Inhibition of death receptor signals by cellular FLIP

Irmler, Martin; Thome, Margot; Hahne, Michael; Schneider, Pascal; Hofmann, Kay; Steiner, Véronique; Bodmer, Jean-Luc; Schröter, Michael; Burns, Kim; Mattmann, Chantal; Rimoldi, Donata; French, Lars E.; Tschopp, Jürg

doi:10.1038/40657

Cited by 2,382 publications

(2,087 citation statements)

References 29 publications

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“…[27][28][29] cFLIP L is structurally similar to procaspase-8 because it contains two aminoterminal death effector domains and a carboxyl-terminal caspase homology domain, but it lacks the cysteine within the active site essential for the catalytic activity of caspase-8, resulting in no enzymatic activity. 20 Thus, cFLIP L competitively inhibits the recruitment of caspase-8 to the cytosolic death domain of the cytotoxic receptor. 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.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that cFLIP, which is structurally similar to procaspase-8, but lacks catalytic activity, acts as a competitive inhibitor of caspase-8 in the DISC formation, which subsequently blocks apical caspase-8 activation. 20 We next examined whether DEX regulates cFLIP expression in cultured hepatocytes. DEX pretreatment significantly upregulated cFLIP L -p43 expression in a time-dependent manner, with maximum expression at 6-8 h, and thereafter maintained its protein level until 18 h (Figure 5b).…”

Section: Dex Increases Cflip Expression By Transcriptional Activationmentioning

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%

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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: 99%

Section: Dex Increases Cflip Expression By Transcriptional Activationmentioning

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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“…41 The identification of vFLIPs rapidly led to the identification of cellular FLIP (cFLIP), which have two forms, a short form structurally related to vFLIP, and a long form, cFLIP L , which contains an additional caspase-like domain but lacks proteolytic activity. 42 Both cFLIP and vFLIP regulate NF-kB activation in response to TNF receptors. 43 …”

Section: Viral and Cellular Flipsmentioning

confidence: 99%

Alternate functions of viral regulators of cell death

et al. 2006

Cell Death Differ

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“…Two splice variants, termed cFLIP-a (cFLIP-long, MW B55 kD) and cFLIP-d (cFLIP-short, MW 25 to 28 kD), are the most widely distributed and well studied isoforms (Irmler et al, 1997;Krueger et al, 2001;Micheau, 2003;Rasper et al, 1998). These proteins inhibit cell death by competing with procaspase-8 for binding to FADD and inhibiting assembly of a functional DISC (Rasper et al, 1998;Scaffidi et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Expression of Cellular FLICE Inhibitory Proteins (cFLIP) in Normal and Traumatic Murine and Human Cerebral Cortex

Hainsworth

Bermpohl

Webb

et al. 2005

J Cereb Blood Flow Metab

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Cellular Fas-associated death domain-like interleukin-1-beta converting enzyme (FLICE) inhibitory proteins (cFLIPs) are endogenous caspase homologues that inhibit programmed cell death. We hypothesized that cFLIPs are differentially expressed in response to traumatic brain injury (TBI). cFLIP-alpha and cFLIP-delta mRNA were expressed in normal mouse brain-specifically cFLIP-delta (but not cFLIP-alpha) protein was robustly expressed. After controlled cortical impact (CCI), cFLIPalpha expression increased initially then decreased to control levels at 12 h, increasing again at 24-72 h (Po0.05). cFLIP-delta expression was decreased in brain homogenates by 12 h after CCI, then increased again at 24 to 72 h (Po0.05). cFLIP-delta immunostaining was markedly reduced in injured cortex, but not hippocampus, at 3 to 72 h after CCI. In cortex, reduced cFLIP-delta staining was found in TUNEL-positive cells, but in hippocampus TUNEL-positive cells expressed cFLIP-delta immunoreactivity. cFLIP-delta was increased in a subset of reactive astrocytes in pericontusional cortex and hippocampus at 48 to 72 h. Low levels of both cFLIP isoforms were detected in human cortical tissue with no TBI, from four patients undergoing brain surgery for epilepsy and o24 h post mortem from three patients without CNS pathologic assessment. In cortical tissue surgically removed o18 h after severe TBI (n ¼ 3), cFLIP-alpha expression was increased relative to epilepsy controls (Po0.05) but not relative to post-mortem controls. The data suggest differential spatial and temporal regulation of cFLIP-alpha and cFLIP-delta expression that may influence the magnitude of cell death and further implicate programmed mechanisms of cell death after TBI.

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Inhibition of death receptor signals by cellular FLIP

Cited by 2,382 publications

References 29 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

Alternate functions of viral regulators of cell death

Expression of Cellular FLICE Inhibitory Proteins (cFLIP) in Normal and Traumatic Murine and Human Cerebral Cortex

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