Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex

Krueger, Andreas; Schmitz, Ingo; Baumann, Sven; Krammer, Peter H.; Kirchhoff, Sabine

doi:10.1074/jbc.m101780200

Cited by 510 publications

(488 citation statements)

References 44 publications

(44 reference statements)

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“…cFLIP is known to be a cellular inhibitor for caspase-8 activation in death receptor-induced apoptosis. 21 We here showed that DEX pretreatment significantly upregulated the cFLIP L -p43 protein level in a time-dependent manner, which was highly correlated with its antiapoptotic effect. Therefore, our results suggest that DEX can inhibit death receptor-mediated hepatocyte apoptosis via the upregulation of the antiapoptotic gene cFLIP.…”

Section: Discussionmentioning

confidence: 58%

“…Therefore, cFLIP L can be recruited to the Fas-and TNF-a-dependent DISC and inhibits full cleavage and release of active caspase-8 from the DISC. 21,30 The suppression of caspase-8 activation inhibits Bid cleavage and mitochondrial cytochrome c release and subsequently suppresses the formation of an apoptosome formed by the interaction with Apaf-1, procaspase-9, and dATP. Therefore, an increase in cFLIP L expression inhibits caspase-9 activation, resulting in the suppression of downstream signaling cascades including caspase-3 activation.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 We examined whether DEX would protect hepatocytes from anti-Fas antibody (Jo2)-induced apoptotic cell death. Incubation of cells with Jo2 þ ActD increased hepatocyte apoptosis, and this apoptosis was significantly suppressed by pretreatment with DEX ( Figure 6a).…”

Section: Dex Also Suppresses Anti-fas Antibody-induced Hepatocyte Apomentioning

confidence: 99%

“…18 cFLIP competes with procaspase-8 at the level of DISC formation. 21 We next investigated whether DEX inhibits the recruitment of procaspase-8 to the DISC. We found that FADD is recruited to the DISC in hepatocytes stimulated with Jo2, but is absent in this complex in nonstimulated cells (Figure 6e).…”

Section: Dex Also Suppresses Anti-fas Antibody-induced Hepatocyte Apomentioning

confidence: 99%

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Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Namkoong

et al. 2005

Cell Death Differ

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Dexamethasone (DEX) pretreatment protected hepatocytes from TNF-a plus actinomycin D (ActD)-induced apoptosis by suppressing caspase-8 activation and the mitochondriadependent apoptosis pathway. DEX treatment upregulated cellular FLICE inhibitory protein (cFLIP) expression, but did not alter the protein levels of Bcl-2, Bcl-xL, Mcl-1, and cIAP as well as Akt activation. The increased cFLIP mRNA level by DEX was inhibited by ActD, indicating that DEX upregulates cFLIP expression at the transcriptional step. DEX also inhibited Jo2-mediated hepatocyte apoptosis by blocking the formation of the death-inducing signaling complex and caspase-8 activation. Specific downregulation of cFLIP expression using siRNA reversed the antiapoptotic effect of DEX by increasing caspase-8 activation. Moreover, DEX administration into mice increased cFLIP expression in the liver and prevented Jo2-induced hepatic injury by inhibiting caspase-8 and -3 activities. Our results indicate that DEX exerts a protective role in death receptor-induced in vitro and in vivo hepatocyte apoptosis by upregulating cFLIP expression.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Dex Also Suppresses Anti-fas Antibody-induced Hepatocyte Apomentioning

confidence: 99%

Section: Dex Also Suppresses Anti-fas Antibody-induced Hepatocyte Apomentioning

confidence: 99%

See 2 more Smart Citations

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Namkoong

et al. 2005

Cell Death Differ

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“…5B), suggesting that the strong DISC activity in day 6 cells, but not the low DISC activity in LTC, is sufficient to overcome this protection by high expression of anti-apoptotic Bcl-2 family members in day 6 cells. c-FLIP is a potent inhibitor of CD95-mediated apoptosis, which acts at the DISC level [15,34,36] through inhibition of caspase-8 activation [37]. Increased expression predominantly of the short splice variant of c-FLIP, c-FLIP S , has been suggested to contribute partially to CD95 resistance of freshly activated day 1 T cells, upon costimulation and upon restimulation of day 6 T cells [38][39][40].…”

Section: Reduced Mitochondrial Depolarization In Ltc After Cd95 Triggmentioning

confidence: 99%

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

et al. 2006

Self Cite

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An adaptive immune response implies expansion of activated T cells and subsequent elimination to maintain homeostasis in a process called activation-induced cell death. Some cells, however, differentiate into memory cells and ensure a strong secondary immune response. To analyze the apoptosis phenotype of memory T cells on a cellular and molecular level, we have established an in vitro model of T cell activation and generation of cells phenotypically and functionally similar to memory cells. These longterm cultured T cells show a CD95-resistant phenotype, although they are still sensitive towards TCR/CD3-mediated apoptosis. Biochemical analysis revealed that these cells shift from CD95 type I (direct signaling from the receptor) during the effector phase to CD95 type II cells (dependent on the mitochondrial amplification loop). Moreover, their mitochondria are protected, probably due to high expression levels of Bcl-x L and Bcl-2. Thus, our data suggest a mechanism how memory T cells acquire resistance towards bystander cell death via the CD95 system.

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Death Receptors

Krammer¹,

Lavrik²

2009

Encyclopedia of Life Sciences

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Apoptosis or programmed cell death is a common property of all multicellular organisms. It can be triggered by a number of factors including ultraviolet (UV) or γ‐irradiation, chemotherapeutic drugs or growth factor withdrawal. A death signal can either be induced by death receptors (extrinsic pathway) or via the mitochondria (intrinsic pathway). The death receptor (DR) family is the subfamily of the tumour necrosis factor receptor (TNFR) superfamily. Stimulation of the death receptors results in the transduction of either apoptotic or survival signals. Here we present a general overview of death receptor signalling and describe the main mechanisms leading to activation of death receptor signalling pathways. Key concepts: Stimulation of the death receptors (DR) leads to apoptosis. All DR are distinguished by the presence of the death domain. Crosslinking of DR with death ligands results in formation of the death‐inducing signalling complex (DISC). Caspases play the central role in the transduction of death receptor apoptotic signal. As a result of DISC formation procaspase‐8 is activated with the formation of the active caspase‐8 heterotetramer, which then triggers apoptotic signal. c‐FLIP proteins block caspase‐8 activation at the DISC and thereby death receptor‐induced apoptosis. There are two types of apoptotic signalling: Type I and Type II cells. Stimulation of DR also might lead to the induction of nonapoptotic pathways.

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Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex

Cited by 510 publications

References 44 publications

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

In vitro generated human memory‐like T cells are CD95 type II cells and resistant towards CD95‐mediated apoptosis

Death Receptors

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