagonist pathways.