%0 Journal Article
%T Chopper Is Prodeath Regardless of the Effect of p75ICD on Sensitivity to Oxidative Stress
%A Alliya Qazi
%A Marc W. Halterman
%A Zhiping Mi
%A Tong Zhang
%A Nina F. Schor
%J Oxidative Medicine and Cellular Longevity
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/391659
%X Background. The intracellular domain (ICD) of the neurotrophin receptor, p75NTR, exhibits variably pro- and antiapoptotic activity and has been implicated in neurodegenerative and neurodestructive disease. The molecular determinants of these cellular effects are not completely understood. The ¡°Chopper¡± domain of p75ICD has been shown to be proapoptotic in in vitro systems in which p75ICD is proapoptotic. The effects of Chopper in systems in which p75ICD is antiapoptotic and, therefore, whether or not Chopper accounts for the variability of the cellular effects of p75ICD are not known. We therefore examined the effects of deletion of Chopper on the effects of p75ICD on in vitro cell culture systems in which p75ICD is pro- or antiapoptotic, respectively. Results. In HN33.11 murine neuroblastoma-hippocampal neuron hybrid cells, p75ICD is antiapoptotic. In NIH 3T3 cells, p75ICD is proapoptotic. In both cell lines deletion of the Chopper domain from p75ICD decreases the incidence of apoptosis resulting from oxidative stress. Thus, irrespective of the nature of the effects of p75ICD on the cell, its Chopper domain is proapoptotic. Conclusions. Expression of p75ICD can enhance or attenuate oxidative induction of apoptosis. Variability of the effects of p75ICD is not related to variability of the effects of its Chopper domain. 1. Background The neurotrophin receptor, p75NTR, has been implicated in the pathogenesis of neurodegenerative and neurodestructive diseases, including Alzheimer¡¯s disease [1¨C3], Parkinson¡¯s disease [4], invasive glioblastoma [5], and chemoresistant neuroblastoma [6]. It can be pro- or antiapoptotic depending on the milieu in which it is expressed [6, 7]. Its activity appears to be mediated by its intracellular domain (p75ICD; [8, 9]). p75ICD can substitute for full-length p75NTR in both protective [8, 9] and death-inducing [7] models. p75NTR is a member of the tumor necrosis factor family of death receptors. As such, its C-terminal, CD95-like death domain was originally assumed to be responsible for its proapoptotic properties. However, the p75NTR death domain does not behave like the death domains of other tumor necrosis factor family death receptors [10¨C12]. The Chopper region at the juxtamembrane end of p75ICD has been shown to be both necessary and sufficient for apoptosis induction by p75NTR. Chopper must be either membrane-anchored or palmitoylated to function in this way; in fact, when it is not, it is a dominant negative influence on this activity in models in which p75NTR is proapoptotic [13]. We have characterized neural crest
%U http://www.hindawi.com/journals/omcl/2011/391659/