Internal ribosome entry site-mediated translation of Apaf-1, but not XIAP, is regulated during UV-induced cell death.
Components of the cellular translation machinery are targets of caspase-mediated cleavage during apoptosis that correlates with the inhibition of protein synthesis, which accompanies apoptosis. Paradoxically, protein synthesis is required for apoptosis to occur in many experimental settings. Previous studies showed that two proteins that regulate apoptosis by controlling caspase activity, XIAP and Apaf-1, are translated by a unique, cap-independent mechanism mediated by an internal ribosome entry site (IRES) that is used preferentially under conditions in which normal cap-dependent translation is repressed. We investigated the regulation of XIAP and Apaf-1 following UVC irradiation. We show that UVC irradiation leads to the inhibition of translation and cell death. Furthermore, IRES-mediated translation of Apaf-1, but not XIAP, is enhanced by UVC irradiation, and this increase in Apaf-1 translation correlated with cell death. The enhanced Apaf-1 IRES-mediated translation is caspase-independent but is negatively modulated by the eIF2alpha kinase protein kinase RNA-like endoplasmic reticulum kinase. These data suggest that progression of UV-induced apoptosis requires IRES-mediated translation of Apaf-1 to ensure continuous levels of Apaf-1 despite an overall suppression of protein synthesis.
Ungureanu
Nicoleta Hosszu
NH
Apoptosis Research Center, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1.
Cloutier
Mireille
M
Lewis
Stephen M
SM
de Silva
Naomi
N
Blais
Jaime D
JD
Bell
John C
JC
Holcik
Martin
M
D000818:Animals; D053477:Apoptotic Protease-Activating Factor 1; D001483:Base Sequence; D016923:Cell Death / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D014176:Protein Biosynthesis / Q000528:radiation effects; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014466:Ultraviolet Rays; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; D019892:eIF-2 Kinase; C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; C496866:XIAP protein, human