TAK1 is Critical for IκB Kinase-mediated Activation of the NF-κB Pathway

Takaesu, Giichi; Surabhi, Rama Mohan; Park, Kyu-Jin; Ninomiya‐Tsuji, Jun; Matsumoto, Kunihiro; Gaynor, Richard B.

doi:10.1016/s0022-2836(02)01404-3

Cited by 357 publications

(294 citation statements)

References 48 publications

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“…Numerous kinases have been linked with the activation of IKK. Accumulating evidence suggests that the well-characterized MAP3K family member TAK1 is the central IKK kinase induced by several stimuli (31)(32)(33). Here, we found that minocycline inhibits TAK1 phosphorylation.…”

Section: Discussionmentioning

confidence: 53%

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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Substantial evidence supports the critical role of NF-kB in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-kB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IkBa kinase (IKK) activation, IkBa phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-b-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-b and TAK1. Further studies demonstrated that minocycline downregulated TGF-b1 expression. Enforced TGF-b1 expression induced NF-kB activity, and minocycline rescued this effect. Consistent with this finding, TGF-b1 knockdown suppressed NF-kB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kB activity is mediated, in part, through inhibition of TGF-b1. Furthermore, the influence of minocycline on NF-kB pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-kB activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-b-NF-kB axis in ovarian cancer.

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Section: Discussionmentioning

confidence: 53%

RETRACTED: Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer

Ataie-Kachoie

Badar

Morris

et al. 2013

Molecular Cancer Research

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“…To examine a requirement for the kinase activity of TAK1, we pretreated cells with vehicle or with 5Z7, a potent and highly selective inhibitor of TAK1 (Bioaustralis) (18,23,26). The cells were left untreated or exposed to the proinflammatory cytokine TNF-␣ for 10 min or to doxorubicin for the time periods indicated in Fig.…”

Section: Resultsmentioning

confidence: 99%

A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage

Yang

Xia

Hermance

et al. 2011

Molecular and Cellular Biology

123

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In multiple tumor types, activation of the transcription factor NF-B increases the resistance of tumor cells to anticancer therapies and contributes to tumor progression. Genotoxic stress induced by chemotherapy or radiation therapy triggers the ATM-dependent translocation of NF-B essential modifier (NEMO), also designated I B kinase ␥ (IKK␥), from the nucleus to the cytosol, resulting in I B kinase activation by mechanisms not yet fully understood. RIP1 has been implicated in this response and found to be modified in cells with damaged DNA; however, the nature of the RIP1 modification and its precise role in the pathway remain unclear. Here, we show that DNA damage stimulates the formation of a cytosolic complex containing ATM, NEMO (IKK␥), RIP1, and TAK1. We find that RIP1 is modified by SUMO-1 and ubiquitin in response to DNA damage and demonstrate that modified RIP1 is required for NF-B activation and tumor cell survival. We show that ATM activates TAK1 in a manner dependent on RIP1 and NEMO. We also reveal TAK1 as a central mediator of the alternative DNA damage response pathway mediated by the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 (MAPKAP-2) kinases. These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance.The DNA damage response activates cell cycle checkpoint and survival pathways that function to prevent DNA replication until damaged DNA is repaired. These pathways include the well-characterized ATM (ataxia telangiectasia mutated)/ CHK2 and ATR (ataxia telangiectasia and Rad-3 related)/ CHK1 pathways and the more recently identified ATM/ ATR/p38 mitogen-activated protein kinase (MAPK)/MAPKactivated protein 2 (MAPKAP-2; hereinafter called MK2) checkpoint that is active in p53-deficient tumor cells (15,19). The transcription factor NF-B regulates apoptosis induced by genotoxic stress and is an attractive therapeutic target in tumor cells whose response to DNA-damaging agents is impaired due to compromised p53 function. Moreover, constitutive NF-B activity is a hallmark of several cancers, and mutations in NF-B pathway components have been associated with the activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), breast cancer, and multiple myeloma (3, 6). Thus, the inclusion of NF-B inhibitors in cancer therapy could have antioncogenic activities as well as augment the tumor chemotherapeutic response.NF-B is normally held in the cytoplasm in an inactive form bound to inhibitor proteins, such as I B␣. Diverse stimuli, such as infection, proinflammatory cytokine production, or treatment with agents that induce DNA damage elicit NF-B-mediated transcriptional activity by activating the cytosolic I B kinase (IKK) complex, consisting of IKK␣ and IKK␤ and a regulatory subunit designated IKK␥ or NF-B essential modifier (NEMO) (hereinafter referred to as NEMO). IKK activation results in I B␣ phosphorylation, ubiquitination, and subsequent degradation. The NF-B (p65/p50) heterodimer is then free to en...

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“…Signaling downstream of RIP1 requires TAK1 for the activation of IKK Shim et al, 2005). Whether TAK1 directly activates IKK or this process proceeds through an intermediary such as MEKK3 is not yet clear (Takaesu et al, 2003;Li et al, 2006). However, it does not appear that TAK1 is involved in the activation of the non-canonical NF-kB pathway .…”

Section: Tnf-r Superfamily Signalingmentioning

confidence: 99%