Ultraviolet Radiation-induced Apoptosis Is Mediated by Activation of CD-95 (Fas/APO-1)

Abstract

Exposure to ultraviolet light (UV) can induce apoptosis in mammalian cells. The mechanism by which UV radiation engages the suicide apparatus is unclear. Here we demonstrate that UV radiation can activate the Fas pathway via receptor aggregation and subsequent recruitment of the death adaptor molecule FADD/MORT1. UV radiation-induced apoptosis was inhibited by both a dominant negative version of FADD (FADD-DN) and the caspase inhibitor CrmA. Thus, activation of the Fas pathway represents a physiologic mechanism by which UV-damaged cells are eliminated.Depletion of the ozone layer by chloro/fluorohydrocarbon pollutants and subsequent increase in exposure to ultraviolet (UV) radiation threatens to significantly increase the incidence of skin cancer. In addition, exposure to UV radiation can lead to photokeratitis, photoconjunctivitis, and permanent retinal blindness. UV irradiation of cells elicits a complex cellular response termed the UV response, which includes the posttranslational activation of pre-existing transcription factors including NF-B and AP-1 (1, 2). Activation of these transcription factors results in the subsequent induction of proinflammatory gene products IL-1 1 and TNF-␣ (3, 4). Prolonged UV exposure results in inhibition of DNA synthesis and subsequent resumption of the cell cycle following repair or apoptosis, a mechanism to rid the organism of irreversibly damaged and potentially cancerous cells. Little is known about the mechanism by which UV radiation triggers apoptosis.It is now evident that the effector arm of the death pathway is composed of caspases, cysteine proteases that cleave death substrates including PARP and lamin B following aspartate residues (reviewed in Ref. 5). To date ten caspases have been identified. They are normally present as single polypeptide inactive zymogens and require cleavage at internal aspartic acid residues to generate the 2-subunit catalytically competent protease. The best understood pathway leading to caspase activation is engagement of the death receptor, CD-95 (Fas/APO-1). Upon activation, an adapter molecule termed FADD is recruited to the cytoplasmic segment of the Fas receptor through a homophilic interaction between a stretch of 60 -80 amino acids, dubbed the death domain that is present in both molecules. The N-terminal segment of FADD encodes a distinct binding module termed the death effector domain (6). Remarkably, an equivalent domain, is present within the prodomain of FLICE (caspase-8). Interaction between the death effector domains allows for the recruitment of the death protease FLICE to the receptor signaling complex. Following conversion to the active dimeric species, FLICE is free to proteolytically activate other downstream zymogen caspases (7), leading to cleavage of death substrates and subsequent apoptotic demise.The ability of enucleated cells to mount a UV response has led to the suggestion that membrane or cytosolic events likely mediate the response (8). UV exposure for example induces rapid tyrosine phosphorylation of the EGF r...

Ultraviolet-irradiation-induced apoptosis is mediated via ligand independent activation of tumor necrosis factor receptor 1

“…Thus, in p53 null H1299 cells, the IRmediated apoptotic signals clearly di er from those of UV's in that they do not appear to engage the plasma membrane component involving FADD or the proximal caspases 8 and 10. Our results are consistent with those reported recently by Datta et al (1997) and Rehemtulla et al (1997) that CrmA did not block IR-induced apoptosis. Using the caspase 3 knock-out cells, Woo et al (1998) have also recently reported that while UVinduced apoptosis was blunted in caspase 3 de®cient cells, IR-induced apoptosis was not.…”

“…TNFR1 and Fas are the membrane death receptors that are known to relay apoptotic signals via FADD (reviewed by Nagata, 1997). UV-induced ligand independent aggregation-mediated activation of Fas has recently been reported (Rehemtulla et al, 1997;Aragane et al, 1998). In MCF-7 cells that express TNFR1 but do not express functional Fas (Keane et al, 1996), the ability of FADD-DN to partly inhibit UV-induced apoptosis, as we noted in the present study, highlights the individual contribution of TNFR1.…”

IL-18 Reduces Ultraviolet Radiation-Induced DNA Damage and Thereby Affects Photoimmunosuppression

“…Therefore, dysregulation of UV-induced apoptosis will affect the photocarcinogenic risk. Several ways exist to inhibit UV-induced apoptosis, e.g., by overexpressing heat shock (29) or antiapoptotic proteins (30,31), by disrupting p53 function (32), or by blocking death receptor activation (33,34). Because these approaches allow the survival of cells carrying DNA damage, they may give rise to mutations and skin cancer.…”

hnRNP A1 regulates UV-induced NF-κB signalling through destabilization of cIAP1 mRNA

“…37 Previous work showed that exposure of cells to UVR results in an inhibition of global protein synthesis. 14,38,39 This observation leads to the question of why an additional regulatory mechanism, such as degradation of cIAP1 mRNA, would be employed by cells to silence the expression of target genes following UVR.…”