Purchase this article with an account.
Nicolas G Bazan, Jorgelina M Calandria, Aram Asatryan; c-REL is a key mediator in RPE cell survival signaling regulated by NPD1. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4559.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Neuroprotectin D1 (NPD1), a docosahexaenoic acid (DHA)-derived lipid mediator, induces cell survival in uncompensated oxidative stress conditions. NPD1 is a critical modulator of homeostatic alterations during rod outer segment phagocytosis (Bazan NG, Invest Ophthalmol Vis Sci. 2007;48:4866-81). NPD1 effects include the down-regulation of pro-apoptotic proteins and the up-regulation of pro-survival counterparts, however the molecular principles underlying this modulation remain unknown.
To define the mechanisms by which NPD1 modulates cell survival, we used human retinal pigment epithelial (RPE) cells as a cellular model. We analyzed the promoter of BIRC3, a pro-survival protein that is up-regulated by NPD1, to find the transcription factors that are implicated in the NPD1-mediated modulation. Finally, we silenced BIRC3 to assess its importance in the NPD1 pathway.
We report here that, in RPE cells, NPD1 induces nuclear translocation and cREL synthesis that, in turn, mediates BIRC3 transcription. NPD1 activates NF-kappaB by an alternate route to canonical signaling, so the opposing effects of TNFR1 and NPD1 on BIRC3 expression are not due to interaction/s between NF-kappaB pathways. BIRC3 promoter contains two binding sites for NF-kappaB that scored highly for cREL and ChIP assay, showing that this binding is enhanced by NPD1. cREL and RelB expression follows a similar pattern of BIRC3, indicating that NPD1 also is required to activate cREL-mediated RelB expression. BIRC3 silencing prevents NPD1 induction of survival against oxidative stress, noticed as increased activation of effector caspases 3 and 7. BIRC3 may exert its effects by modulation of RIP1 activity, which participates in regulation of the formation of complexes II and III.
These results suggest that cREL, which follows a periodic pattern augmented by the lipid mediator, regulates a cluster of NPD1-dependent genes after cREL nuclear translocation. Thus, NPD1 bioactivity governs key counter-regulatory gene transcription events decisive for RPE/photoreceptor cell integrity when confronted with potential disruptions of homeostasis.
This PDF is available to Subscribers Only