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Swornim M Shrestha, Jorgelina Muriel Calandria, Khanh Do, Jonathan D Wren, Nicolas G Bazan; Neuroprotectin D1 (NPD1) homeostatic response induces transcription events that targets a NF-kB member, cREL in Retinal Pigment Epithelial cells (RPE). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3614.
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NPD1 triggers transcriptional networks that leads to the expression of a cluster of proteins decisive in inflammatory modulation, apoptotic regulation and RPE cell survival at the onset of uncompensated oxidative stress. At the transcriptional level, this docosanoid mediator up-regulates pro-survival genes such as BIRC3 and down-regulates others related to apoptosis and inflammation (J. Calandria et al. Cell Death and Diff. ,in press). To set forth this regulation, a complex network of events must occur upstream of the observed targeted genes.
We analyzed a data set of genes obtained in a microarray screening exploration. Control and 15-LOX-1 silenced ARPE-19 cells were treated with OS and OS + NPD1 for 2 and 6 hours to observe the early and late transcriptional regulation exerted by NPD1. The set of regulated genes was confirmed by real-time PCR and analyzed with Ingenuity Pathway Analysis (Qiagen, Redwood City, CA).
Genes differentially expressed after the addition of NPD1 at 2 and 6 hours in 15-LOX-1 RPE stably silenced cells, which display low synthesis of NPD1, were analyzed. The TGFβ1 pathway was strongly implicated in both time points (p<10-9 and p<10-26 respectively) as a potential upstream regulator, exerting its effect through downstream NF-kB signaling. Downstream transcription factors implicated were STAT3, Myc, NFkB1 and cREL, which have been linked to the NPD1 pro-survival response to oxidative stress. Downstream of cREL , the network includes the regulation of Ataxin-1, mutant proteostatic signaling and BIRC3.
NPD1 executes a complex assemble of processes through transcriptional regulation of a set of genes interfering with pathways such as TGFβ1 signaling, to increase RPE cell survival after homeostatic disruptions. Because photoreceptors depend on the functional integrity of RPE cells, these events directly contribute to sustain photoreceptor cell function and vision.
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