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T. Shinohara, D.P. Singh, N. Fatma, D. Magana-Arachchi; Decline of Insulin/igf Signaling Up-regulates Expression of Ledgf and a Stress-associated Gene Network in Lecs . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3138.
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Purpose: Age-related cataract is linked with aging. Aging has postulated to be determined by a gene network of individual species. Age-mutants (daf-2 and age-1) in nematode have been demonstrated to increase stress-resistance including heat, UV, and oxidants and long-lived under those stresses. From these studies, longevity is linked to stress tolerance in nematode and fruit fly. LEDGF is a survival factor to prolong survival of a wide range of cell types under stresses and is a regulatory factor for up-regulation of a stress-associated gene network to induce stress-tolerance in mammalian cells. In this study, we investigated whether insulin/IGF signaling (daf-2 and age-1) regulates the expression of ledgf gene. Methods: Mouse lens epithelial cells (LECs) and rat LEC explants were cultured with and without insulin/IGF or TGF-ß and quantified levels of LEDGF in these cells. Immunohistochemistry of the explants was evaluated and Trypan blue staining was used to evaluate cell death under heat stress (42°C). Results: Lens epithelial cell explants treated with higher levels of insulin/IGF (10 µg/ml) differentiated into lens fiber-like cells and suppressed the expression of ledgf gene. In contrast, the explants treated with low levels of antibody to insulin/IGF up-regulated the expression of ledgf gene and survived well under heat stress. These results suggest that excess signaling of insulin/IGF suppressed, but decline of the insulin/IGF signaling up-regulated the expression of ledgf gene. In addition, TGF-ßsuppressed the expression of ledgf gene, which is consistent with suppression of tolerance in the daf-2 or age-1 mutants in nematode. Conclusions: We found that decline of insulin/IGF signaling stimulates the expression of ledgf gene and acquires stress tolerance in LECs. Higher levels of insulin/IGF induce lens fiber differentiation and suppress the expression of ledgf gene. Thus, levels of insulin/IGF signaling, which regulates the expression of ledgf gene, plays a central role in survival, stress tolerance, and perhaps differentiation and prolong lifespan of LECs.
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