Insulin-like growth factor receptor-1 and nuclear factor κB are crucial survival signals that regulate caspase-3-mediated lens epithelial cell differentiation initiation

J Biol Chem. 2012 Mar 9;287(11):8384-97. doi: 10.1074/jbc.M112.341586. Epub 2012 Jan 24.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Avian Proteins / genetics
  • Avian Proteins / metabolism*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism*
  • Cell Differentiation / physiology*
  • Cell Survival / physiology
  • Cells, Cultured
  • Chick Embryo
  • Chickens / genetics
  • Chickens / metabolism*
  • Enzyme Activation / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Gene Expression Regulation / physiology
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Lens Capsule, Crystalline / cytology
  • Lens Capsule, Crystalline / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / physiology*


  • Avian Proteins
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Receptor, IGF Type 1
  • Caspase 3