Molecular Linkage Between the Kinase ATM and NF-κB Signaling in Response to Genotoxic Stimuli

Wu, Zhao-Hui; Shi, Yujun; Tibbetts, Randal S.; Miyamoto, Shigeki

doi:10.1126/science.1121513

Cited by 482 publications

(574 citation statements)

References 22 publications

Supporting

Mentioning

545

Contrasting

Unclassified

Order By: Relevance

“…This effect was accompanied by a reduction of IKK1/2 phosphorylation and an increase in IkBa expression (Figure 2d). These effects of ATMI and KU55933 on P39 cells were obtained after an incubation period as short as 1-2 h. We found that nuclei from P39 cells also contained, in addition to p65 (Figure 2e), the IKK subunit NEMO (Figure 2f) as well as PIDD (Figure 2g), which is two proteins that have previously been reported to interact with ATM (Huang et al, 2003;Habraken and Piette, 2006) and to shuttle between the nucleus and the cytoplasm (Janssens et al, 2005;Habraken and Piette, 2006;Wu et al, 2006). Of note, upon addition of either of the two ATMIs, p65, NEMO and PIDD moved from the nucleus to the cytoplasm (Figures 2e-h).…”

Section: Resultsmentioning

confidence: 53%

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

et al. 2008

View full text Add to dashboard Cite

The anti-apoptotic transcription factor nuclear factor-jB (NF-jB) is constitutively activated in CD34 þ myeloblasts from high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Inhibition of NF-jB by suppressing the canonical NF-jB activation pathway, for instance by knockdown of the three subunits of the inhibitor of NF-jB (IjB) kinase (IKK) complex (IKK1, IKK2 and NEMO) triggers apoptosis in such cells. Here, we show that an MDS/AML model cell line exhibits a constitutive interaction, within the nucleus, of activated, S1981-phosphorylated ataxia telangiectasia mutated (ATM) with NEMO. Inhibition of ATM with two distinct pharmacological inhibitors suppressed the activating autophosphorylation of ATM, blocked the interaction of ATM and NEMO, delocalized NEMO as well as another putative NF-jB activator, PIDD, from the nucleus, abolished the activating phosphorylation of the catalytic proteins of the IKK complex (IKK1/2 on serines 176/180), enhanced the expression of IjBa and caused the relocalization of NF-jB from the nucleus to the cytoplasm, followed by apoptosis. Knockdown of ATM with small-interfering RNAs had a similar effect that could not be enhanced by knockdown of NEMO, PIDD and the p65 NF-jB subunit, suggesting that an ATM inhibition/ depletion truly induced apoptosis through inhibition of the NF-jB system. Pharmacological inhibition of ATM also induced the nucleocytoplasmic relocalization of p65 in malignant myeloblasts purified from patients with highrisk MDS or AML, correlating with the induction of apoptosis. Altogether, these results support the contention that constitutively active ATM accounts for the activation of NF-jB in high-risk MDS and AML.

show abstract

Section: Resultsmentioning

confidence: 53%

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Furthermore, explorative network analysis identified AS genes involved in RNA post‐transcriptional modifications in direct relation with histone H3 and RNA polymerase II and the NF‐κB complex as a major upstream and central node. Interestingly, the IKK/NF‐κB signaling pathway has been proposed to be one of the key mediators of aging (Huang et al ., 2003; Wu et al ., 2006). …”

Section: Discussionmentioning

confidence: 99%

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

et al. 2015

View full text Add to dashboard Cite

SummaryAlternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome‐wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild‐type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3–3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson–Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild‐type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.

show abstract

“…In the nucleus, NEMO establishes a complex with p53-inducible protein with a death domain and receptor interacting protein 1, allowing NEMO sumoylation (Janssens and Tschopp, 2006). Then, sumo-NEMO is recognized and phosphorylated by ATM (Ataxia Telangiectasia Mutated), tagged by ubiquitination, which induces its release from ATM and its cytoplasmic translocation allowing NF-kB activation (Wu et al, 2006). Thus, NEMO provides a means to link nuclear DNA damage to the activation of the cytoplasmic IKK complex (Huang et al, 2003).…”

mentioning

confidence: 99%

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

et al. 2008

View full text Add to dashboard Cite

NF-kB interferes with the effect of most anti-cancer drugs through induction of anti-apoptotic genes. Targeting NF-kB is therefore expected to potentiate conventional treatments in adjuvant strategies. Here we used a pharmacological inhibitor of the IKK2 kinase (AS602868) to block NF-kB activation. In human colon cancer cells, inhibition of NF-kB using 10 mM AS602868 induced a 30 -50% growth inhibitory effect and strongly enhanced the action of SN-38, the topoisomerase I inhibitor and CPT-11 active metabolite. AS602868 also potentiated the cytotoxic effect of two other antineoplasic drugs: 5-fluorouracil and etoposide. In xenografts experiments, inhibition of NF-kB potentiated the antitumoural effect of CPT-11 in a dose-dependent manner. Eighty-five and 75% decreases in tumour size were observed when mice were treated with, respectively, 20 or 5 mg kg À1 AS602868 associated with 30 mg kg À1 CPT-11 compared to 47% with CPT-11 alone. Ex vivo tumour analyses as well as in vitro studies showed that AS602868 impaired CPT-11-induced NF-kB activation, and enhanced tumour cell cycle arrest and apoptosis. AS602868 also enhanced the apoptotic potential of TNFa on HT-29 cells. This study is the first demonstration that a pharmacological inhibitor of the IKK2 kinase can potentiate the therapeutic efficiency of antineoplasic drugs on solid tumours.

show abstract

Molecular Linkage Between the Kinase ATM and NF-κB Signaling in Response to Genotoxic Stimuli

Cited by 482 publications

References 22 publications

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

ATM mediates constitutive NF-κB activation in high-risk myelodysplastic syndrome and acute myeloid leukemia

Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Contact Info

Product

Resources

About