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Jungeun Lee, Jung-Ha Choi, Choun-Ki Joo; Retinal pigment epithelial cells evade apoptosis during TGF-β1-induced epithelial-mesenchymal transition adopting survivin. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2472.
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Members of the transforming growth factorβ(TGF-β) superfamily are multifunctional cytokines that regulate cellular processes, including cell-cycle arrest, differentiation, morphogenesis, and apoptosis. TGF-β promotes extracellular matrix production and suppresses cell proliferation. Morphogenetic responses to TGF-β members include cell migration and epithelial-mesenchymal transitions (EMTs), which are critical during embryogenesis, development of fibrotic diseases, and advanced carcinoma spreading. The purpose of this study is to clarify how can survive human retinal pigment epithelial cells during TGF-β induced EMT.
Serum-starved ARPE-19 cells were incubated with vehicle alone or 10ng/ml TGF-β1. Flow cytometric analysis of ARPE-19 cells treated for 24 h with 10 ng/ml TGF-β1, followed by incubation with Annexin V-FITC and propidium iodide (PI), showed the apoptotic fraction. Using siRNA targeting for Survivin, we show that these proteins are critical to TGF-β1 induced EMT. To determine the key signaling mediator responsible for the up-regulation of survivin in response to TGF-β1, we used kinase inhibitors to individually block each signaling pathway in ARPE-19 cells treated with TGF-β1, and then examined the level of survivin expression.
Apoptosis analysis showed that the apoptosis was not induced in ARPE-19 cells treated with TGF-β1. Using siRNA targeting for Survivin, we show that cell apoptosis increased in treated ARPE-19 cells lacking survivin compared to control cells treated with TGF-β1 only. Inhibition of MEK or PI3K blocked the up-regulation of survivin following TGF-β1 treatment, while inhibition of Rho did not.
In conclusion, we showed that induction of EMT in human RPE cells led to up-regulation of Survivin expression, and inhibition of Survivin iduced apoptosis. We demonstrate that Survivin involves in the Transforming Growth Factor β1-mediated Epithelial-Mesenchymal Transition of retinal pigment epithelial cells by evading cell apoptosis.
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