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J. L. Walker, L. Zhang, A. S. Menko; A Requirement for IGF-1R/ERK Survival Signaling During Lens Cell Differentiation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1134.
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Previously our lab has demonstrated that activation of apoptosis-related pathways induced lens cell differentiation. We now elucidate survival signaling mechanisms that regulate this lens differentiation-inducing pathway.
Primary quail lens cell cultures, which recapitulate lens cell differentiation in vitro were used as a model system for studying the mechanisms of induction of apoptotic and survival signaling pathways involved in lens differentiation. Activation and/or expression of insulin-like growth factor receptor (IGF-1R), ERK, p27, and caspase 3 cleavage were examined during lens cell differentiation by immunoblot analysis. IGF-1R mediated signaling pathways were studied by stimulating lens cells with its ligand, IGF-1. To assess the roles of IGF-1R and ERK in lens cell differentiation and survival primary lens cell cultures were treated with inhibitors, PPP (or AG1024) and UO126, respectively. Expression of survival proteins and differentiation markers were determined under these various conditions by immunoblot analysis.
We now show that activation of IGF-1R, well known for its role in cell survival, and one of its effectors, ERK, are greatly increased coincident with accumulation of the cyclin dependent kinase inhibitor (CDKI), p27. Induction of CDKI’s is necessary for cell cycle withdraw and initiation of lens differentiation. These changes are concomitant with an increase in caspase 3 cleavage, an indicator of activation of the intrinsic mitochondrial death pathway. Proper lens cell differentiation requires the activation of apoptotic pathways concurrent with the induction of pro-survival molecules. In this differentiating lens culture system both IGF-1R and ERK activate or induce Bcl-2 family members involved in promoting cell survival. ERK activation was IGF-1R dependent and inhibition of ERK repressed phosphorylation of the Bcl-2 family member, Bad at serine112, activating its death inducing properties. Activation of this ERK pathway also was required for lens cell differentiation. Inhibition of IGF-1R, suppressed ERK activation, induced changes in Bcl-2 family members, and blocked lens cell differentiation.
As apoptotic-like pathways guide the initiation of differentiation, activation of IGF-1R and ERK signaling provide crucial cell survival signals to ensure proper execution of this lens differentiation pathway.
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