Human alphaA- and alphaB-crystallins prevent UVA-induced apoptosis through regulation of PKCalpha, RAF/MEK/ERK and AKT signaling pathways.
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.
Liu
Jin-Ping
JP
The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
Schlosser
Ryan
R
Ma
Wei-Ya
WY
Dong
Zigang
Z
Feng
Hao
H
Lui
Long
L
Huang
Xiao-Qing
XQ
Liu
Yan
Y
Li
Davis Wan-Cheng
DW
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism* / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D014466:Ultraviolet Rays; D038202:alpha-Crystallin A Chain / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000378:metabolism; D038201:alpha-Crystallins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D011518:Proto-Oncogene Proteins; D038202:alpha-Crystallin A Chain; D038203:alpha-Crystallin B Chain; D038201:alpha-Crystallins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases