NF-κB activation results in rapid inactivation of JNK in TNFα-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-κB

Javelaud, Delphine; Besançon, Françoise

doi:10.1038/sj.onc.1204570

Cited by 115 publications

(122 citation statements)

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“…Such an NF-kB-dependent negative loop on JNK activation has recently been reported in other cell systems including murine embryonic fibroblasts, 3DO T cells, ovarian epithelial cancer cells and Ewing's sarcoma cells. 37,39,41,42 Surprisingly, sst2 inhibits JNK activity in both TNFa-treated or -untreated cells, which is dependent on sst2-activated NF-kB, as sst2-mediated JNK inhibition is indeed abolished by an NF-kB inhibitor. Thus, the GPCR sst2 is an additional type of receptor, beside death receptor to TNFa and the cytokine receptor to IL-1, which transduces NF-kB-mediated inhibition of JNK.…”

Section: Discussionmentioning

confidence: 95%

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

et al. 2006

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Somatostatin is a multifunctional hormone that modulates cell proliferation, differentiation and apoptosis. Mechanisms for somatostatin-induced apoptosis are at present mostly unsolved. Therefore, we investigated whether somatostatin receptor subtype 2 (sst2) induces apoptosis in the nontransformed murine fibroblastic NIH3T3 cells. Somatostatin receptor subtype 2 expression induced an executioner caspase-mediated apoptosis through a tyrosine phosphatase SHP-1 (Src homology domain phosphatase-1)-dependent stimulation of nuclear factor kappa B (NF-jB) activity and subsequent inhibition of the mitogenactivated protein kinase JNK. Tumor necrosis factor a (TNFa) stimulated both NF-jB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFa-induced apoptosis by (1) upregulating TNFa receptor protein expression, and sensitizing to TNFa-induced caspase-8 activation; (2) enhancing TNFamediated activation of NF-jB, resulting in JNK inhibition and subsequent executioner caspase activation and cell death. We have here unraveled a novel signaling mechanism for a G protein-coupled receptor, which directly triggers apoptosis and crosstalks with a death receptor to enhance death ligand-induced apoptosis. Somatostatin is a regulatory peptide which is mostly expressed in the central and peripheral nervous system, in the gastro-intestinal tract and in the pancreas. Somatostatin acts via a family of five G protein-coupled receptors (GPCR), somatostatin receptor subtypes 1-5 (sst1-sst5) that are variably expressed throughout numerous tissues ranging from the central nervous system to the endocrine and immune systems. 1 Somatostatin or its analogues promote growth inhibition of various normal and tumor cells, both in vitro and in vivo. Somatostatin affects cell growth indirectly by inhibiting either trophic or growth factor synthesis and/or secretion, or their respective intracellular pathways. Somatostatin antiproliferative action also results from a direct blockade of cell cycle and/or induction of apoptosis. 2 Whereas somatostatin effect on cell cycle arrest has been extensively studied, mechanisms for somatostatin-induced apoptosis and receptor subtype implication are only partially elucidated. Somatostatin has been shown to induce cell death in both normal and tumoral cell models 3-9 . Among the five somatostatin receptors, sst3 and sst2 have been found to play a critical role in somatostatin-induced apoptosis of normal and tumor cells, respectively. 3,5,10 Mechanisms for somatostatin apoptotic action were shown to rely on the mitochondrial pathway through activation either of sst2 or sst3. However, signaling pathways coupling sst2 receptor to apoptosis have been partially elucidated.We have previously demonstrated that expression of sst2 in the nontransformated murine fibroblastic NIH3T3 cells results in a cell growth inhibition, which was dependent on the activation of the tyrosine phosphatase Src homology domain phosphatase-1 (SHP-1). 11 sst2...

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Section: Discussionmentioning

confidence: 95%

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

et al. 2006

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“…A large number of reports have demonstrated the anti-apoptotic effect of NF-κB in a wide variety of cell types. The protective role of NF-κB is shown in a large variety of cell types, including the human breast carcinoma (Liu et al, 1996) , T cells (Van Antwerp et al, 1996;Chu et al, 1997;Khoshnan et al, 2000), fibroblasts and macrophages (Beg and Baltimore, 1996), endothelial cells (Stehlik et al, 1998), EBV-infected lymphoblastoid cells (Asso-bonnet et al, 1998), non-small lung cancer cells , glomerular mesangial cells (Sugiyama et al, 1999), human ovarian cancer cells (Shao et al, 1997), human pancreatic cancer cell lines (Kajino et al, 2000), Ewing sarcoma cells (Javelaud and Besancon, 2001), cardiomyocytes (Bergmann et al, 2001), mouse embryos , and HT1080 fibrosarcoma . Treatment of RelA-deficient (the transcriptionally active subunit of NF-κB) mouse fibroblasts and macrophages with TNF significantly reduced cell viability, whereas RelA +/+ cells were unaffected.…”

Section: Anti-apoptotic Effects Of Nf-κbmentioning

confidence: 99%

“…Javelaud and Besancon demonstrated that the repression of JNK activation by NF-κB is involved in the anti-apoptotic effect of this transcription factor in TNF α-treated Ewing sarcoma cells (Javelaud and Besancon, 2001). Also, NF-κB exercises its anti-apoptotic effects through NF-κB-inducing kinases (NIK).…”

Section: Anti-apoptotic Effects Of Nf-κbmentioning

confidence: 99%

Nuclear Factor-κB Activation: A Question of Life or Death

Shishodia¹,

Aggarwal²

2002

BMB Reports

206

168

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Apoptosis is a mode of cell death that plays an important role in both pathological and physiological processes. Research during the last decade has delineated the entire machinery needed for cell death, and its constituents were found to pre-exist in cells. The apoptotic cascade is triggered when cells are exposed to an apoptotic stimulus. It has been known for several years that inhibitors of protein synthesis can potentiate apoptosis that is induced by cytokines and other inducers. Until 1996, it was not understood why protein synthesis inhibitors potentiate apoptosis. Then three reports appeared that suggested the role of the transcription factor NF-κB activation in protecting the cells from TNF-induced apoptosis. Since then several proteins have been identified that are regulated by NF-κB and are involved in cell survival, proliferation, and protection from apoptosis. It now seems that when a cell is attacked by an apoptotic stimulus, the cell responds first by activating anti-apoptotic mechanisms, which may or may not be followed by apoptosis. Whether or not a cell undergoes proliferation, the survival, or apoptosis, appears to involve a balance between the two mechanisms. Inhibitors of protein synthesis seem to suppress the appearance of protein that are involved in anti-apoptosis. The present review discusses how NF-κB controls apoptosis.

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“…While progress in understanding this program has undoubtedly been made, it remains unclear as to which genes are most critical to this activity of NF-kB, and ultimately, by which mechanisms their products inhibit the apoptotic signaling cascade. Recently, an important piece of this puzzle -pertaining to the control of tumor necrosis factor (TNF)a-induced apoptosis -has been found, with the demonstration that activation of NF-kB shuts down the cJun-N-terminal kinase (JNK) cascade [1][2][3][4] (Figure 1). NF-kB is widely utilized by nature to marshal rapid cellular and organismal responses to environmental challenges.…”

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confidence: 99%