Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli

Berchtold, Craig M.; Wu, Zhao-Hui; Huang, Tony T.; Miyamoto, Shigeki

doi:10.1128/mcb.01772-06

Cited by 28 publications

(27 citation statements)

References 94 publications

(137 reference statements)

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“…Current models suggest that DNA damage increases nuclear export of ATM into the cytoplasm. 44,45 However, our determination that PACS-2 is required for redistribution of ATM to the cytoplasm and that cytoplasmic PACS-2 interacts with ATM suggests that Figure 6 Cytoplasmic PACS-2 mediates Bcl-xL reporter expression. HCT116 cells were transfected with a luciferase expression plasmid under the control of p21 or Bcl-xL promoter together with PACS-2 or PACS-2ΔNLS and the transcription factor p53 or p65.…”

Section: Discussionmentioning

confidence: 99%

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

et al. 2016

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Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2 − / − thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

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Section: Discussionmentioning

confidence: 99%

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

et al. 2016

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“…Hinz et al [70] recently provided evidence that ATM export to the cytoplasm (and to the plasma membrane) is a critical step in DSB-induced NF-κB activation, but is not dependent on NEMO in HepG2 and HeLa cells. Since leptomycin B, a potent inhibitor of the nuclear export receptor CRM1/exportin 1 [71], does not prevent the export of NEMO and IKK activation induced by genotoxic stimuli [52,72], the nuclear export of NEMO and ATM is probably CRM1 independent. Genetic evidence showed that RCC1 (Ran guanine nucleotide exchange factor) is required for NF-κB activation by CPT [72], suggesting that Ran-GTP is likely involved in the NEMO and ATM export step.…”

Section: Nuclear Export Of Nemo and Atmmentioning

confidence: 99%

“…Since leptomycin B, a potent inhibitor of the nuclear export receptor CRM1/exportin 1 [71], does not prevent the export of NEMO and IKK activation induced by genotoxic stimuli [52,72], the nuclear export of NEMO and ATM is probably CRM1 independent. Genetic evidence showed that RCC1 (Ran guanine nucleotide exchange factor) is required for NF-κB activation by CPT [72], suggesting that Ran-GTP is likely involved in the NEMO and ATM export step. Consistent with this idea, a complex between NEMO and Ran is transiently induced following VP16 treatment [72].…”

Section: Nuclear Export Of Nemo and Atmmentioning

confidence: 99%

“…Genetic evidence showed that RCC1 (Ran guanine nucleotide exchange factor) is required for NF-κB activation by CPT [72], suggesting that Ran-GTP is likely involved in the NEMO and ATM export step. Consistent with this idea, a complex between NEMO and Ran is transiently induced following VP16 treatment [72]. Identification of the nuclear export receptor(s) for ATM and NEMO will shed light on whether ATM export is NEMO-dependent in different cell systems and will also provide a crucial missing piece in the nuclear-to-cytoplasmic signaling puzzle.…”

Section: Nuclear Export Of Nemo and Atmmentioning

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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“…10,11 Thereafter, ATM phosphorylates NEMO, followed by its monoubquitinylation and export to the cytosol. [11][12][13][14] Inside the cytosol, NEMO activates IκB kinase β (IKKβ) 11,12 to phosphorylate inhibitors of κBs (IκBs), followed by their ubiquitinylation-mediated degradation. 15 Since NF-κB dimers are retained in the cytosol by binding to IκBs, degradation of the latter leads to release of NF-κB, enabling its entry into the nucleus to drive the transcription of dedicated target genes.…”

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confidence: 99%

Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

Poltz

Franke

Schweitzer

et al. 2009

AABC

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Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio-and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio-and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB).Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD), receptor-interacting protein 1 (RIP1), and protein inhibitor of activated STAT y (PIASy) as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio-and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.

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Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli

Cited by 28 publications

References 94 publications

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

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

Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

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