Radiation-induced cell signaling: inside-out and outside-in

Valerie, Kristoffer; Yacoub, Adly; Hagan, Michael P.; Curiel, David T.; Fisher, Paul B.; Grant, Steven; Dent, Paul

doi:10.1158/1535-7163.mct-06-0596

Cited by 286 publications

(247 citation statements)

References 149 publications

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“…A concept of a nuclear-to-cytoplasmic signaling pathway was postulated to explain, such a signaling mechanism by Stein et al in 1989 [39]. However, dissection of NF-κB activation pathways induced by genotoxic agents is complicated by the co-induction of different types of DNA damages as well as other cell stresses, including oxidative stress in different cellular compartments (e.g., [40][41][42][43][44][45], Figure 1). Thus, unlike NF-κB signaling induced by cell surface receptors where the signal initiation event can be precisely defined, the necessary and sufficient signal initiation event induced by various genotoxic agents is still being addressed in the literature.…”

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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Section: A Signal Transduction Paradoxmentioning

confidence: 99%

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

2010

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“…The net balance of signaling by the cytoprotective ERK1/2 pathway and the stress-related JNK1/2 and p38 MAP kinase pathways has been suggested to determine whether cells survive or undergo apoptotic cell death on exposure to various insults [21].…”

Section: The Combination Of An Erk Pathway Inhibitor and A Low Concenmentioning

confidence: 99%

Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells

Tanimura

Uchiyama

Watanabe

et al. 2009

Biochemical and Biophysical Research Communications

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The extracellular signal-regulated kinase (ERK) signaling pathway is constitutively activated in many human tumor cell types. Given the cytoprotective role of this pathway, we examined whether its specific blockade might sensitize human tumor cells to the induction of apoptosis by various anticancer drugs. Although blockade of ERK signaling alone did not induce substantial cell death, it resulted in marked and selective enhancement of the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the ERK pathway is constitutively activated. The synergistic activation of c-Jun NH 2 -terminal kinase by the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent appeared to be responsible, at least in part, for this effect.These results suggest that administration of the combination of an ERK pathway inhibitor and a microtubule-destabilizing agent is a potential chemotherapeutic strategy for the treatment of tumor cells with constitutive activation of the ERK pathway.

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“…Radiation induces a myriad of cellular responses, including genotoxic stress signaling, cell cycle arrest, activation of a complex DNA repair machinery, and metabolic changes (Valerie, et al, 2007;Jeggo and Löbrich 2006;Spitz et al, 2004). ATM, or ataxia-telangiectasia mutated was first identified in AT patients in 1995 (Savitsky et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data

Hu¹,

Huang²,

Cheema³

et al. 2008

J Proteomics Bioinform

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Functional analysis and interpretation of large-scale proteomics and gene expression data require effective use of bioinformatics tools and public knowledge resources coupled with expert-guided examination. An integrated bioinformatics approach was used to analyze cellular pathways in response to ionizing radiation. ATM, or ataxia-telangiectasia mutated , a serine-threonine protein kinase, plays critical roles in radiation responses, including cell cycle arrest and DNA repair. We analyzed radiation responsive pathways based on 2D-gel/MS proteomics and microarray gene expression data from fibroblasts expressing wild type or mutant ATM gene. The analysis showed that metabolism was significantly affected by radiation in an ATM dependent manner. In particular, purine metabolic pathways were differentially changed in the two cell lines. The expression of ribonucleoside-diphosphate reductase subunit M2 (RRM2) was increased in ATM-wild type cells at both mRNA and protein levels, but no changes were detected in ATM-mutated cells. Increased expression of p53 was observed 30min after irradiation of the ATM-wild type cells. These results suggest that RRM2 is a downstream target of the ATM-p53 pathway that mediates radiation-induced DNA repair. We demonstrated that the integrated bioinformatics approach facilitated pathway analysis, hypothesis generation and target gene/protein identification.

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Radiation-induced cell signaling: inside-out and outside-in

Cited by 286 publications

References 149 publications

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

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

Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells

Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data

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