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Thomas, D.D., Ridnour, L.A., Isenberg, J.S., Flores-Santana, W., Switzer, C.H., Donzelli, S., Hussain, P., Vecoli, C., Paolocci, N., Ambs, C., Colton, C.A., Harris, C.C., Roberts, D.D. and Wink, D.A. (2008) The chemical biology of nitric oxide: Implications in cellular signaling. Free Radical Biology & Medicine, 45, 18-31. doi:10.1016/j.freeradbiomed.2008.03.020

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• TITLE: Nitric oxide leads to cytoskeletal reorganization in the retinal pigment epithelium under oxidative stress

  AUTHORS: Srinivas R. Sripathi, Weilue He, Ji-Yeon Um, Trevor Moser, Stevie Dehnbostel, Kimberly Kindt, Jeremy Goldman, Megan C. Frost, Wan Jin Jahng

  KEYWORDS: Oxidative Stress; Nitric Oxide; Retinal Pigment Epithelium; PP2A; Vimentin

  JOURNAL NAME: Advances in Bioscience and Biotechnology, Vol.3 No.8, December 27, 2012

  ABSTRACT: Light is a risk factor for various eye diseases, including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). We aim to understand how cytoskeletal proteins in the retinal pigment epithetlium (RPE) respond to oxidative stress, including light and how these responses affect apoptotic signaling. Previously, proteomic analysis revealed that the expression levels of vimentin and serine/threonine protein phosphatase 2A (PP2A) are significantly increased when mice are exposed under continuous light for 7 days compared to a condition of 12 hrs light/dark cycling exposure using retina degeneration 1 (rd1) model. When melatonin is administered to animals while they are exposed to continuous light, the levels of vimentin and PP2A return to a normal level. Vimentin is a substrate of PP2A that directly binds to vimentin and dephosphorylates it. The current study shows that upregulation of PP2Ac (catalytic subunit) phosphorylation negatively correlates with vimentin phosphorylation under stress condition. Stabilization of vimentin appears to be achieved by decreased PP2Ac phosphorylation by nitric oxide induction. We tested our hypothesis that site-specific modifications of PP2Ac may drive cytoskeletal reorganization by vimentin dephosphorylation through nitric oxide signaling. We speculate that nitric oxide determines protein nitration under stress conditions. Our results demonstrate that PP2A and vimentin are modulated by nitric oxide as a key element involved in cytoskeletal signaling. The current study suggests that external stress enhances nitric oxide to regulate PP2Ac and vimentin phosphorylation, thereby stabilizing or destabilizing vimentin. Phosphorylation may result in depolymerization of vimentin, leading to nonfilamentous particle formation. We propose that a stabilized vimentin might act as an anti-apoptotic molecule when cells are under oxidative stress.