The canonical intrinsic mitochondrial death pathway has a non-apoptotic role in signaling lens cell differentiation

J Biol Chem. 2005 Jun 10;280(23):22135-45. doi: 10.1074/jbc.M414270200. Epub 2005 Apr 12.


The mitochondrial cell death pathway is known for its role in signaling apoptosis. Here, we describe a novel function for the mitochondrial cell death pathway in signaling initiation of differentiation in the developing lens. Most remarkably, we induced lens cell differentiation by short-term exposure of lens epithelial cells to the apoptogen staurosporine. Activation of apoptosis-related pathways induced lens epithelial cells to express differentiation-specific markers and to undergo morphogenetic changes that led to formation of the lens-like structures known as lentoids. The fact that multiple stages of differentiation are expressed at a single stage of development in the embryonic lens made it possible to precisely determine the timing of expression of proteins associated with the apoptotic pathway. We discovered that there was high expression in the lens equatorial epithelium (the region of the lens in which differentiation is initiated) of pro-apoptotic molecules such as Bax and Bcl-x(S) and release of cytochrome c from mitochondria. Furthermore, we found significant caspase-3-like activity in the equatorial epithelium, yet this activity was far lower than that associated with lens cell apoptosis. These apoptotic pathways are likely regulated by the concurrent expression of prosurvival molecules, including Bcl-2 and Bcl-x(L); phosphorylation of Bad; and high expression of inhibitor of apoptosis proteins chicken IAP1, IAP3, and survivin. This finding suggests that prosurvival pathways allow pro-apoptotic molecules to function as molecular switches in the differentiation process without tipping the balance toward apoptosis. We call this process apoptosis-related Bcl-2- and caspase-dependent (ABC) differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Apoptosis*
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cell Death
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Chickens
  • Cytochromes c / metabolism
  • Cytosol / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblast Growth Factors / metabolism
  • Immunoblotting
  • Inhibitor of Apoptosis Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Lens, Crystalline / cytology*
  • Membrane Potentials
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Models, Biological
  • Neoplasm Proteins
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Staurosporine / pharmacology
  • Subcellular Fractions / metabolism
  • Survivin
  • bcl-2-Associated X Protein
  • bcl-Associated Death Protein
  • bcl-X Protein


  • Actins
  • BIRC5 protein, human
  • Carrier Proteins
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Survivin
  • bcl-2-Associated X Protein
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Fibroblast Growth Factors
  • Insulin-Like Growth Factor I
  • Cytochromes c
  • Extracellular Signal-Regulated MAP Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Staurosporine