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K. Ikesugi, M.L. Mulhern, R. Yamamoto, T. Shinohara; The Unfolded Protein Response (UPR) Induced by Endoplasmic Reticulum (ER) Stress; A Base for Cataract Formation in Ocular Lens . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2891.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The pivotal role of ER in the life of cells has been known, but the part it plays in the progression of human diseases has only recently been appreciated. We hypothesize that unfolded protein aggregates are recognized in the endoplasmic reticulum (ER) in lens epithelial cells (LECs) and generate the unfolded protein response (UPR), which initiates diverse signaling responses to eliminate unfolded protein aggregates. In the UPR, GRP78/Bip releases 3 proteins : IRE1, ATF6 and PERK. PERK phosphorylates eIF2α, and eIF2α–P activates ATF4, CHOP and other chaperon proteins. However, if they fail to remove the aggregates, the cell undergoes apoptosis. Cataract is a major ocular disease and apoptotic LECs are considered to be an etiology. We investigated whether the UPR induced by ER stress leads to apoptosis in LECs. Methods:Human LECs were cultured under hypo–(0 mM) or hyper–(300 mM) glucose, three experimental UPR inducers [homocysteine (5 mM), Ca++ ionophore A23187 (1 µM), or tunicamycin (5 µg/ml)] and three environmental stress conditions [oxidative (10 µM of H2O2), heat(42oC), or osmotic(50 mM galactose)]. Total proteins were extracted from the cells. Protein blot analysis with antibody to UPR enzymes, GRP78/Bip, ATF4, CHOP, LEDGF and Caspase–12 was conducted to quantify the amount of each enzyme. Results:Elevated levels of UPR enzymes were found in the LECs treated with homocysteine, Ca++ ionophore A23187, tunicamycin and hypo–glucose for 24 hrs. These results indicated that the UPR was induced by ER stress in LECs. Levels of the UPR enzymes did not change in LECs treated with three environmental stresses and hyper glucose for 24 hrs, indicating that these stresses did not induce the UPR. Conclusions:The UPR was induced by homocysteine, Ca++ ionophore, and tunicamycin and deprivation of glucose in LECs. The UPR is one of the important apoptotic pathways in LECs and cataract formation. Recently, the UPR has been also known to generate reactive oxygen species (ROS) in cells, which induces the UPR dependent apoptosis. We will further discuss whether ROS generated by the UPR induce LEC death.
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