A High Dose of Ionizing Radiation Induces Tissue-Specific Activation of Nuclear Factor-κB In Vivo

Zhou, Daohong; Brown, Stephen; Yu, Tao; Chen, Gang; Barve, Shirish; Kang, Bann C.; Thompson, John S.

doi:10.2307/3580209

Cited by 71 publications

(51 citation statements)

References 23 publications

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“…Our findings are consistent with reports that IR-induced NF-κB pro-survival signaling is prominent in radiosensitive tissues and is required for induction of anti-apoptotic Bcl-2 proteins. [35][36][37] But to our knowledge, this study is the first to uncover the mechanism that promotes this IR-induced cytoprotective pathway in vivo. Together with our report that PACS-2 mediates the p53-dependent induction of p21, these findings suggest PACS-2 coordinates p53/p21-dependent cell cycle arrest with NF-κB/Bcl-xL-dependent pro-survival signaling to support DNA repair in response to genotoxic damage.…”

Section: Discussionmentioning

confidence: 91%

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: 91%

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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“…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]. Most normal tissues in mice, except for the bone marrow, spleen, lymph nodes and intestine, also do not activate NF-κB in response to 8.5 Gy of whole body radiation [109,110]. Activation of IKK and NF-κB may be achieved in kidney and lung tissues after a relatively high dose (20 Gy) of radiation [49].…”

Section: Additional Nf-κb Signaling By Genotoxic Agentsmentioning

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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“…Cytosolic and mitochondrial samples for glutathione measurement were precipitated with 10% trichloroacetic acid, centrifuged, and stored at Ϫ80°C. Preparation of nuclear extracts was adapted from the method described by Zhou et al 26 The cytosolic contamination of nuclear extracts, checked by the expression of the ␤-actin protein, was found to be nil.…”

Section: Methodsmentioning

confidence: 99%

Alcohol increases tumor necrosis factor α and decreases nuclear factor-κb to activate hepatic apoptosis in genetically obese mice

Robin¹,

Demeilliers²,

Sutton³

et al. 2005

Hepatology

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Both obesity and alcohol can cause oxidative stress, cytokine induction, and steatohepatitis. To determine the consequences of their combination, we compared the hepatic effects of moderate ethanol binges in lean and obese ob/ob mice. Mice received water or ethanol (2.5 g/kg) by gastric intubation daily for 4 days, and were killed 2 hours after the last administration. Some obese mice also received pentoxifylline, an inhibitor of tumor necrosis factor-␣ (TNF-␣) production, before each ethanol administration. In lean mice, these moderate ethanol doses did not increase plasma TNF-␣ and hepatic caspase-3 activity, but triggered some apoptotic hepatocytes. Naive ob/ob mice had a few necrotic and apoptotic hepatocytes, but exhibited little oxidative stress, possibly because of adaptive increases in manganese superoxide dismutase, heat shock protein 70 (Hsp70), mitochondrial cytochrome c, and mitochondrial DNA. Alcohol administration to ob/ob mice did not increase oxidative stress despite increased CYP2E1, but increased plasma TNF-␣, further increased Hsp70, and profoundly decreased p65 nuclear factor B (NF-B) protein and DNA-binding activity in nuclear extracts. Caspase-3 was activated, and more apoptotic hepatocytes were found in intoxicated obese mice than naive obese mice. In intoxicated obese mice, pentoxifylline fully prevented the increase in plasma TNF-␣ the decrease in nuclear NF-B activity, and the increase in hepatic caspase-3, and it also decreased hepatic triglycerides. In conclusion, obese mice develop adaptations that may limit oxidative stress. Moderate ethanol intoxication does not increase oxidative stress in obese mice, but increases TNF-␣ and also decreases nuclear NF-B activity, thus unleashing the apoptotic effects of TNF-␣. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/ 0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:1280-1290

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A High Dose of Ionizing Radiation Induces Tissue-Specific Activation of Nuclear Factor-κB In Vivo

Cited by 71 publications

References 23 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

Alcohol increases tumor necrosis factor α and decreases nuclear factor-κb to activate hepatic apoptosis in genetically obese mice

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