Induction of BIM(EL) following growth factor withdrawal is a key event in caspase-dependent apoptosis of 661W photoreceptor cells.
Apoptosis of photoreceptor cells in the early postnatal period is a normal feature of mammalian retinal development. The role of mitochondria and caspases in the process has been well established; however, the identification of key apoptotic mediators still remains elusive. Here we report that BIM(EL), a pro-apoptotic BCL-2 family member, may be one such molecule. Following growth factor deprivation, BIM(EL) was up-regulated in mouse 661W cone photoreceptors. This event correlated with the release of mitochondrial apoptogenic factors into the cytosol, the activation of caspases and apoptosis. Moreover, a similar behaviour was observed in response to UV radiation, ionomycin or H(2)O(2) treatments. We identified the PI3K-Akt-FKHRL1 signalling cascade as the main regulatory pathway of BIM(EL) expression in these cells. Finally, using RNA interference, we were able to silence BIM(EL) expression and subsequently suppress caspase-3 activation. In conclusion, we propose BIM(EL) as a critical factor in mitochondria-dependent apoptosis of 661W photoreceptors.
Gómez-Vicente
Violeta
V
Cell Development and Disease Laboratory, Department of Biochemistry, Biosciences Research Institute, University College Cork, Cork, Ireland.
Doonan
Francesca
F
Donovan
Maryanne
M
Cotter
Thomas G
TG
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002867:Chromones / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012160:Retina / Q000166:cytology / Q000254:growth & development; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002867:Chromones; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009025:Morpholines; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases