TNF-Induced Recruitment and Activation of the IKK Complex Require Cdc37 and Hsp90

Chen, Guoqing; Cao, Ping; Goeddel, David V.

doi:10.1016/s1097-2765(02)00450-1

Cited by 374 publications

(329 citation statements)

References 45 publications

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“…NF-kB, nuclear factor-kB. (Broemer et al, 2004) and for constitutive and inducible IKK and NF-kB activation (Chen et al, 2002;Field et al, 2003;Broemer et al, 2004;Pittet et al, 2005;Mitsiades et al, 2006). Our results demonstrate that, in turn, NF-kB activity can influence hsp90a expression.…”

mentioning

confidence: 62%

The activity of hsp90α promoter is regulated by NF-κB transcription factors

et al. 2007

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Heat-shock proteins (HSP) 90 exert a relevant role in the survival and response to therapy of many neoplastic cell types. Here, we show that the promoter of hsp90a gene, that encodes the inducible form of HSP90, is regulated by nuclear factor-jB (NF-jB) activity. Indeed, we found that NF-jB factors bound to one of the two putative consensus sequences present in the hsp90a-flanking region; mutation of such motif hampered the phorbol-myristate-13-acetatestimulated expression of a luciferase reporter gene under the control of the hsp90a promoter. Furthermore, the downmodulation of NF-jB (p65) levels by a specific small interfering (si) RNA resulted in reducing the levels of endogenous HSP90a protein. These findings disclose a previously unrecognized mechanism that contributes to connect NF-jB factors and HSPs in cell defence machinery.

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mentioning

confidence: 62%

The activity of hsp90α promoter is regulated by NF-κB transcription factors

et al. 2007

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“…The IKK complex is composed of the IKK proteins, and several other adaptor proteins complexes (Chen et al, 2002). To determine whether ANXA1 associates with the IKK complex, lysates from MCF7-EV, MCF7-V5 and MDA-231 cells were subjected to gel-filtration chromatography followed by western blot analysis of the fractions with antibodies against phospho-IKKa, IKKb, NEMO, receptor interacting protein (RIP), ANXA1, TAK1, TRADD (TNF receptor-1-associated death domain protein) and p52 antibodies.…”

Section: Resultsmentioning

confidence: 99%

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

et al. 2011

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The molecular mechanisms underlying constitutive nuclear factor-jB (NF-jB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-jB activity, suggesting that ANXA1 may be required for the constitutive activity of IjB kinase (IKK) and NF-jB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-jB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKc or NEMO, but not IKKa or IKKb. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-jB. Downstream targets of NF-jB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-jB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-jB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1-deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-jB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.

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“…Similarly, GA treatment also leads to IKK degradation. However, the GAinduced IKK degradation is not through the proteasome but rather mediated by autophagy [21], which resembles the NIK degradation induced by GA. Interestingly, disruption of Hsp90/IKK association abolishes the recruitment of IKK to the tumor necrosis factor (TNF) receptor I (TNFR-I) and subsequent activation of IKK induced by TNF, a prototypic stimulator of the canonical NF-κB signaling [31]. Surprisingly, disruption of the Hsp90/NIK interaction does not affect NIK binding to its downstream factors IKKα or p100 and subsequent recruitment of IKKα to p100, essential steps for p100 processing (Figures 2 and 6).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Hsp90 has been found to be involved in signaling complex assembly [31]. We thus also examined whether Hsp90 is required for the formation of NIK/IKKα/p100 complex, a step serving as a molecular switch for p100 processing [12,14].…”

Section: Hsp90 Is Dispensable For Nik-mediated Ikkα Recruitment To P100mentioning

confidence: 99%

Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

Qing

Yan

et al. 2007

Cell Res

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NF-κB-inducing kinase (NIK) is required for NF-κB activation based on the processing of NF-κB2 p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein (Hsp90) and autophagy. Functional inhibition of Hsp90 by the anti-tumor agent geldanamycin (GA) efficiently disrupts its interaction with NIK, resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of the α subunit of IκB kinase to p100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function of autophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.

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TNF-Induced Recruitment and Activation of the IKK Complex Require Cdc37 and Hsp90

Cited by 374 publications

References 45 publications

The activity of hsp90α promoter is regulated by NF-κB transcription factors

The activity of hsp90α promoter is regulated by NF-κB transcription factors

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

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