Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer

Bagnoli, Marina; Canevari, Silvana; Mezzanzanica, Delia

doi:10.1016/j.biocel.2009.11.015

Cited by 134 publications

(128 citation statements)

References 29 publications

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“…Evidently, a candidate target molecule for the pathway described is the cellular FLICE inhibitory protein (cFLIP), a catalytically inactive homolog of caspases-8 and -10 able to prevent their activation by obstructing binding sites on the DISC. 40 Thus, deregulation of cFLIP is a prerequisite for efficient initiation of DISC-mediated caspase-8 processing. Suppression of the cFLIP short and long isoforms in response to 5-FU occurred, however, not only in a p53-but also in a Ca 2 þ -independent fashion as determined by analyzing its expression level in the presence of BAPTA and in HCT116 p53 À / À cells (Supplementary Figure S4 and S5).…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

et al. 2012

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5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2 þ ) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2 þ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2 þ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FUinduced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 À / À cells confirmed the importance of a Ca 2 þ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.

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Section: Discussionmentioning

confidence: 99%

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

et al. 2012

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“…Like caspase-8, FLIP's N-terminus contains two death effector domains (DEDs), and its C-terminus has a caspase-like domain that is proteolytically inactive. 9 Transcripts from the murine FLIP gene can undergo alternative splicing to produce two different forms, FLIP-L and FLIP-R. In humans, a second short isoform, FLIP-S, is also produced that, like FLIP-R, harbors two DEDs but does not contain the caspase-8-like domain that is present in the FLIP-L form.…”

mentioning

confidence: 99%

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

et al. 2011

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Binding of TNF to TNF receptor-1 can give a pro-survival signal through activation of p65/RelA NF-jB, but also signals cell death. To determine the roles of FLICE-inhibitory protein (FLIP) and caspase-8 in TNF-induced activation of NF-jB and apoptosis, we used mouse embryonic fibroblasts derived from FLIP and caspase-8 gene-deleted mice, and treated them with TNF and a smac-mimetic compound that causes degradation of cellular inhibitor of apoptosis proteins (cIAPs). In cells treated with smac mimetic, TNF and Fas Ligand caused wild-type and FLIP À/À MEFs to die, whereas caspase-8 À/À MEFs survived, indicating that caspase-8 is necessary for death of MEFs triggered by these ligands when IAPs are degraded. By contrast, neither caspase-8 nor FLIP was required for TNF to activate p65/RelA NF-jB, because IjB was degraded, p65 translocated to the nucleus, and an NF-jB reporter gene activated normally in caspase-8 À/À or FLIP À/À MEFs. Reconstitution of FLIP À/À MEFs with the FLIP isoforms FLIP-L, FLIP-R, or FLIP-p43 protected these cells from dying when treated with TNF or FasL, whether or not cIAPs were depleted. These results show that in MEFs, caspase-8 is necessary for TNF-and FasL-induced death, and FLIP is needed to prevent it, but neither caspase-8 nor FLIP is required for TNF to activate NF-jB. Ligation of members of the TNF receptor superfamily typically triggers activation of transcription factors such as NF-kB, as well as proteins that can lead to cell death, such as RIPK1 and caspase-8. 1,2 The regulatory pathways that culminate in a pro-survival or apoptosis signal depend on the specific receptor that is ligated and the actions of proteins that transduce and modulate the signals flowing from it. For example, cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) and TNF receptor-associated factors (TRAF2 and TRAF3) are needed to prevent apoptosis of cells exposed to TNF, and favor activation of canonical (p65/RelA) NF-kB versus non-canonical (p100) NF-kB2. [3][4][5] Although TNF alone does not kill wild-type (WT) MEFs, it does cause apoptosis of MEFs in which genes for TRAF2 or p65/RelA NF-kB are deleted. 6 TNF can also kill MEFs that are mutant for cIAP1, and those in which cIAPs are depleted owing to treatment with a synthetic IAP antagonist 'smac-mimetic' compound. 7 These experiments indicate that pathways requiring cIAPs, TRAF2, and p65/RelA are normally able to block TNF-induced pro-apoptotic signals. Because treatment of cells with the translational inhibitor cycloheximide also sensitizes MEFs to killing by TNF, these experiments suggest that NF-kB drives the expression of cell death-inhibitory genes. 8 One of the NF-kB-regulated genes that is proposed to inhibit TNF-induced apoptosis is FLICE-inhibitory protein (FLIP). FLIP is structurally related to caspase-8. Like caspase-8, FLIP's N-terminus contains two death effector domains (DEDs), and its C-terminus has a caspase-like domain that is proteolytically inactive. 9 Transcripts from the murine FLIP gene can undergo alternative splicing to pro...

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“…33 In addition, signaling through c-FLIP, which is known to exert strong antiapoptotic effects by binding to the adapter protein FADD and competing for the recruitment of caspase-8, could be a mechanism mediating antiapoptotic activities of Fas. 34 In summary, we here provide genetic evidence showing conclusively that, in murine skin, Fas is an essential element of pathways that restrict keratinocyte apoptosis in eczematous dermatitis and on UVB irradiation. Neither contact allergen-nor UVB-induced keratinocyte apoptosis depend on the expression of Fas by epidermal keratinocytes in vivo.…”

Section: In Vivo Functions Of Fas In the Epidermismentioning

confidence: 54%

Enhanced contact allergen- and UVB-induced keratinocyte apoptosis in the absence of CD95/Fas/Apo-1

et al. 2010

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FAS/CD95/Apo-1 is a ubiquitously expressed cell-surface receptor involved in the initiation of programmed cell death. Its function in epidermal keratinocytes has been incompletely defined. Available evidence from in vitro studies points to important roles of Fas in the pathogenesis of contact dermatitis and in keratinocyte apoptosis induced by ultraviolet light. To define functions of Fas in the epidermis in vivo, we have generated mice with epidermis-specific deletion of the fas gene and tested its requirement for 2,4-dinitrofluorobenzene-induced contact dermatitis and for ultraviolet light B (UVB)-induced keratinocyte apoptosis. We report here our unexpected finding that keratinocyte apoptosis induced by both a contact allergen and UVB irradiation was significantly enhanced in Fas-negative epidermis. Expression of Fas by epidermal keratinocytes was neither necessary for the normal development of contact hypersensitivity of the skin, nor required for keratinocyte apoptosis following UVB irradiation. Our study results thus show that in the epidermis in vivo Fas exerts antiapoptotic effects that outweigh its proapoptotic role in contact hypersensitivity responses of the skin and in the tissue response of the epidermis to UVB irradiation.

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Cellular FLICE-inhibitory protein (c-FLIP) signalling: A key regulator of receptor-mediated apoptosis in physiologic context and in cancer

Cited by 134 publications

References 29 publications

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

In mouse embryonic fibroblasts, neither caspase-8 nor cellular FLICE-inhibitory protein (FLIP) is necessary for TNF to activate NF-κB, but caspase-8 is required for TNF to cause cell death, and induction of FLIP by NF-κB is required to prevent it

Enhanced contact allergen- and UVB-induced keratinocyte apoptosis in the absence of CD95/Fas/Apo-1

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