Inactivation of BAD by IKK Inhibits TNFα-Induced Apoptosis Independently of NF-κB Activation

Yan, Jie; Xiang, Jialing; Lin, Yutin; Ma, Jinfeng; Zhang, Jiyan; Zhang, Hao; Sun, Jisheng; Danial, Nika N.; Liu, Jing; Lin, Anning

doi:10.1016/j.cell.2012.12.021

Cited by 89 publications

(98 citation statements)

References 48 publications

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“…For example, IKKβ can inhibit cell death in an NF-κB-independent manner by phosphorylating BAD, a BH3-only proapoptotic protein, to prime it for inactivation (40). We also found that IKKβ phosphorylation of BAD is important for adipocyte survival in obesity (34).…”

Section: Discussionmentioning

confidence: 48%

“…Although much attention has been focused on the NF-κB-dependent functions of IKKβ, IKKβ can regulate inflammation, apoptosis, cell proliferation, and metabolic homeostasis through NF-κB-independent mechanisms by phosphorylating other key molecules such as SNAP-23, IRF7, p53, BAD, and XBP1 (39,40,57). For example, IKKβ can inhibit cell death in an NF-κB-independent manner by phosphorylating BAD, a BH3-only proapoptotic protein, to prime it for inactivation (40).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to NF-κB-dependent functions, IKKβ also plays key roles in regulating many physiological functions including immunity and cancer through NF-κB-independent pathways by phosphorylating other key proteins (34,39,40). Phosphorylation of several critical β-catenin amino acid residues including serine-33 (ser33), ser37, and ser45 by glycogen synthase kinase 3β (GSK3β) and priming kinase casein kinase Iα (CKIα) is essential for ubiquitin ligase-mediated ubiquitination and degradation of β-catenin (41-43).…”

Section: E-h)mentioning

confidence: 99%

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IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

Sui¹,

Liu²,

Park³

et al. 2018

JCI Insight

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: E-h)mentioning

confidence: 99%

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IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

Sui¹,

Liu²,

Park³

et al. 2018

JCI Insight

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“…Functions for IKK2 other than NF-κB activation have been described in other cell types (23). We therefore wished to assess whether IKK2 was regulating IL-7Rα expression in peripheral T cells by activating NF-κB signaling.…”

Section: Ikk2mentioning

confidence: 99%

NF-κB signaling mediates homeostatic maturation of new T cells

Silva

Cornish

Ley

et al. 2014

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

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Interleukin (IL)-7 is critical for the maintenance of the peripheral T-cell compartment of the adaptive immune system. IL-7 receptor α ( IL-7Rα) expression is subject to developmental regulation and new T cells induce expression as they leave the thymus, which is essential for their long-term survival. It is not understood how this expression is regulated. Here, we identify a role for the Nuclear Factor κ-B (NF-κB) signaling pathway in controlling expression of IL-7Rα in new T cells. Perturbations to NF-κB signaling, either by deletion of Inhibitor of Kappa-B Kinase-2 (IKK2) or by inhibiting Rel dimer activity, prevented normal IL-7Rα expression in new T cells. Defective IL-7Rα expression resulted in impaired survival and homeostatic cell division responses by T cells that could be attributed to their failure to express IL-7Rα normally. Surprisingly, NF-κB signaling was only required transiently in new T cells to allow their normal expression of IL-7Rα, because IKK2 deletion in mature T cells had no effect on IL-7Rα expression or their normal homeostatic responsiveness. Therefore, we identify a developmental function for NF-κB signaling in the homeostatic maturation of new T cells, by regulating IL-7Rα expression. M aintaining T lymphocytes in sufficient numbers and at an appropriate composition of differentiation states and subtypes is essential for effective immunity. The immune system has evolved a number of homeostatic mechanisms to ensure the size and composition of the T-cell compartment remains remarkably stable over time. The cytokine interleukin (IL)-7 plays a central role in regulating homeostasis of the T-cell compartment. It is essential for normal development of αβ and γδ T cells in the thymus and provides vital survival signals for both naive and memory T cells in the periphery (1). IL-7 is produced by stromal cell components in bone marrow, thymus, and in peripheral lymphoid compartments (2), and there is extensive evidence that production of IL-7 is a key factor that determines and limits the overall size of the peripheral T-cell compartment (3, 4). The receptor for IL-7 is a member of the common-gamma chain (γc) family of cytokine receptors and consists of a heterodimeric complex of IL-7Rα and γc (5).In T cells, IL-7 signaling is primarily regulated at the level of IL-7Rα expression. During T-cell development in the thymus, expression of IL-7Rα by thymocytes is subject to dynamic developmental regulation. IL-7Rα is essential for survival and development of CD4 CD8 double negative (DN) thymocytes (6). Expression is lost at the CD4 CD8 double positive (DP) stage, ensuring that onward development of DP thymocytes is restricted to those that successfully undergo positive selection (7). Immediately following selection, however, IL-7Rα is immediately reexpressed and recent studies suggest that the strength of T-cell receptor (TCR)-mediated positive selection signaling determines the extent of reexpression by SP thymocytes (8). Following egress from the thymus, new T cells continue to mature as recent ...

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“…TNF-a has pleiotropic functions in inflammatory progression depending on cell type or biological context 7 . In certain conditions, TNF-a induces apoptosis; however, recent studies have indicated that TNF-a may promote hepatocellular carcinogenesis by activating a variety of signal pathways related to cell proliferation, differentiation and survival [8][9][10] . The mechanism of inflammation linked to TNF-a and involved in hepatocellular carcinogenesis still needs to be fully elucidated.…”

mentioning

confidence: 99%

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

et al. 2015

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G-protein-coupled receptors (GPCR) constitute the largest known superfamily for signal transduction and transmission, and they control a variety of physiological and pathological processes. GPCR adaptor b-arrestins (ARRBs) play a role in cancerous proliferation. However, the effect of ARRBs in inflammation-mediated hepatocellular carcinogenesis is unknown. Here we show that ARRB1, but not ARRB2, is upregulated in inflammation-associated hepatocellular carcinoma (HCC) and paracancerous tissues in humans. A genotoxic carcinogen, diethylnitrosamine (DEN), significantly induces hepatic inflammation, TNF-a production and ARRB1 expression. Although ARRB1 deficiency does not affect hepatic inflammation and TNF-a production, it markedly represses hepatocellular carcinogenesis by suppressing malignant proliferation in DEN-treated mice. Furthermore, TNF-a directly induces hepatic ARRB1 expression and enhances ARRB1 interaction with Akt by binding to boost Akt phosphorylation, resulting in malignant proliferation of liver cells. Our data suggest that ARRB1 enhances hepatocellular carcinogenesis by inflammation-mediated Akt signalling and that ARRB1 may be a potential therapeutic target for HCC.

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Inactivation of BAD by IKK Inhibits TNFα-Induced Apoptosis Independently of NF-κB Activation

Cited by 89 publications

References 48 publications

IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

NF-κB signaling mediates homeostatic maturation of new T cells

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

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