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Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy.

Safa AR - J Carcinog Mutagen (2013)

Bottom Line: The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation.Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents.Hence, c-FLIP is an important target for cancer therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, IN 46202, USA ; Indiana University Simon Cancer Center, Indiana University School of Medicine, IN 46202, USA.

ABSTRACT
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

No MeSH data available.


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Structures of c-FLIP variants and cleavage products. c-FLIP isoforms (c-FLIPL, c-FLIPS, and c-FLIPR) contain two death effector domains (DED1 and DED2) at their N termini which are required for DISC recruitment. In addition to two DEDs, c-FLIPL has a significant similarity to caspase-8 and has a large (p20) and a small (p12) caspase-like domain which are catalytically inactive. c-FLIPS and c-FLIPR consist of two DEDs and a small C terminus. c-FLIPL can be cleaved by caspase-8 generating the N-terminal fragment p43-FLIP or p22-FLIP. The phosphorylation (P) sites and ubiquitination (U) sites are indicated [35,37,60]. The p20/p12 regions interact with TRAF2 and RIP1, respectively, and Ku70 binds to DED2 [57].
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Figure 2: Structures of c-FLIP variants and cleavage products. c-FLIP isoforms (c-FLIPL, c-FLIPS, and c-FLIPR) contain two death effector domains (DED1 and DED2) at their N termini which are required for DISC recruitment. In addition to two DEDs, c-FLIPL has a significant similarity to caspase-8 and has a large (p20) and a small (p12) caspase-like domain which are catalytically inactive. c-FLIPS and c-FLIPR consist of two DEDs and a small C terminus. c-FLIPL can be cleaved by caspase-8 generating the N-terminal fragment p43-FLIP or p22-FLIP. The phosphorylation (P) sites and ubiquitination (U) sites are indicated [35,37,60]. The p20/p12 regions interact with TRAF2 and RIP1, respectively, and Ku70 binds to DED2 [57].

Mentions: Viral FLICE-Inhibitory Proteins (v-FLIPs) were first identified by a bioinformatic search for a novel death effector domain (DED-containing virus-encoded apoptotic regulatory proteins) by Thome et al. [29]. These authors described six v-FLIPs and showed that cells expressing v-FLIPs were resistance to Fas (CD95/APO-1)-, TRAILR1-, and TNFR1-Induced Apoptosis [29,30]. v-FLIPs contain two DEDs, bind to the DED of FADD and interfere with the FADD-procaspase 8 interaction, leading to suppressed recruitment of procaspase-8 to the DISC and its activation [29]. Shortly after the characterization of v-FLIPs, the mammalian cellular homologue was identified and termed c-FLIP [31]. c-FLIP is also known as Casper, iFLICE, FLAME-1, CASH, CLARP, MRIT, or usurpin [32]. c-FLIP consists of 13 distinct spliced variants, three of which are expressed as proteins: the 26 kDa short form (c-FLIPS), the 24 kDa form of c-FLIP (c-FLIPR), and the 55 kDa long form (c-FLIPL) [33-37] (Figure 2). The three c-FLIP variants can interact with the adaptor protein FADD. The structures of c-FLIPS and the viral FLIP (v-FLIP) proteins are similar, except that the two DEDs of c-FLIPS are followed by 20 amino acids that appear to be crucial for its ubiquitination and targeting for proteasomal degradation [32,34-36]. c-FLIPR also contains two DEDs but lacks the additional carboxy (C)-terminal amino acids that are present in c-FLIPS. The C-terminus of c-FLIPL is longer than that of c-FLIPS and closely resembles the structure of caspases-8 and -10 [32,34-36], but this region of c-FLIPL does not contain a functional caspase domain. This lack of caspase activity is the result of several amino acid substitutions, particularly the crucial cysteine residue in the catalytic domain which is necessary for the catalytic activity of caspases [32,34]. Additionally, c-FLIPL has a caspase-8 cleavage site at position Asp-376 (LEVD); c-FLIPL cleavage at this site produces the proteolytic fragment variant p43c-FLIP [18,19]. The C-terminal region of c-FLIPS and c-FLIPR play a crucial role in ubiquitination and degradation as well as the anti-apoptotic function of these isoforms [18,19,36]. In humans, a single nucleotide polymorphism in a 3' splice site of the c-FLIP gene determines whether c-FLIPS or c-FLIPR is made [37]. An intact splice site directs production of c-FLIPS, but the splice-dead variant causes production of c-FLIPR [37].


Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy.

Safa AR - J Carcinog Mutagen (2013)

Structures of c-FLIP variants and cleavage products. c-FLIP isoforms (c-FLIPL, c-FLIPS, and c-FLIPR) contain two death effector domains (DED1 and DED2) at their N termini which are required for DISC recruitment. In addition to two DEDs, c-FLIPL has a significant similarity to caspase-8 and has a large (p20) and a small (p12) caspase-like domain which are catalytically inactive. c-FLIPS and c-FLIPR consist of two DEDs and a small C terminus. c-FLIPL can be cleaved by caspase-8 generating the N-terminal fragment p43-FLIP or p22-FLIP. The phosphorylation (P) sites and ubiquitination (U) sites are indicated [35,37,60]. The p20/p12 regions interact with TRAF2 and RIP1, respectively, and Ku70 binds to DED2 [57].
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Structures of c-FLIP variants and cleavage products. c-FLIP isoforms (c-FLIPL, c-FLIPS, and c-FLIPR) contain two death effector domains (DED1 and DED2) at their N termini which are required for DISC recruitment. In addition to two DEDs, c-FLIPL has a significant similarity to caspase-8 and has a large (p20) and a small (p12) caspase-like domain which are catalytically inactive. c-FLIPS and c-FLIPR consist of two DEDs and a small C terminus. c-FLIPL can be cleaved by caspase-8 generating the N-terminal fragment p43-FLIP or p22-FLIP. The phosphorylation (P) sites and ubiquitination (U) sites are indicated [35,37,60]. The p20/p12 regions interact with TRAF2 and RIP1, respectively, and Ku70 binds to DED2 [57].
Mentions: Viral FLICE-Inhibitory Proteins (v-FLIPs) were first identified by a bioinformatic search for a novel death effector domain (DED-containing virus-encoded apoptotic regulatory proteins) by Thome et al. [29]. These authors described six v-FLIPs and showed that cells expressing v-FLIPs were resistance to Fas (CD95/APO-1)-, TRAILR1-, and TNFR1-Induced Apoptosis [29,30]. v-FLIPs contain two DEDs, bind to the DED of FADD and interfere with the FADD-procaspase 8 interaction, leading to suppressed recruitment of procaspase-8 to the DISC and its activation [29]. Shortly after the characterization of v-FLIPs, the mammalian cellular homologue was identified and termed c-FLIP [31]. c-FLIP is also known as Casper, iFLICE, FLAME-1, CASH, CLARP, MRIT, or usurpin [32]. c-FLIP consists of 13 distinct spliced variants, three of which are expressed as proteins: the 26 kDa short form (c-FLIPS), the 24 kDa form of c-FLIP (c-FLIPR), and the 55 kDa long form (c-FLIPL) [33-37] (Figure 2). The three c-FLIP variants can interact with the adaptor protein FADD. The structures of c-FLIPS and the viral FLIP (v-FLIP) proteins are similar, except that the two DEDs of c-FLIPS are followed by 20 amino acids that appear to be crucial for its ubiquitination and targeting for proteasomal degradation [32,34-36]. c-FLIPR also contains two DEDs but lacks the additional carboxy (C)-terminal amino acids that are present in c-FLIPS. The C-terminus of c-FLIPL is longer than that of c-FLIPS and closely resembles the structure of caspases-8 and -10 [32,34-36], but this region of c-FLIPL does not contain a functional caspase domain. This lack of caspase activity is the result of several amino acid substitutions, particularly the crucial cysteine residue in the catalytic domain which is necessary for the catalytic activity of caspases [32,34]. Additionally, c-FLIPL has a caspase-8 cleavage site at position Asp-376 (LEVD); c-FLIPL cleavage at this site produces the proteolytic fragment variant p43c-FLIP [18,19]. The C-terminal region of c-FLIPS and c-FLIPR play a crucial role in ubiquitination and degradation as well as the anti-apoptotic function of these isoforms [18,19,36]. In humans, a single nucleotide polymorphism in a 3' splice site of the c-FLIP gene determines whether c-FLIPS or c-FLIPR is made [37]. An intact splice site directs production of c-FLIPS, but the splice-dead variant causes production of c-FLIPR [37].

Bottom Line: The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation.Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents.Hence, c-FLIP is an important target for cancer therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Toxicology, Indiana University School of Medicine, IN 46202, USA ; Indiana University Simon Cancer Center, Indiana University School of Medicine, IN 46202, USA.

ABSTRACT
Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.

No MeSH data available.


Related in: MedlinePlus