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S. Basu, J. L. Walker, A. S. Menko; Role of IGF-1R/NFB Signaling in the Survival Pathway That Regulates Lens Cell Differentiation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3483.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies from our laboratory have demonstrated that initiation of lens cell differentiation involves activation of the mitochondrial death pathway. This pathway is able to act as a molecular switch in differentiation without causing apoptosis because of the coordinate induction of survival signaling molecules including Bcl-2 family members and inhibitor of apoptosis proteins (IAPs). This study investigates IGF 1 receptor (IGF 1R) signaling through Nuclear Factor Kappa B (NFΚB, RelA/p50), a transcription regulator of Bcl 2 and IAP proteins, as the upstream regulator of these survival pathways.
Activation of IGF-1R and NFΚB were blocked using the PPP (1µM) and SN50 (18µM) inhibitors, respectively, in primary quail lens cell cultures that mimic lens cell differentiation as it occurs in vivo. Expression of Bcl 2, Bcl xL, survivin, ch IAP1/2, NFΚB, IGF 1R and activation of IGF 1R were determined by Western blot analysis. Subcellular localization of NFΚB was determined by confocal imaging of immunostained samples.
In lens cell cultures activation of IGF 1R and expression of NFΚB were induced coordinate with differentiation initiation. Inhibiting activation of IGF-1R decreased the expression of NFΚB and blocked its translocation to the nucleus. This effect on expression and localization of NFΚB was accompanied by a concomitant decrease in the expression of anti-apoptotic molecules like Bcl-2, Bcl-xl and survivin, all targets of NFΚB transcriptional regulation. Preliminary studies with the NFΚB inhibitor SN50 support our findings with the IGF 1R inhibitor; induction of survival molecules such as ch IAP1/2 and survivin are blocked indicating that NFΚB is a downstream effector of IGF 1R signaling in the induction of survival pathways required for lens cell differentiation.
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