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-x L . Caspase-8 activation, proapoptotic 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 (DC m ) in response to radiation was inhibited by overexpression of Bcl-2/Bcl-x L Jurkat cells genetically de®cient for caspase-8 were found to be completely resistant towards CD95. However, radiationinduced 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.

Agonists of an ecdysone-inducible mammalian expression system inhibit Fas Ligand- and TRAIL-induced apoptosis in the human colon carcinoma cell line RKO

“…45 Several publications suggest a 'feedback loop' of Casp-3 activating Casp-8 downstream of mitochondrial damage, which by itself is inhibited by Bcl-x L . 51,52 In addition, inactivation of Casp-8 on mitochondria of Bcl-x L -expressing MCF7 cells has been published as another regulatory mechanism for Bcl-x L to prevent apoptosis.…”

Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on Celecoxib-induced apoptosis

“…Jurkat cells stably expressing Bcl-xL or Bcl-2 and the respective Vector control were prepared as described before [1,24].…”

“…Stress situation like hypoxia, DNA damage, growth factor withdrawal, and chemotherapeutic agents initiate the intrinsic apoptotic pathway which ultimately results in the release of cytochrome C from the mitochondria into the cytosol where caspases become activated to execute apoptosis [1][2][3][4].…”

Radiation induced CNS toxicity – molecular and cellular mechanisms

“…TNFα-R1, CD95, TRAIL-R1, TRAIL-R2) the adapter FADD mediates activation of caspase-8 (Belka et al, 2000). In case of TNF-α an additional linker molecule denoted TRADD is required for the recruitment of FADD (Hsu et al, 1996).…”

“…In contrast to receptor mediated apoptosis, radiation induced apoptosis primarily relies on mitochondrial damage followed by caspase activation (Belka et al, 2000). P53 mediated activation of BAX may serve as paradigm for the stress activated mitochondrial apoptosis pathway (Miyashita and Reed, 1995).…”