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Karen Alvarez-Delfin, Miryam A. Fragoso, Amit K. Patel, Rei E. Nakamura, Hyun Yi, Abigail S. Hackam; The Wnt/beta-catenin Pathway Cross-talks with STAT3 Signaling to Regulate Survival of Retinal Pigment Epithelium Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4767.
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Wnt/beta-catenin signaling is an essential pathway that regulates numerous cellular processes, including cell survival. The mechanisms of pro-survival Wnt signaling are mostly unknown. In age related macular degeneration (AMD), oxidative stress contributes to retinal pigmented epithelium (RPE) cell death, leading to loss of vision. We previously demonstrated that the Wnt pathway protects an RPE cell line from oxidative stress. Signal transducer and activator of transcription proteins (STATs) are a well-described family of transcription factors. STAT3 induces expression of anti-apoptotic genes in many tissues and is a downstream mediator of protective growth factors and cytokines. In this study, we investigated whether pro-survival Wnt signaling is mediated by STAT3 in the RPE.
Wnt3a was used to activate Wnt/beta-catenin signaling in the human retinal pigmented epithelium cell line ARPE-19. Oxidative stress was induced with hydrogen peroxide or paraquat and cell viability was measured using Cell Titer Blue. Activation of STAT3 was measured using an antibody against the activated STAT3 protein (Phospho-Tyr705) by immunohistochemistry. STAT3 expression was reduced using specifically targeted siRNA and confirmed by quantitative PCR and Western blotting.
The Wnt3a ligand induced Wnt signaling in the ARPE-19 cell line and significantly increased the viability of cells exposed to oxidative stress by up to 51% (n=4, p<0.05). Wnt3a also increased STAT3 activation and nuclear translocation by 10-fold (n=3, p<0.001). Furthermore, reducing STAT3 levels, using siRNA, eliminated Wnt3a-induced protection from oxidative stress.
These data demonstrate a previously unknown link between Wnt3a-mediated activation of STAT3 and cell survival, indicating a cross-talk between two important pro-survival signaling pathways in the retina.
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