Human alphaA- and alphaB-crystallins prevent UVA-induced apoptosis through regulation of PKCalpha, RAF/MEK/ERK and AKT signaling pathways

Exp Eye Res. 2004 Dec;79(6):393-403.

Abstract

AlphaA- and alphaB-crystallins are distinct antiapoptotic regulators. Regarding the antiapoptotic mechanisms, we have previously demonstrated that under staurosporine treatment, HalphaA- and HalphaB-crystallins can interact with Bax and Bcl-XS, proapoptotic members of the Bcl-2 family, to sequester their translocation into mitochondria, and thus prevent the staurosporine-induced apoptosis. In the present study, we further compared the anti-apoptotic mechanisms of HalphaA- and HalphaB-crystallin in preventing human lens epithelial cells from UVA-induced apoptosis. UVA-irradiation of human lens epithelial cells turned on the apoptotic death program. Moreover, associated with the activation of the death program, UVA also activated the RAF/MEK/ERK signaling pathway. In contrast, p38 kinase and JNK1/2 signaling pathways were not activated. Inhibition of the RAF/MEK/ERK pathway by a dominant negative mutant RAF1 greatly attenuated UVA-induced apoptosis. Expression of the exogenous human alphaB-crystallin prevented UVA-induced activation of RAF/MEK/ERK pathway and thus substantially abrogated UVA-induced apoptosis. In contrast, expression of the exogenous human alphaA-crystallin did not prevent UVA-induced activation of RAF/MEK/ERK pathway. Instead, it activated AKT kinase pathway to promote survival and thus counteracted the UVA-induced apoptosis. Together, our results for the first time reveal that by regulating multiple signaling pathways the two alpha-crystallins can prevent stress-induced apoptosis through different mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Corrected and Republished Article

MeSH terms

  • Apoptosis / physiology
  • Apoptosis / radiation effects*
  • Cells, Cultured
  • Enzyme Activation / physiology
  • Epithelial Cells / metabolism
  • Humans
  • Lens, Crystalline / metabolism*
  • Lens, Crystalline / radiation effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Protein Kinase C / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Signal Transduction
  • Ultraviolet Rays
  • alpha-Crystallin A Chain / metabolism
  • alpha-Crystallin B Chain / metabolism
  • alpha-Crystallins / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Proto-Oncogene Proteins
  • alpha-Crystallin A Chain
  • alpha-Crystallin B Chain
  • alpha-Crystallins
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases