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Subhasree Basu, Ni Zhai, Adele De Arcangelis, Elisabeth Georges-Labouesse, A. Sue Menko; α6 Integrin Is Upstream To The IGF-1R-mediated Survival Signal That Regulates Lens Epithelial Cell Differentiation Initiation In A Mammalian Model. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2777.
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Previous studies from our laboratory demonstrated a role for the canonical mitochondrial death pathway in the initiation of lens epithelial cell differentiation through its activation of the caspase-3 protease. We have shown that the ability of this pathway to function as a molecular switch in lens differentiation depends on the concurrent induction of the survival molecules that regulate it, including proteins in the Bcl-2 and the Inhibitor of Apoptosis Protein (IAP) families. Previously, in studies with primary quail lens cell cultures, we showed that α6 integrin is an upstream inducer of an IGF-1R-mediated survival-signaling pathway that is responsible for induction of these survival proteins and regulation of the canonical mitochondrial death pathway so that it signals lens differentiation initiation, not death. Now we have extended these studies by examining how IGF-1R-dependent survival signaling is effected in mouse lenses that have developed in the absence of α6 integrin.
Expression or activation of survival and death pathway molecules including IGF-1R, Bcl-2, survivin, and caspase-3 was determined in lenses from both wild-type and α6 integrin knockout mice at E18.5 by confocal analysis of immunostained lens sections. Induction of apoptosis was examined by TUNEL assay.
We show here that the absence of α6 integrin in the developing mouse lens blocked the activation of IGF-1R (p-IGF-1R), resulting in decreased expression of the survival proteins Bcl-2 and survivin and increased activation of caspase-3. However, unlike with acute siRNA knockdown of α6 integrin in lens cell cultures the level of activation of caspase-3 in the germline knockout of α6 integrin was not high enough to induce apoptosis, likely due to induction of a compensatory survival signal.
α6 integrin is the upstream regulator of the IGF-1R survival-signaling pathway and responsible for modulating the level of caspase-3 activation for its role in lens cell differentiation initiation in the mammalian lens.
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