title: Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis.
abstract: Activation of the CD95 death receptor as well as ionizing radiation induces apoptotic cell death in human lymphoma cells. The activation of caspases is a hallmark of apoptosis induction irrespective of the apoptotic trigger. In contrast to death receptor signaling, the exact mechanisms of radiation-induced caspase activation are not well understood. We provide evidence that both, radiation and CD95 stimulation, induce the rapid activation of caspase-8 and BID followed by apoptosis in Jurkat T-cells. To analyse the relative position of caspase-8 within the apoptotic cascade we studied caspase activation and apoptosis in Jurkat cells overexpressing Bcl-2 or Bcl-xL. Caspase-8 activation, pro-apoptotic BID cleavage and apoptosis in response to radiation were abrogated in these cells, while the responses to CD95 stimulation were only partially attenuated by overexpression of Bcl-2 family members. In parallel, the breakdown of the mitochondrial transmembrane potential (DeltaPsim) in response to radiation was inhibited by overexpression of Bcl-2/Bcl-xL Jurkat cells genetically deficient for caspase-8 were found to be completely resistant towards CD95. However, radiation-induced apoptotic responses in caspase-8-negative cells displayed only a modest reduction. We conclude that ionizing radiation activates caspase-8 and BID downstream of mitochondrial damage suggesting that, in contrast to CD95, both events function as executioners rather than initiators of the apoptotic process.
authors.affiliation: Department of Radiation Oncology, University of Tuebingen, Hoppe Seyler Str. 3, D-72076 Tuebingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Belka
authors.forename: J
authors.initials: J
authors.lastname: Rudner
authors.forename: S
authors.initials: S
authors.lastname: Wesselborg
authors.forename: A
authors.initials: A
authors.lastname: Stepczynska
authors.forename: P
authors.initials: P
authors.lastname: Marini
authors.forename: A
authors.initials: A
authors.lastname: Lepple-Wienhues
authors.forename: H
authors.initials: H
authors.lastname: Faltin
authors.forename: M
authors.initials: M
authors.lastname: Bamberg
authors.forename: W
authors.initials: W
authors.lastname: Budach
authors.forename: K
authors.initials: K
authors.lastname: Schulze-Osthoff
mesh_terms: D017209:Apoptosis / Q000528:radiation effects*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology / Q000528:radiation effects; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism* / Q000502:physiology / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects; D004789:Enzyme Activation / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology / Q000528:radiation effects; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000528:radiation effects; D008928:Mitochondria / Q000502:physiology / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism* / Q000502:physiology / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology / Q000528:radiation effects; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology*
chemical_list: C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases