Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

Sethi, Gautam; Ahn, Kwang Seok; Chaturvedi, Madan M.; Aggarwal, Bharat B.

doi:10.1038/sj.onc.1210544

Cited by 99 publications

(77 citation statements)

References 30 publications

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“…Although we could show that EGF induces a significant increase in NF-kB-dependent gene expression in HEK293T cells overexpressing EGFR, we were unable to detect neither phosphorylation of IkBa at Ser-32 and Ser-36 nor its proteasome-dependent degradation. It has previously been shown that EGF-mediated NF-kB activation in non-small cell lung adenocarcinoma cell lines occurs through IkBa phosphorylation at Tyr-42 (Sethi et al, 2007). However, we were unable to detect IkBa Tyr-42 phosphorylation in HEK293T cells (data not shown).…”

Section: Discussioncontrasting

confidence: 46%

ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells

et al. 2008

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Section: Discussioncontrasting

confidence: 46%

ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells

et al. 2008

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“…By contrast, that mutant EGFR induced NF-kB activation occurred without phosphorylation of IkB at Ser32. This finding is consistent with previous report by G. Sethi, who showed that EGF-induced NF-kB activation is require of phosphorylation of IkB at tyrosine 42 but not serine 32/36 (25). These 2 pathways are redundant in EGFR mutant lung cancer cell lines.…”

Section: Discussionsupporting

confidence: 83%

“…NF-kB subunit p65/RelA is determined to be required for K-Ras-induced lung tumorigenesis (26). Furthermore, NSCLC containing EGFR mutation shows elevated NF-kB activity (25). Recently, an increase of the IkBa level predicts improved progression-free and overall survival in patients with EGFR mutant NSCLC treated with erlotinib (27).…”

Section: Introductionmentioning

confidence: 99%

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TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

Jing

Chen

et al. 2014

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2-[(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IkB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-kB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-kB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-kB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-kB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers. Mol Cancer Ther; 13(3); 617-29. Ó2014 AACR.

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“…In addition to TNFR1, TRADD may mediate signaling downstream of the death receptors (and TNFR superfamily members) DR3 and DR6 (5,6). As well, recent TRADD knockdown studies have indicated that TRADD may be involved in signaling mediated by receptors unrelated to the TNFR superfamily, such as in IFN␥ receptor (7)(8)(9). These findings give tantalizing hints of the potential breadth of TRADD functions.…”

Section: Tnf ͉ Innate Immunitymentioning

confidence: 97%

Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

Chen

Chio

Lin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

103

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Tumor necrosis factor receptor 1-associated death domain protein (TRADD) is the core adaptor recruited to TNF receptor 1 (TNFR1) upon TNF␣ stimulation. In cells from TRADD-deficient mice, TNF␣-mediated apoptosis and TNF␣-stimulated NF-B, JNK, and ERK activation are defective. TRADD is also important for germinal center formation, DR3-mediated costimulation of T cells, and TNF␣-mediated inflammatory responses in vivo. TRADD deficiency does not enhance IFN␥-induced signaling. Importantly, TRADD has a novel role in TLR3 and TLR4 signaling. TRADD participates in the TLR4 complex formed upon LPS stimulation, and TRADD-deficient macrophages show impaired cytokine production in response to TLR ligands in vitro. Thus, TRADD is a multifunctional protein crucial both for TNFR1 signaling and other signaling pathways relevant to immune responses. TNF ͉ innate immunityT umor necrosis factor alpha (TNF␣) is a pleiotropic cytokine involved in a broad range of biological activities, including inflammation and cell differentiation, survival, and death (1). TNF␣ mediates these activities by engaging two distinct cell surface receptors: TNFR1 and TNFR2. Activation of TNFR1 leads to the recruitment of the intracellular death domain (DD)-containing adaptor TNFR-associated DD protein (TRADD) through a homotypic interaction with DD of TNFR1. On one hand, the recruitment of TRADD can promote the association of the TNFR1 complex with Fas-associated DD (FADD), which induces caspase activation and cell death. On the other hand, TRADD can also recruit receptor-interacting protein kinase 1 (RIP1) and TNFR-associated factor-2 (TRAF2), which trigger NF-B activation, leading to cell survival and proinflammatory responses (1).TRADD was originally identified in a yeast two-hybrid screen performed to identify TNFR1-interacting proteins (2). Intriguingly, TRADD is the first adaptor protein identified that binds directly to the DD of TNFR1 but transduces signals resulting in either apoptosis or NF-B activation (2-4). Indeed, TRADD overexpression in 293T cells activates both apoptotic and cellsurvival signaling pathways (2). In addition to TNFR1, TRADD may mediate signaling downstream of the death receptors (and TNFR superfamily members) DR3 and DR6 (5, 6). As well, recent TRADD knockdown studies have indicated that TRADD may be involved in signaling mediated by receptors unrelated to the TNFR superfamily, such as in IFN␥ receptor (7-9). These findings give tantalizing hints of the potential breadth of TRADD functions.To date, a knockout animal model has yet to be reported for TRADD, even though this important adaptor was identified more than ten years ago. In this study, we generate TRADD knockout mice by using conditional gene targeting and show that not only is TRADD indispensable for TNF␣-induced NF-B activation and apoptosis in vitro and TNF␣-induced inflammatory responses in vivo, but also that this molecule is involved in germinal center (GC) formation, T cell costimulation, and TLR signaling. Our TRADD knockout mice represent a very useful t...

show abstract

Epidermal growth factor (EGF) activates nuclear factor-κB through IκBα kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IκBα

Cited by 99 publications

References 30 publications

ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells

ABINs inhibit EGF receptor-mediated NF-κB activation and growth of EGF receptor-overexpressing tumour cells

TPCA-1 Is a Direct Dual Inhibitor of STAT3 and NF-κB and Regresses Mutant EGFR-Associated Human Non–Small Cell Lung Cancers

Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors

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