Radiation-induced apoptosis in retinal progenitor cells is p53-dependent with caspase-independent DNA fragmentation.
Caspases are important executioners of the endogenous cell death program. However, their function is not restricted to the induction of cell death. Caspases may process cytokines and contribute to cell differentiation or lymphocyte proliferation. In addition to their pleiotropic functions we show evidence that, under certain conditions, caspases are activated during apoptosis without executing the cell death program. Following whole body irradiation, p53 and caspases were activated in both the cerebellum and eye of postnatal day 5 mice. Although p53 activation and cell death kinetics were similar in both the cerebellum and eye, the processing of caspases was protracted and reduced in the eye. In particular, retinal caspase activation appeared not to be the executioner of cell death; incubation of retinal and cerebellar explants in the presence of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone prevented DNA fragmentation, a hallmark of apoptosis, only in cerebellar granule cells. In contrast, in retinal cells no impairment of DNA fragmentation was observed in the presence of N-benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone, indicating p53-dependent but caspase-independent cell death pathways despite caspase activation.
Herzog
Karl-Heinz
KH
Institute for Genetics, University of Stuttgart-Hohenheim, Garbenstrasse 30, D-70599 Stuttgart, Germany. khherzog@uni-hohenheim.de
Schulz
Adriana
A
Buerkle
Corina
C
Gromoll
Christian
C
Braun
Johann S
JS
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000528:radiation effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002531:Cerebellum / Q000528:radiation effects; D053938:DNA Fragmentation / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011827:Radiation; D012160:Retina / Q000166:cytology*; D013234:Stem Cells / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
D051033:Apoptosis Inducing Factor; D016159:Tumor Suppressor Protein p53; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases