Tumor Necrosis Factor (TNF) Receptor-associated Factor 7 Is Required for TNFα-induced Jun NH2-terminal Kinase Activation and Promotes Cell Death by Regulating Polyubiquitination and Lysosomal Degradation of c-FLIP Protein

Scudiero, Ivan; Zotti, Tiziana; Ferravante, Angela; Vessichelli, Mariangela; Reale, Carla; Masone, Maria Chiara; Leonardi, Antonio; Vito, Pasquale; Stilo, Romania

doi:10.1074/jbc.m111.300137

Cited by 40 publications

(28 citation statements)

References 42 publications

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“…20, 21, 39 Data from Figure 5c illustrate that the proteasome inhibitor MG132 inhibited the hyperthermia-mediated downregulation of c-FLIP L , but there was no restoration of c-FLIP L for lysosomal proteases inhibitor NH 4 Cl, confirming the existence of proteasome-mediated, but not lysosome-mediated, degradation of the protein. Ubiquitination assays further proved that the ubiquitination of c-FLIP L increased upon hyperthermia.…”

Section: Discussionmentioning

confidence: 88%

“…19 Indeed, several studies show that c-FLIP L is degraded via the proteasome or lysosome pathway. 20, 21 To verify which pathway was involved in hyperthermia-induced downregulation of c-FLIP L , we used the proteasome inhibitor MG132 and lysosomal proteases inhibitor ammonium chloride (NH 4 Cl). Figure 5c shows that treatment with MG132, but not NH 4 Cl, restored c-FLIP L expression completely, confirming the existence of proteasome-mediated degradation of the protein, whereas lysosome-mediated degradation was not involved.…”

Section: Resultsmentioning

confidence: 99%

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Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

et al. 2013

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Colorectal cancer is the third leading cause of cancer-related mortality in the world; the main cause of death of colorectal cancer is hepatic metastases, which can be treated with hyperthermia using isolated hepatic perfusion (IHP). In this study, we report that mild hyperthermia potently reduced cellular FLIP(long), (c-FLIPL), a major regulator of the death receptor (DR) pathway of apoptosis, thereby enhancing humanized anti-DR4 antibody mapatumumab (Mapa)-mediated mitochondria-independent apoptosis. We observed that overexpression of c-FLIPL in CX-1 cells abrogated the synergistic effect of Mapa and hyperthermia, whereas silencing of c-FLIP in CX-1 cells enhanced Mapa-induced apoptosis. Hyperthermia altered c-FLIPL protein stability without concomitant reductions in FLIP mRNA. Ubiquitination of c-FLIPL was increased by hyperthermia, and proteasome inhibitor MG132 prevented heat-induced downregulation of c-FLIPL. These results suggest the involvement of the ubiquitin-proteasome system in this process. We also found lysine residue 195 (K195) to be essential for c-FLIPL ubiquitination and proteolysis, as mutant c-FLIPL lysine 195 arginine (arginine replacing lysine) was left virtually un-ubiquitinated and was refractory to hyperthermia-triggered degradation, and thus partially blocked the synergistic effect of Mapa and hyperthermia. Our observations reveal that hyperthermia transiently reduced c-FLIPL by proteolysis linked to K195 ubiquitination, which contributed to the synergistic effect between Mapa and hyperthermia. This study supports the application of hyperthermia combined with other regimens to treat colorectal hepatic metastases.

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Section: Discussionmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

et al. 2013

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“…However, the conditions required for differentiation and related mechanisms of OC precursors are not yet understood, which impedes the prevention and treatment of this disease. As an important inflammatory initiating factor, tumor necrosis factor-α (TNF-α) plays a critical role in the differentiation of multiple inflammatory and tumor cells (Scudiero et al, 2012). Vessel endothelial growth factor (VEGF) works as an angiogenesis regulating factor and has shown a powerful accelerating function of fracture healing in some studies (Won et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Expression of TNF-α, VEGF, and MMP-3 mRNAs in synovial tissues and their roles in fibroblast-mediated osteogenesis in ankylosing spondylitis

Liu¹,

He²,

Tan³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to explore the mRNA levels of tumor necrosis factor-α (TNF-α), vessel endothelial growth factor (VEGF), and matrix metalloproteinase-3 (MMP-3) in synovial tissues in ankylosing spondylitis (AS), and to analyze the functions of these proteins in the differentiation of AS synovial tissue fibroblasts into osteoblasts (OB) and osteoclasts. Synovial tissue samples from 22 AS patients and 22 normal individuals were collected. In situ hybridization was utilized to detect TNF-α, VEGF, and MMP-3 transcripts. After counting numbers of positive cells, Spearman analysis was used to determine the correlation between transcriptional levels of the three mRNAs and the AS disease activity index (BASDAI) and the C-response protein (CRP) levels. With the addition of TNF-α, VEGF, or both factors into cultured normal synovial fibroblasts, osteocalcin (bone gla protein, BGP) secretion levels were compared. We found that expression of TNF-α, VEGF, and MMP-3 was identified exclusively in the disease group. mRNA levels were significantly positively (2015) correlated with BASDAI (r = 0.42, 0.38, and 0.47, respectively; P < 0.05) and CRP (r = 0.44, 0.34, and 0.47 respectively; P < 0.05) scores. The secretion level of BGP in normal synovial fibroblasts increased progressively with increasing concentrations of VEGF or TNF-α (P < 0.01 compared to levels before treatment). Furthermore, co-incubation using both VEGF and TNF-α significantly elevated BGP levels compared to the single addition of VEGF or TNF-α (P < 0.01). These results suggest TNF-α, VEGF, and MMP-3 might directly participate in the differentiation of fibroblasts into OBs.

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“…One of the protein families that bind to both TNFRs is the TNF receptor-associated factors (TRAFs) [3,4]. Up to now, seven members of the TRAF family have been described [4,5]. All the TRAFs contain a C-terminal TRAF domain that mediates the interaction with TNF receptors and hetero- or homodimerization among the TRAF family members [3].…”

Section: Introductionmentioning

confidence: 99%

“…TRAF1 can associate with multiple TNFR family members and can also bind several protein kinases and adaptor proteins, suggesting that it likely possesses multiple functions in cytokine signaling networks [15]. TRAF7 is the last member of the TRAF family that has been identified and recent data indicate that TRAF7 regulates the activation of cellular stress pathways, as well as unconventional ubiquitination events and differentiation of muscle tissue [5]. TRAF2, TRAF3 and TRAF6 are E3 ubiquitine ligases that play a pivotal role in the control of NF-κB activation by innate and adaptive immunity stimuli [16].…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Nef Interacts with HCV Core, Recruits TRAF2, TRAF5 and TRAF6, and Stimulates HIV-1 Replication in Macrophages

Khan¹,

Abbas²,

Varin³

et al. 2013

J Innate Immun

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Tumor necrosis factor receptor-associated factor (TRAF) signaling plays a central role in many biological activities, such as the regulation of immune and inflammatory responses and control of apoptosis, which are key events in the pathogenesis of the human immunodeficiency virus (HIV)-1 and the hepatitis C virus (HCV) infections. Here we show that TRAF2, TRAF5 and TRAF6 interact with the HIV-1 Nef protein, an immunomodulatory viral protein expressed and released by cells infected by the virus. We also found that TRAF2 and TRAF5 interact with the HCV Core protein. Interestingly, we observed that HIV-1 Nef interacts with HCV Core. The activation of TRAF (2, 5, 6) - mediated by HIV-1 Nef and HCV Core - enhanced the activation of the nuclear factor-kappa B (NF-κB) and increased HIV-1 replication in monocyte- derived macrophages (MDMs). The knockdown of TRAF2, TRAF5 and TRAF6 resulted in decreased NF-κB activation and reduced HIV-1 replication in MDMs. Our results reveal a mechanism by which the activation of the TRAF pathway by HIV-1 Nef and HCV Core favors the replication of HIV-1 in macrophages and could be a critical factor for optimal replication of HIV-1 in macrophages of HIV-HCV-coinfected patients.

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Tumor Necrosis Factor (TNF) Receptor-associated Factor 7 Is Required for TNFα-induced Jun NH2-terminal Kinase Activation and Promotes Cell Death by Regulating Polyubiquitination and Lysosomal Degradation of c-FLIP Protein

Cited by 40 publications

References 42 publications

Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

Expression of TNF-α, VEGF, and MMP-3 mRNAs in synovial tissues and their roles in fibroblast-mediated osteogenesis in ankylosing spondylitis

HIV-1 Nef Interacts with HCV Core, Recruits TRAF2, TRAF5 and TRAF6, and Stimulates HIV-1 Replication in Macrophages

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