Association of the Adaptor TANK with the IκB Kinase (IKK) Regulator NEMO Connects IKK Complexes with IKKε and TBK1 Kinases

Chariot, Alain; Leonardi, Antonio; Muller, Jean-Noel; Bonif, Marianne; Brown, Keith; Siebenlist, Ulrich

doi:10.1074/jbc.m205069200

Cited by 144 publications

(154 citation statements)

References 41 publications

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“…The anti-TANK antibody was previously described. 41 Mouse strains and mouse mammary epithelial cell isolation. Mdm2 hypomorphic mice were previously described.…”

Section: Methodsmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubuleassociated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. Cell Death and Differentiation (2014) 21, 811-824; doi:10.1038/cdd.2014.2; published online 31 January 2014Restoration of p53 tumor suppressor function in cancer cells expressing wild-type (WT) p53 is a promising therapeutic approach. 1 Reactivation of p53 activity can be achieved by small molecular inhibitors that disrupt the interaction between p53 and its main E3 ligase MDM2. As a result, targeted cells undergo cell cycle arrest and apoptosis through p53 stabilization. 2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.Oncogenic pathways include AKT-dependent signaling cascades. Indeed, AKT promotes cell proliferation, survival, migration and angiogenesis by targeting numerous substrates ranging from anti-apoptotic transcription factors to regulators of protein synthesis. 6,7 Mutations or altered expressions of various AKT-activating signaling molecules have been described in human malignancies, thereby defining AKT as a hallmark of tumor development and progression. 8,9 AKT activation by estrogens requires the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). 10 Initially identified as a corepressor of pre-B-cell leukemia homeobox protein 1 (PBX1), 11 HPIP assembles a signaling complex that connects the p85 subunit of PI3K and ERa to microtubules in order to properly activate AKT. 10 Likewise, HPIP also promotes the growth and differentiation of hematopoietic cells through AKT. 12 Because correct reg...

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“…The anti-TANK antibody was previously described. 41 Mouse strains and mouse mammary epithelial cell isolation. Mdm2 hypomorphic mice were previously described.…”

Section: Methodsmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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“…A yeast-two hybrid screening experiment suggested that the C-terminal portion of IKKι/ε could specifically associate with the N-terminal domain of TANK (TRAF-associated NF-κB activator) (26). The most recent biochemical evidence provided by Chariot et al (27) demonstrated that physical interaction of IKKι/ε with TANK is sufficient to promote the association of TANK with IKKγ. Thus, it is possible that IKKι/ε may associate with a subset of classic IKK complex and act as an upstream kinase to activate IKKα or IKKβ.…”

Section: Kinase Pathways Leading To the Activation Of Nf-κbmentioning

confidence: 99%

Signaling from toxic metals to NF-kappaB and beyond: not just a matter of reactive oxygen species.

Chen

Shi

2002

Environ Health Perspect

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The nuclear factor kappa B (NF-kappaB) family of transcription factors controls expression of a number of early response genes associated with inflammatory responses, cell growth, cell cycle progression, and neoplastic transformation. These genes include a multitude of cytokines, chemokines, adhesion molecules, immune receptors, stress proteins, apoptotic or anti-apoptotic regulators, and several oncogenes. Accumulating evidence indicates that a variety of toxic metals are able to affect the activation or activity of NF-kappaB, but the molecular mechanisms involved in this process remain largely unknown. The signaling pathways mediating cytokine- or microorganism-induced NF-kappaB activation have been well established recently. Whether the same signaling systems are involved in metal-induced NF-kappaB activation, however, is unclear. In the present review, we have attempted to evaluate and update the possible mechanisms of metal signals on the activation and function of NF-kappaB.

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“…Genes of interest were TANK, BNIP3, Blk and Bcl10, all of which have the potential to modulate entry into apoptosis. TANK, which was decreased following Sox11 knockdown, can have prosurvival activity through its binding to NEMO (NF-κB essential modulator) (Chariot et al, 2002) and subsequent activation of the transcriptional regulator NF-κB (Bonif et al, 2006). TANK works with the co-inducer TRAF2 (TNF receptor-associated factor 2) to increase NF-κB activity and this increase in activity generally induces genes favoring neuron survival (Mattson and Meffert, 2006).…”

Section: Genes Related To Cell Survival and Apoptosis May Be Transcrimentioning

confidence: 99%

SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth

et al. 2006

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The transcription factor Sox11 is expressed at high levels in developing sensory neurons and injured adult neurons but little is known about its transcriptional targets and function. In this study we examined the role of Sox11 using Neuro2a neuroblastoma cells and cultured mouse dorsal root ganglia (DRG) neurons. Results show Sox11 has an essential role in regulation of neuron survival and neurite outgrowth in Neuro2a cells and primary sensory neurons. Neuro2a cells increase expression of Sox11 as they differentiate in culture. Following addition of 20μM retinoic acid (RA), a stimulus for differentiation that enhances neurite growth and differentiation, Sox11 level rises. RNAi-mediated knockdown of Sox11 in RA-differentiated Neuro2a cells caused a decrease in neurite growth and an increase in the percent of apoptotic cells. RNA expression analysis showed that Sox11 knockdown modulated the level of mRNAs encoding several genes related to cell survival and death. Further validation in the Neuro2a model showed Sox11 knockdown increased expression of the proapoptotic gene BNIP3 (Bcl2 interacting protein 1 NIP3) decreased expression of the anti-apoptotic gene TANK (TRAF family member-associated NFκB activator). Cultured primary DRG neurons also express Sox11 and treatment with Sox11 siRNA caused a significant decrease in neurite growth and branching and a decrease in mRNA encoding actin-related protein complex 3 (Arpc3), an actin organizing protein that may be involved in axon growth. The percent of apoptotic neurons also increased in cultures of DRG neurons treated with Sox11 siRNA. Similar to Neuro2a cells, a decrease in TANK gene expression occurred, suggesting at least some overlap in Sox11 transcriptional targets in Neuro2a and DRG neurons. These data are consistent with a central role for Sox11 in regulating events that promote neurite growth and neuron survival.

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Association of the Adaptor TANK with the IκB Kinase (IKK) Regulator NEMO Connects IKK Complexes with IKKε and TBK1 Kinases

Cited by 144 publications

References 41 publications

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

Signaling from toxic metals to NF-kappaB and beyond: not just a matter of reactive oxygen species.

SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth

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