A new role for ATM

Valentin-Vega, Yasmine A.; Kastan, Michael B.

doi:10.4161/auto.19693

Cited by 81 publications

(40 citation statements)

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“…Interestingly, at least some of these effects take place in the cytoplasm, indicating a non-nuclear function of ATM in regulating metabolism. Furthermore, a similar role in metabolism was shown in the yeast Aspergillus nidulans 46, and ATM also localizes to mitochondria affecting mitophagy47. Together, these reports indicate an evolutionary conserved function of ATM in regulating metabolic homeostasis.…”

Section: Discussionsupporting

confidence: 63%

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

et al. 2016

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Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.

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Section: Discussionsupporting

confidence: 63%

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

et al. 2016

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“…It is also possible that autophagy protects against severe sepsis because its activation increases the degradation of pro-inflammatory mediators with an important role in sepsis, like HMGB1 (Li et al, 2011). In addition, increased effective autophagy can be beneficial in sepsis due to its critical role in the removal of damaged mitochondria in an ATM-dependent manner(Valentin-Vega and Kastan, 2012). The molecular mechanisms at the basis of epirubicin-induced protection in sepsis by autophagy are certainly an interesting topic for future studies.…”

Section: Discussionmentioning

confidence: 99%

Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis

et al. 2013

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Summary Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fancony Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.

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“…In fact, an exciting breakthrough in the biology of ATM was the realization that it not only responds to nuclear DNA damage, but also is redox sensitive (e.g., dimerizes in response to oxidization) and signals differently in response to oxidative stress versus double-strand breaks 2425. Furthermore, we and others have described mitochondrial defects in A-T patient cells and mouse models of the disease 26272829, with reducing mtROS having some beneficial effects on the pathology observed in the latter 30. An intriguing possibility is that in the absence of the ROS-sensing function of ATM, mtROS production is not kept in check and this leads to the well-documented oxidative stress in A-T 31.…”

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confidence: 99%

Live longer on MARS: a yeast paradigm of mitochondrial adaptive ROS signaling in aging

Shadel

2014

MIC

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Adaptive responses to stress, including hormesis, have been implicated in longevity, but their mechanisms and outcomes are not fully understood. Here, I briefly summarize a longevity mechanism elucidated in the budding yeast chronological lifespan model by which Mitochondrial Adaptive ROS Signaling (MARS) promotes beneficial epigenetic and metabolic remodeling. The potential relevance of MARS to the human disease Ataxia-Telangiectasia and as a potential anti-aging target is discussed.

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A new role for ATM

Cited by 81 publications

References 0 publications

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis

Live longer on MARS: a yeast paradigm of mitochondrial adaptive ROS signaling in aging

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