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JeongGoo Lee, J Martin Heur; Wnt10b enhances human corneal endothelial cell proliferation through β-catenin and Rac1 activation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4896.
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Wnt10b activates β-catenin dependent pathways for regulation of cellular functions that play crucial roles in wound healing including cell proliferation. Elucidation of Wnt10b signaling for induction of cell proliferation could help identify potential therapeutic targets for patients with vision loss due to endothelial dysfunction. However, Wnt10b signaling in corneal endothelial cells (CEC) has not been well characterized.
Expression and/or activation of Wnt10b, LRP-6, β-catenin, Rac1, Tiam1 and Cyclin D1 were analyzed by immunoblotting. MTT assay was employed to measure cell proliferation rates. Activation of Rac1 and RhoA were determined by Rac-GTP pull-down assay and RhoA specific G-LISA assay, respectively.
Transient induction of Wnt10b by IL-1b-stimulation proceeds through both NF-kB and AP-1 pathway in human CECs. This leads to phosphorylation of LRP-6, resulting in activation of disheveled and subsequent nuclear translocation of Rac1 and β-catenin. Formation of nuclear β-catenin-Rac1 complex induced expression of Cyclin D1. Induction of cell proliferation by Wnt10b was completely blocked by NSC23766 (Rac1 inhibitor), but not by ML141 (Cdc42 inhibitor). Co-treatment of both Wnt10b and RhoA activator resulted in ~20% decrease of proliferation compared to Wnt10b treatment, suggesting that Rac1 plays key role for cell proliferation, whereas Cdc42 and RhoA have limited effect on cell proliferation induced by Wnt10b in human CECs.
These findings suggest that Wnt10b induced by IL-1β through NF-kB and AP-1 in human CEC promotes cell proliferation through activation of Rac1 and β-catenin.
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