ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin

Yoshida, Kaori; Ozaki, Toshinori; Furuya, Kazushige; Nakanishi, M.; Kikuchi, Hiromi; Yamamoto, Hideki; Ono, Sayaka; Koda, Tadayuki; Omura, Ken; Nakagawara, Akira

doi:10.1038/sj.onc.1210722

Cited by 48 publications

(45 citation statements)

References 21 publications

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“…For example, checkpoint pathways involving ATM, ATR and p38 MAPK are operational on DNA damage and replicational stress (Reinhardt et al, 2007;Grallert and Boye, 2008). Although we could not detect a lack of ATM or CHK1 activation in HU-treated HCT-116 p53À cells, these kinases could regulate p53-dependent NF-kB actions, possibly collateral with RSK1 and MEK1 that govern the nuclear p53/p65 cross talk (Armstrong et al, 1995;Ryan et al, 2000;Bohuslav et al, 2004;Yoshida et al, 2008). Our data and a recent report (Kawauchi et al, 2008a) reveal physical interactions between p65 and p53, which may allow an IkB kinase a-dependent transit of CBP (Huang et al, 2007).…”

Section: Control Of Activated Nf-jb By P53mentioning

confidence: 51%

Cross talk between stimulated NF-κB and the tumor suppressor p53

et al. 2010

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Nuclear factor-jB (NF-jB) and p53 critically determine cancer development and progression. Defining the cross talk between these transcription factors can expand our knowledge on molecular mechanisms of tumorigenesis. Here, we show that induction of replicational stress activates NF-jB p65 and triggers its interaction with p53 in the nucleus. Experiments with knockout cells show that p65 and p53 are both required for enhanced NF-jB activity during S-phase checkpoint activation involving ataxiatelangiectasia mutated and checkpoint kinase-1. Accordingly, the pro-inflammatory cytokine tumor necrosis factora (TNF-a) also triggers formation of a transcriptionally active complex containing nuclear p65 and p53 on jB response elements. Gene expression analyses revealed that, independent of NF-jB activation in the cytosol, TNFinduced NF-jB-directed gene expression relies on p53. Hence, p53 is unexpectedly necessary for NF-jB-mediated gene expression induced by atypical and classical stimuli. Remarkably, data from gain-and loss-of function approaches argue that anti-apoptotic NF-jB p65 activity is constitutively evoked by a p53 hot-spot mutant frequently found in tumors. Our observations suggest explanations for the outstanding question why p53 mutations rather than p53 deletions arise in tumors of various origins.

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Section: Control Of Activated Nf-jb By P53mentioning

confidence: 51%

Cross talk between stimulated NF-κB and the tumor suppressor p53

et al. 2010

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“…It has been reported previously that HuR function is regulated by a series of DNA damage response kinases (33). As IKK␣ is also involved in mediating DNA damage response downstream of ataxia-telangiectasia mutated (34), this finding adds IKK␣ to the list of DNA damage response kinases involved in HuR regulation.…”

Section: Discussionmentioning

confidence: 66%

The mRNA-stabilizing Factor HuR Protein Is Targeted by β-TrCP Protein for Degradation in Response to Glycolysis Inhibition

Chu

Chuang

Kulp

et al. 2012

Journal of Biological Chemistry

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Background: HuR regulates expression of many oncogenic proteins by modulating mRNA stability. Results: Glycolysis inhibition facilitates HuR degradation through a novel ␤-TrCP-mediated mechanism. Conclusion: This mechanism underlies the complexity in the regulation of HuR turnover under different stress stimuli. Significance: The ability of glycolysis inhibitors to target expression of oncogenic proteins by promoting HuR degradation might foster novel strategies for cancer therapy.

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“…This process is critical for CDDP-induced apoptosis. [35][36][37][38] Moreover, IKK␣ inhibits squamous cell carcinogenesis by acting as a major cofactor in a transforming growth factor ␤-Smad2/3 signaling pathway that is Smad4 independent. 37,38 Unlike IKK␣, IKK is amplified/overexpressed in a number of breast cancers, and functions as an oncogene.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of IKBKE Is Associated with Tumor Progression, Poor Prognosis, and Cisplatin Resistance in Ovarian Cancer

Guo

Shu

et al. 2009

The American Journal of Pathology

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I-kappa-B kinase e (IKBKE; IKK) has been recently identified as a breast cancer oncogene, and its alteration appears to be an early event in breast cancer development. In this study, we demonstrated that IKK is frequently overexpressed and activated in human ovarian cancer cell lines and primary tumors. Of 96 ovarian cancer specimens examined, 63 exhibited elevated levels of IKK. Furthermore, alterations of IKK were associated with late-stage and highgrade tumors, suggesting a role of IKK in ovarian tumor progression rather than in tumor initiation. Overall survival in patients with elevated levels of IKK was significantly lower than patients whose tumors expressed normal levels of IKK. Moreover, both early and late-stage tumors that overexpressed IKK conferred a poor prognosis, as compared with those that did not possess elevated IKK levels. Notably, overexpression of IKK rendered cells resistant to cisplatin, whereas knockdown of IKK overcame cisplatin resistance in both A2780CP and C13 cells, which express high levels of endogenous IKK. Therefore, these data demonstrate for the first time that deregulation of IKK is a highly recurrent event in human ovarian cancer and could play a pivotal role in tumor progression and cisplatin resistance. IKK could also serve as a prognostic marker and potential therapeutic target for this malignancy. The I-kappa-B kinase (IKK), also named IKBKE/IKKi, is a serine/threonine protein kinase that belongs to the IKK family. The IKK protein has 33% and 31% identity at the amino acid level with IKK␣ and IKK␤, respectively, is primarily activated by interferon and mediates interferon signaling.1,2 The activated IKK stimulates the transcription factor interferon regulatory factors 3 and phosphorylates signal transducer and activator of transcription 1,3,4 IKK also shares some function with IKK␣ and IKK␤ to activate nuclear factor (NF)B pathway by phosphorylation and degradation of IB␣.5-7 However, IKK mainly mediates NFB activation induced by interferon, phorbol 12-myristate 13-acetate or the T-cell receptor, but not by tumor necrosis factor and interleukin 1, which activate IKK␣ and IKK␤.Previous studies have revealed an important role for IKK␣ and IKK␤ in tumorigenesis via regulation of various signal transduction pathways. 8 -11 Using complementary genetic approaches, Boehm and colleagues recently identified IKK as a breast cancer oncogene by dissecting the downstream pathways sufficient for RAS to induce neoplastic transformation. Although RAS can stimulate many pathways, such as the mitogen-activated protein kinase, phosphoinositide 3 kinase, and ral guanine nucleotide dissociation stimulator signaling pathways, a fullblown transformation phenotype of immortalized human cells could be acquired only by the simultaneous expression of constitutively activated mitogen-activated protein kinase kinase together with a myristoylated AKT. Further, by screening a myristoylated kinase expression library for kinases that act in the place of AKT in the RAS-AKT pathway to promote cellular tr...

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ATM-dependent nuclear accumulation of IKK-α plays an important role in the regulation of p73-mediated apoptosis in response to cisplatin

Cited by 48 publications

References 21 publications

Cross talk between stimulated NF-κB and the tumor suppressor p53

Cross talk between stimulated NF-κB and the tumor suppressor p53

The mRNA-stabilizing Factor HuR Protein Is Targeted by β-TrCP Protein for Degradation in Response to Glycolysis Inhibition

Deregulation of IKBKE Is Associated with Tumor Progression, Poor Prognosis, and Cisplatin Resistance in Ovarian Cancer

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