NF-κB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage

Wuerzberger-Davis, Shelly M.; Nakamura, Yasuko; Seufzer, Bradley J.; Miyamoto, Shigeki

doi:10.1038/sj.onc.1209815

Cited by 75 publications

(53 citation statements)

References 64 publications

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“…Genotoxic insults causing DNA DSBs induce SUMOylation of NEMO resident in the nucleus, blocking its export. Concomitantly, activated ATM allows removal of SUMO residues from NEMO, permitting NEMO ubiquitination (20,68). The ATM-ubiquitinated NEMO complex then migrates to the cytoplasm, where it activates the IKK complex, leading to RelA nuclear transport and culminating in the induction of NF-B-responsive genes.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Rosato

Kolla

Hock

et al. 2010

Journal of Biological Chemistry

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In accord with the recently described DNA damage/ATM/NEMO pathway, SUMOylation site mutant NEMO (K277A or K309A) cells exposed to LBH-589 displayed diminished ATM/NEMO association, NEMO and p65/RelA nuclear localization/activation, and MnSOD2 up-regulation. These events were accompanied by increased ROS production, ␥-H2AX formation, and cell death. Together, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-B pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-B activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity.Chromatin structure and gene expression are regulated by reversible acetylation of lysine residues in histone tails, a process comprising a component of the histone code (1). Histone acetylation is regulated reciprocally by histone deacetylases (HDACs) 2 and histone acetylase transferases (2). Histone deacetylase inhibitors, a group of structurally diverse compounds, have shown encouraging activity in certain hematopoietic malignancies, including cutaneous T-cell lymphoma and acute leukemia (3,4). Numerous mechanisms have been proposed to account for HDACI-mediated lethality, including oxidative damage, up-regulation of death receptors or proapoptotic proteins (e.g. Bim), down-regulation of anti-apoptotic proteins, and more recently, DNA damage induction and/or interference with DNA repair proteins (3,5,6).HDACIs also increase acetylation of various non-histone proteins including chaperone proteins (7), DNA repair proteins (e.g. Ku70) (8), and transcription factors, e.g. YY-1, E2F, and NF-B (9, 10). Of the latter, NF-B is a particularly important determinant of HDACI actions, particularly proliferation, differentiation, and cell death (11-13). NF-B consists of a family of proteins including p65/RelA, RelB, c-Rel, p105, p100, p52, and p50, which form homo-and heterodimers, of which p65/ p50 is the most abundant (14). Various cytokines (e.g. TNF␣, interleukin-1, and lipopolysaccharides) and environmental stresses trigger the classical NF-B pathway by activating the IKK complex, which consists of IKK␣, IKK␤, and IKK␥/NEMO (NF-B-essential modulator) (15). This leads to phosphorylation (Ser-32/Ser-36), ubiquitination, and proteasomal degradation of IB␣, resulting in p65 nuclear translocation, DNA binding, and activation of prosurvival genes, including . Other stimuli (e.g. CD-40 ligation, lymphotoxin-␤, and B-cell-activating factor (BAFF)) activate the alternative (noncanonical) NF-B pathway through a complex consisting of NF-B-inducing kinase (NIK) and IKK␣ but not IKK␤ (16). A third, atypical, UV light-associated pathway activates p65 via p38 mitogen-activated protein kinase (MAPK) and CSII * This work was supported, in whole or in part, by National Institutes of Health Grants CA63753, CA93738, and CA100866 from the National Cancer Institute, the Leukemia and Lymphoma Society of America, and Lymphoma SPORE Award 1P50 CA130805. This work was al...

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Rosato

Kolla

Hock

et al. 2010

Journal of Biological Chemistry

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“…The authors found that LBH-589 causes nuclear localization of NEMO and promotes its interaction with ATM in an oxidative stress-dependent manner. Oxidative stress can activate ATM [84] and cause SUMOylation of NEMO [57]. NF-κB activation by LBH-589 is inhibited in cells expressing SUMOylation-defective NEMO-DK (K277A/ K309A) mutant [83].…”

Section: Atm-nemo Signaling In Oxidative Stressmentioning

confidence: 99%

“…For example, activation of NF-κB as measured by electrophoretic mobility shift assay by DSB inducers is readily detectable in various cell lines, such as HEK293 embryonic kidney fibroblasts, HeLa cervical cancer, U2OS osteosarcoma, CEM T leukemic and 70Z/3 pre-B leukemic cells, among others [52,55,57,60,64,66,68]. In contrast, NF-κB activation by VP16 or IR in primary MEFs and MEF lines, or many human normal cell types, is frequently undetectable or only weakly detected even at relatively high doses, despite efficient ATM activation [11,55,59,64,68].…”

Section: Additional Nf-κb Signaling By Genotoxic Agentsmentioning

confidence: 99%

“…NEMO modifications in genotoxic stress signaling ATM activation is a frequently necessary, but insufficient intermediate event leading to NF-κB activation (e.g, [52,57]). An insight into the presence of a parallel signaling event that collaborates with ATM in NF-κB signaling in response to genotoxic agents came from the analysis of the NEMO-deficient 1.3E2 mouse pre-B cell line that fails to activate NF-κB by canonical inducers.…”

Section: A Signal Transduction Paradoxmentioning

confidence: 99%

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Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

2010

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A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxinexposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

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“…The reactions were terminated with a solution containing EDTA, sodium dodecyl sulfate (SDS) and bromophenol blue, and the samples were run on a non-denaturing 6% polyacrylamide gel and imaged by autoradiography (Byun et al, 2002;Wuerzberger-Davis et al, 2007).…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

β-Lapachone suppresses radiation-induced activation of nuclear factor-κB

Dong

Lee

et al. 2010

Exp Mol Med

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Anticancer effects of β-lapachone (β-lap) are due to generation of ROS and metabolic catastrophes as a result of NAD(P)H:quinone oxidoreductase (NQO1)-mediated futile cycling between the oxidized and reduced forms of β-lap. It has been shown that NQO1 is also essential for the TNF-induced activation of NF-κB and that β-lap suppresses the TNF-induced NF-κB activation. We investigated whether or not NQO1 is involved and β-lap suppresses the radiation-induced NF-κB activation using A549 human lung cancer cells and NQO1-knock down A549 cells (shNQO1 A549 cells). Irradiation with 4 Gy markedly increased the DNA binding activity of NF-κB in A549 cells, but not in the shNQO1 A549 cells, thus demonstrating that NQO1 plays a pivotal role in irradiation-induced NF-κB activation. Treatment with 10 μM β-lap for 4 h almost completely abrogated the radiation-induced increase in NF-κB activation and the transcription of NF-κB target genes such as bcl2, gadd45β and cyclinD1. Moreover, β-lap markedly suppressed the activation of IκB kinase γ (IKKγ) and the subsequent phosphorylation of IκBα, thereby inhibiting NF-κB activation. It is concluded that β-lap suppresses the radiation-induced activation of NF-κB by interrupting the involvement of NQO1 in the activation of NF-κB, thereby inhibiting the transcription of survival signals. The radiosensitization caused by β-lap may, in part, be attributed to β-lap-induced suppression of NF-κB activation.

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NF-κB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage

Cited by 75 publications

References 64 publications

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

β-Lapachone suppresses radiation-induced activation of nuclear factor-κB

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