XIAP regulates bi-phasic NF-κB induction involving physical interaction and ubiquitination of MEKK2

Winsauer, Gabriele; Resch, Ulrike; Hofer‐Warbinek, Renate; Schichl, Yvonne M.; Martin, Rainer de

doi:10.1016/j.cellsig.2008.08.004

Cited by 37 publications

(36 citation statements)

References 36 publications

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“…Together, these data suggest an active role for IKK in the LT enhancement of NF-B activation observed in this study and as reported previously (24). With regard to the mechanism leading to enhanced IKK activation, we provide evidence that LT cotreatment enhances expression of MEKK2, an upstream kinase that has been linked to IKK activation (38,48). Indeed, MEKK2 is thought to specifically control the late phase of NF-B activity through assembly of a complex with IKK and IB proteins (37).…”

Section: Discussionmentioning

confidence: 90%

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Warfel

D’Agnillo

2009

Journal of Biological Chemistry

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Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-B in tumor necrosis factor-␣-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-B activation is associated with the enhanced degradation of the inhibitory proteins IB␣ and IB␤ but not IB⑀. Moreover, this was accompanied by enhanced activation of the IB kinase complex (IKK), which is responsible for targeting IB proteins for degradation. Importantly, LT enhancement of IB␣ degradation was completely blocked by a selective IKK␤ inhibitor, whereas IB␤ degradation was attenuated, suggesting a mechanistic link. Consistent with the above data, LT-cotreated cells show elevated phosphorylation of two IKK substrates, IB␣ and p65, both of which were blocked by incubation with the IKK␤ inhibitor. Consistent with NF-B activation, LT increased transcription of the NF-B regulated gene CD40. Conversely, LT inhibited transcription of another NF-B-regulated gene, CCL2. This inhibition was linked to the LT-mediated suppression of another CCL2-regulating transcription factor, AP-1 (activator protein-1). These data suggest that LT-mediated enhancement of NF-B is IKKdependent, but importantly, the net effect of LT on the transcription of proinflammatory genes is driven by the cumulative effect of LT on the particular set of transcription factors that regulate a given promoter. Together, these findings provide new mechanistic insight on how LT may disrupt the host response to anthrax.

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Section: Discussionmentioning

confidence: 90%

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Warfel

D’Agnillo

2009

Journal of Biological Chemistry

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“…In addition, stimulation of cells induces transient protein-protein interactions involved in specific signal transduction pathways, and the strength and duration of stimulation is critically involved in the life or death decision of cells. XIAP is known as a potent inhibitor of apoptosis not only through its direct inhibition of caspases 3, 7 and 9, but also through modulation of cellular signalling within the TGFβ, NFκB and JNK pathways (Birkey Reffey et al, 2001;Hofer-Warbinek et al, 2000;Lewis et al, 2004;Sanna et al, 2002;Winsauer et al, 2008;Yamaguchi et al, 1999). By using a yeast two-hybrid screening approach, we identified the proapoptotic protein Siva1 as a novel XIAP-interacting protein.…”

Section: Discussionmentioning

confidence: 99%

“…during TCR-mediated activation-induced cell death (AICD) (Gudi et al, 2006). In the light of these reports, as well as the previous finding that XIAP enhances NFκB signalling (Hofer-Warbinek et al, 2000;Lewis et al, 2004;Winsauer et al, 2008), we next investigated whether Siva1 interferes with XIAPinduced NFκB activation. Siva1 reduced XIAP-induced NFκB activation in a dose-dependent fashion as measured by reporter gene assays in HEK293 cells ( Fig.…”

Section: Siva1 Interacts With Xiapmentioning

confidence: 99%

Siva1 is a XIAP-interacting protein that balances NFκB and JNK signalling to promote apoptosis

Resch

Schichl

Winsauer

et al. 2009

Journal of Cell Science

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XIAP is known as a potent inhibitor of apoptosis, but in addition is involved in cellular signalling, including the NFκB, JNK and TGFβ pathways. Our search for XIAP-interacting partners led us to Siva1, a proapoptotic protein that is known to play a role in T-cell apoptosis through a caspase-dependent mitochondrial pathway. The interaction sites between XIAP and Siva1 were mapped to the RING domain of XIAP and the N-terminal, SAH-containing and death-homology-region-containing domains of Siva1. Co-immunoprecipitation experiments showed that XIAP, Siva1 and TAK1 form a ternary complex in Jurkat T cells. Reporter-gene analysis revealed that Siva1 inhibits XIAP- and TAK1-TAB1-mediated NFκB activation. By contrast, Siva1 increased XIAP- and TNFα-mediated AP1 activity and prolonged TNFα-induced JNK activation, whereas knock down of Siva1 resulted in reduced JNK activation. This suggests that Siva1 differentially modulates signalling by JNK and NFκB and shifts the balance between these pathways towards enhanced JNK activation, a situation that promotes apoptosis. Ectopically expressed Siva1 increased caspase-3 activity, which was inhibited by XIAP in a ubiquitin-ligase-dependent manner. In line with this, Siva1 was lysine-48-linked polyubiquitylated by XIAP. Our findings suggest that, via physical interaction with XIAP and TAK1, Siva1 diminishes NFκB and enhances JNK activity to favour apoptosis.

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“…siRNA duplexes targeting human MEKK2 were synthesized and purified by RiboBio (Guangzhou, China) [29] . siRNA duplexes containing non-specific sequences were used as a negative control (NC).…”

Section: Cell Culturementioning

confidence: 99%

Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2

Kong

Zhang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the mechanism underlying the increase of hepatoma cell proliferation by hepatitis B virus X protein (HBx). Methods: HepG2, H7402 and HepG2.2.15 cells, which constitutively replicated hepatitis B virus were used. The effects of HBx on hepatoma cell proliferation were examined using 5-ethynyl-2-deoxyuridine (EdU) incorporation assay and MTT assay. The expression level of MEKK2 was measured using RT-PCR, Western blot and luciferase reporter gene assay. The activity of activator protein 1 (AP-1) was detected using luciferase reporter gene assay. The phosphorylation levels of JNK and c-Jun were measured using Western blot. The expression levels of HBx and MEKK2 in 11 clinical hepatocellular carcinoma (HCC) tissues were measured using real time PCR and Western blot. In addition, the expression of MEKK2 in 95 clinical HCC tissues was examined using immunohistochemistry. Results: HBx significantly enhanced HepG2-X cell proliferation. In HepG2-X, H7402-X and HepG2.2.15 cells, the expression level of MEKK2 was remarkably increased. In HepG2.2.15 cells, HBx was found to activate JNK and AP-1, which were the downstream effectors of MEKK2 in HepG2-X and HepG2.2.15 cells. In 11 clinical HCC tissues, both HBx and MEKK2 expression levels were remarkably increased, as compared to those in the corresponding peritumor tissues. In 95 clinical HCC tissues, the rate of detection of MEKK2 was 85.3%. Conclusion: HBx promotes hepatoma cell proliferation via upregulating MEKK2, which may be involved in hepatocarcinogenesis.

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XIAP regulates bi-phasic NF-κB induction involving physical interaction and ubiquitination of MEKK2

Cited by 37 publications

References 36 publications

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Siva1 is a XIAP-interacting protein that balances NFκB and JNK signalling to promote apoptosis

Hepatitis B virus X protein promotes hepatoma cell proliferation via upregulation of MEKK2

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