c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity

Quintavalle, Cristina; Incoronato, Mariarosaria; Puca, Loredana; Acunzo, Mario; Zanca, Ciro; Romano, Giulia; Garofalo, Michela; Iaboni, Margherita; Croce, Carlo M.; Condorelli, Gerolama

doi:10.1038/cdd.2010.65

Cited by 30 publications

(26 citation statements)

References 35 publications

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“…It was first discovered as an oncogene within the mouse leukemia virus [31,32] and as a homolog of protein kinase C [33]. Thereafter, there have been many exciting breakthroughs elucidating the mechanism of upstream regulation of AKT [34-36]. AKT promotes cell survival through the phosphoinositide 3-kinase (PI3K) pathway.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of heat-induced apoptosis in rat small intestine and IEC-6 cells through the AKT signaling pathway

Gao

Yin

et al. 2013

BMC Vet Res

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BackgroundAs the world warms up, heat stress is becoming a major cause of economic loss in the livestock industry. Long-time exposure of animals to hyperthermia causes extensive cell apoptosis, which is harmful to them. AKT and AKT-related serine–threonine kinases are known to be involved in signaling cascades that regulate cell survival, but the mechanism remains elusive. In the present study, we demonstrate that phosphoinositide 3-kinase (PI3K) /AKT signal pathway provides protection against apoptosis induced by heat stress to ascertain the key point for treatment.ResultsUnder heat stress, rats showed increased shedding of intestinal epithelial cells. These rats also had elevated levels of serum cortisol and improved expression of heat shock proteins (Hsp27, Hsp70 and Hsp90) in response to heat stress. Apoptosis analysis by TUNEL assay revealed a higher number of villi epithelial cells that were undergoing apoptosis in heat-treated rats than in the normal control. This is supported by gene expression analysis, which showed an increased ratio of Bax/Bcl-2 (p < 0.05), an important indicator of apoptosis. During heat-induced apoptosis, more AKTs were activated, showing increased phosphorylation. An increase of BAD phosphorylation, which is an inhibitory modification, ensued. In rat IEC-6 cell line, a significant higher level of AKT phosphorylation was observed at 2 h after heat exposure. This coincided with a marked reduction of apoptosis.ConclusionTogether, these results suggest that heat stress caused damages to rat jejunum and induced apoptosis to a greater degree. HSPs and pro-survival factors were involved in response to heat stress. Among them, AKT played a key role in inhibiting heat-induced apoptosis.

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Section: Resultsmentioning

confidence: 99%

Inhibition of heat-induced apoptosis in rat small intestine and IEC-6 cells through the AKT signaling pathway

Gao

Yin

et al. 2013

BMC Vet Res

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“…In particular, we focused on AKT, a serine-threonine kinase that prevents apoptosis induced by various stress conditions by interacting with apoptotic modulators such as BAD [39], Caspase-9 [40], FOXO3 [41] and Bcl-w [42]. AKT has previously been shown to interact with c-FLIP L, which inhibits its function and blocks its ability to activate the substrate GSK3β [30]. Interestingly, several studies point to the involvement of AKT in ER stress response.…”

Section: Discussionmentioning

confidence: 99%

“…C. Quintavalle et al [30] demonstrated that c-FLIP interacts with AKT and inhibits its ability to bind to and regulate its substrate GSK3β, probably by sequestering AKT and limiting its access to the target protein. Interestingly, we have previously demonstrated that a pool of c-FLIP proteins localizes at ER [22].…”

Section: C-flip−/− Cells Display Greater Akt Activation Than Wtmentioning

confidence: 99%

“…In addition to its involvement in apoptosis modulation, c-FLIP plays important roles in controlling proliferation [26] and cardiac hypertrophy after pressure overload [27]. Furthermore, c-FLIP can activate several pro-survival signalling pathways by regulating proteins such as NF-κB, ERK and AKT [28][29][30]. More recently, we demonstrated that c-FLIP −/− mouse embryonic fibroblasts (MEFs) display an enlarged ER structure and strong lipid accumulation [22,31].…”

Section: Introductionmentioning

confidence: 99%

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A novel role of c-FLIP protein in regulation of ER stress response

Conti

Petrungaro

Marini

et al. 2016

Cellular Signalling

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Cellular-Flice-like inhibitory protein (c-FLIP) is an apoptosis modulator known to inhibit the extrinsic apoptotic pathway thus blocking Caspase-8 processing in the Death Inducing Signalling Complex (DISC). We previously demonstrated that c-FLIP localizes at the endoplasmic reticulum (ER) and that c-FLIP-deficient mouse embryonic fibroblasts (MEFs) display an enlarged ER morphology. In the present study, we have addressed the consequences of c-FLIP ablation in the ER stress response by investigating the effects of pharmacologically-induced ER stress in Wild Type (WT) and c-FLIP-/- MEFs. Surprisingly, c-FLIP-/- MEFs were found to be strikingly more resistant than WT MEFs to ER stress-mediated apoptosis. Analysis of Unfolded Protein Response (UPR) pathways revealed that Pancreatic ER Kinase (PERK) and Inositol-Requiring Enzyme 1 (IRE1) branch signalling is compromised in c-FLIP-/- cells when compared with WT cells. We found that c-FLIP modulates the PERK pathway by interfering with the activity of the serine threonine kinase AKT. Indeed, c-FLIP-/- MEFs display higher levels of active AKT than WT MEFs upon ER stress, while treatment with a specific AKT inhibitor of c-FLIP-/- MEFs subjected to ER stress restores the PERK but not the IRE1 pathway. Importantly, the AKT inhibitor or dominant negative AKT transfection sensitizes c-FLIP-/- cells to ER stress-induced cell death while the expression of a constitutively active AKT reduces WT cells sensitivity to ER stress-induced death. Thus, our results demonstrate that c-FLIP modulation of AKT activity is crucial in controlling PERK signalling and sensitivity to ER stress, and highlight c-FLIP as a novel molecular player in PERK and IRE1-mediated ER stress response.

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“…Further characterizing the CaM/c-FLIP interaction may provide a new therapeutic target for developing anticancer therapies [117]. By co-immunoprecipitation experiments, Quintavalle et al [118] demonstrated that the interaction between Akt and c-FLIPL enhances the anti-apoptotic functions of Akt by modulating Gsk3-β activity. Moreover, these authors have shown that c-FLIPL overexpression interferes with Gsk3-β phosphorylation levels and induces resistance to TRAIL in cancer cells.…”

Section: C-flip Activates Cytoprotective and Proliferation Pathwaysmentioning

confidence: 99%

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

2013

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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.

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c-FLIPL enhances anti-apoptotic Akt functions by modulation of Gsk3β activity

Cited by 30 publications

References 35 publications

Inhibition of heat-induced apoptosis in rat small intestine and IEC-6 cells through the AKT signaling pathway

Inhibition of heat-induced apoptosis in rat small intestine and IEC-6 cells through the AKT signaling pathway

A novel role of c-FLIP protein in regulation of ER stress response

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

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