Futile caspase-8 activation during the apoptotic cell death induced by DNA damaging agents in human B-lymphoblasts.
Caspase-8 plays an essential role in apoptosis induced by Fas activation. Moreover, caspase-8 can be processed also in response to exposure to genotoxic agents. To decipher the role of caspase-8 in DNA damaging agent (DDA)-induced apoptosis as well as the pathway(s) leading to its activation in response to genotoxic stress, we investigated caspase-8 processing induced by ionizing radiation (IR) or mitomycin C (MMC) treatment in human B-lymphoblasts. Altogether, our observations establish that caspase-8 is actively processed in both receptor-mediated and DDA-induced cell death. However, while Fas-dependent apoptosis absolutely required caspase-8 activity, it is not necessary for completion of the apoptotic program induced by IR and MMC. Experiments performed to understand the molecular pathway(s) of the caspase-8 activation after DDA demonstrated that for both IR and MMC, the Fas/Fas-L interaction is dispensable. Data obtained from caspase inhibitors and from lymphoblasts carrying mutations in ATM and FANCC proteins, involved in DDA response, clearly showed that distinct mechanisms are responsible for caspase-8 activation by IR and MMC in B-lymphoblasts. IR-dependent processing of caspase-8 involves ATM, mitochondrial collapse, FANCC, and caspase-3 activation. Caspase-8 activation by MMC evokes the mitochondrial pathways involving FANCC but not ATM. Collectively, our data indicate that caspase-8 activation is essentially a bystander effect and not a major determinant of the behavior of DDA-exposed cells.
Vit
J P
JP
UPR 2169, Institut André Lwoff IFR 2249 CNRS, 7, Rue Guy Môquet, 94801 Villejuif Cedex, France.
Guillouf
C
C
Rosselli
F
F
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D053222:Fas Ligand Protein; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D016685:Mitomycin / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology*; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011506:Proteins / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497651:FANCC protein, human; C505661:FASLG protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D009153:Mutagens; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D016685:Mitomycin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases