Abstract
It is now known that the function of the caspase family of proteases is not restricted to effectors of programmed cell death. For example, there is a significant non-apoptotic role for caspase-3 in cell differentiation. Our own studies in the developing lens show that caspase-3 is activated downstream of the canonical mitochondrial death pathway to act as a molecular switch in signaling lens cell differentiation. Importantly, for this function, caspase-3 is activated at levels far below those that induce apoptosis. We now have provided evidence that regulation of caspase-3 for its role in differentiation induction is dependent on the insulin-like growth factor-1 receptor (IGF-1R) survival-signaling pathway. IGF-1R executed this regulation of caspase-3 by controlling the expression of molecules in the Bcl-2 and inhibitor of apoptosis protein (IAP) families. This effect of IGF-1R was mediated through NFκB, demonstrated here to function as a crucial downstream effector of IGF-1R. Inhibition of expression or activation of NFκB blocked expression of survival proteins in the Bcl-2 and IAP families and removed controls on the activation state of caspase-3. The high level of caspase-3 activation that resulted from inhibiting this IGF-1R/NFκB signaling pathway redirected cell fate from differentiation toward apoptosis. These results provided the first evidence that the IGF-1R/NFκB cell survival signal is a crucial regulator of the level of caspase-3 activation for its non-apoptotic function in signaling cell differentiation.
Highlights
Low levels of caspase-3 activity acts as a molecular switch in lens differentiation without causing apoptosis
We investigated likely upstream survival signals, such as insulin-like growth factor-1 receptor (IGF-1R), that have the potential to induce expression of Bcl-2 and inhibitor of apoptosis protein (IAP) survival proteins [13, 14] during the initiation events of lens cell differentiation and thereby enable caspase-3 to act as a molecular switch in this differentiation process
In the current study we examined whether IGF-1R was a required upstream signal in the pathway that regulates caspase-3 activation in differentiating lens epithelial cells
Summary
Low levels of caspase-3 activity acts as a molecular switch in lens differentiation without causing apoptosis. IGF-1R/NFB Control of Caspase-3-induced Lens Differentiation activation cleaves ICAD releasing CAD (caspase-activated DNase) at the low levels required for it to initiate a conserved genomic reprogramming that is required for differentiation initiation [4] In this instance, the cleavage of the p21 promoter (a critical differentiation regulator) by CAD [4, 11] induces p21 expression, altering cell fate. We investigated likely upstream survival signals, such as insulin-like growth factor-1 receptor (IGF-1R), that have the potential to induce expression of Bcl-2 and IAP survival proteins [13, 14] during the initiation events of lens cell differentiation and thereby enable caspase-3 to act as a molecular switch in this differentiation process. The results reveal that when the IGF-1R/NFB survival signal is blocked, caspase-3 activation is elevated, blocking initiation of lens epithelial cell differentiation and inducing cell death by apoptosis
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have