A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB

Lee, Su‐Jae; Dimtchev, Alexandre; Lavin, Martin F.; Dritschilo, Anatoly; Jung, Mira

doi:10.1038/sj.onc.1202088

Cited by 126 publications

(79 citation statements)

References 19 publications

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“…IkBSR expression in LNCaP cells also blocked the increase in ceramide levels after cells were exposed to TNF-a and irradiation, suggesting that NF-kB activity was necessary for the response to irradiation (Figure 7a). 32,41,42 Increasing ceramide levels by treating LNCaP(IkBSR) cells with bacterial sphingomyelinase was still able to activate cell death, but to a (Figure 7b). 25 Interruption of the intrinsic apoptosis pathway in LNCa-P(IkBSR) cells was further elucidated by analysis of mitochondrial membrane depolarization (DC m ).…”

Section: Attenuation Of the Intrinsic Pathway Interferes With The Effmentioning

confidence: 99%

Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells

et al. 2003

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The sphingomyelin metabolites ceramide and sphingosine are mediators of cell death induced by c-irradiation. We studied the production of ceramide and the effects of exogenous ceramide on apoptosis in LNCaP prostate cancer cells that are highly resistant to c-irradiation-induced cell death. LNCaP cells can be sensitized to c-irradiation by tumor necrosis factor a (TNF-a) and, to a lesser degree, by the agonistic FAS antibody CH-11. TNF-a activated intrinsic and extrinsic apoptosis pathways and increased ceramide and sphingosine levels in irradiated LNCaP cells. CH-11 activated only the extrinsic apoptosis pathways and had a negligible effect on ceramide and sphingosine levels in irradiated LNCaP cells. Exogenous ceramide and bacterial sphingomyelinase sensitized LNCaP cells to radiation-induced apoptosis and had a synergistic effect on cell death after irradiation with TNF-a, but not with CH-11. Cell death effects after exposure to ceramide and irradiation were blocked by the serine protease inhibitor TLCK (Na-p-tosyl-L-lysinechloromethylketone), but not by the caspase inhibitor z-VAD (2-val-Ala-Asp(oMe)-CH 2 F). During LNCaP cell apoptosis induced by exogenous ceramide, we observed activation of caspase-9, but not caspases-8, -3, or -7. The effect of ceramide occurred largely via the intrinsic mitochondrial apoptosis pathway and enhanced TNF-a, but not CH-11 effects on irradiated cells. The data show that ceramide enhanced activation of the intrinsic apoptotic pathway and enhanced cell death induced by TNF-a with or without cirradiation. TNF-a and c-irradiation elevated levels of endogenous ceramide and activated the intrinsic cell death pathway.

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Section: Attenuation Of the Intrinsic Pathway Interferes With The Effmentioning

confidence: 99%

Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells

et al. 2003

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“…First, IKK and NF-κB activation by ionizing radiation (IR), topoisomerase (TOP) II-targeting drugs, VP16 (etoposide) and doxorubicin/adriamycin, and a TOP I-targeting drug camptothecin (CPT) in a variety of cell lines also requires the nuclear DSB-responsive ATM kinase activity [49,[50][51][52][53][54]. Second, cyotoplasts resulting from enucleation (physical removal of nucleus from a cell) fail to release NF-κB from IκBα on CPT treatment, but NF-κB can be released by TNFα, thus, demonstrating the essential requirement of intact nucleus for CPT signaling [55].…”

Section: A Signal Transduction Paradoxmentioning

confidence: 99%

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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“…A functional ATM is required for the degradation of IkB-a and subsequent activation of NF-kB following exposure to IR, radiomimetic drugs and topoisomerase inhibitors, but not TNF-a (Lee et al, 1998b;Piret et al, 1999). The pathway leading from ATM to IkB-a degradation is not known, but it should involve the transduction of a signal generated in the nucleus to the IKK complex in the cytoplasm.…”

Section: Induction Of Nf-kbmentioning

confidence: 99%

ATM: A mediator of multiple responses to genotoxic stress

1999

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The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxiatelangiectasia. ATM-de®cient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modi®cations induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identi®cation of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the e cient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.

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A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB

Cited by 126 publications

References 19 publications

Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells

Role of ceramide in mediating apoptosis of irradiated LNCaP prostate cancer cells

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

ATM: A mediator of multiple responses to genotoxic stress

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