The ATM protein kinase: regulating the cellular response to genotoxic stress, and more

Shiloh, Yosef; Ziv, Yael

doi:10.1038/nrm3546

Cited by 1,354 publications

(1,385 citation statements)

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“…This notion is in keeping with the growing recognition that a number of cancers are directly or indirectly associated with history of infection 60 . Pharmacologic targeting of DNA-damage-responses regulated by the Ser/Thr protein kinase ataxia telangiectasia-mutated (ATM) 61 provides a robust protective response against severe sepsis elicited by polymicrobial infection in mice 62 (Fig. 4).…”

Section: Expression Of Xbp1 Also Protects Caenorhabditis Elegans Agmentioning

confidence: 99%

“…DNA damage. DNA double strand breaks, one of the most deleterious forms of DNA damage, are sensed by the Mre11/Rad50/Nbs1 complex, which activates ATM, a master regulator of the double stranded DNA damageresponse 61 . Under homeostasis ATM exists essentially as a homodimer, dissociating into active monomers in response to DNA double strand breaks 61 .…”

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

“…DNA double strand breaks, one of the most deleterious forms of DNA damage, are sensed by the Mre11/Rad50/Nbs1 complex, which activates ATM, a master regulator of the double stranded DNA damageresponse 61 . Under homeostasis ATM exists essentially as a homodimer, dissociating into active monomers in response to DNA double strand breaks 61 . ATM orchestrates an adaptive cellular response involving substrate proteins that regulate cell cycle progression, metabolic adaptation or programmed cell death 61 .…”

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

“…Under homeostasis ATM exists essentially as a homodimer, dissociating into active monomers in response to DNA double strand breaks 61 . ATM orchestrates an adaptive cellular response involving substrate proteins that regulate cell cycle progression, metabolic adaptation or programmed cell death 61 . Autophagy relies on the cellular vesicular system initiated by a process of nucleation of damaged organelles, elongation and maturation leading to lysosome (Lys) fusion, and allowing for degradation and recycling of their components 68 .…”

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

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Tissue damage control in disease tolerance

Soares

Gozzelino

Weis

2014

Trends in Immunology

153

174

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The deposited article is a prost-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article, and it hasn't any supplementary materials associated.Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, SFRH/BPD/44256/2008); European Commission 7th Framework grant: (ERC-2011-AdG. 294709-DAMAGECONTROL); Deutsche Forschungsgemeinschaft grant: (DFG WE 4971/3-1).info:eu-repo/semantics/publishedVersio

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Section: Expression Of Xbp1 Also Protects Caenorhabditis Elegans Agmentioning

confidence: 99%

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

Section: Unfolded Protein Response (Upr) Accumulation Of Misfolded Pmentioning

confidence: 99%

See 2 more Smart Citations

Tissue damage control in disease tolerance

Soares

Gozzelino

Weis

2014

Trends in Immunology

153

174

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“…Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. [1][2][3] Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.…”

mentioning

confidence: 99%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. Throughout their lives, organisms are exposed to a wide range of harmful substances. These compounds, often referred to as xenobiotics, may enter the body through direct contact, inhalation or ingestion, and can originate from many sources including pharmaceuticals, pesticides, plant toxins and pollutants. The ubiquitous and varied nature of xenobiotic pressure is reflected in the complexity of conserved cellular defense mechanisms that respond to these chemical compounds, and metazoans have thus developed a range of pathways that activate survival responses or trigger programmed cell death to eliminate damaged cells. 1 Xenobiotic pathways control the expression and activation of heat shock proteins, oxidative stress components, DNA repair enzymes, hypoxia response factors and several groups of xenobiotic-metabolizing enzymes. In eukaryotes, environmental challenges that activate stress response programs are relayed through a complex signaling cascade. Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. 1-3 Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.We performed a quantitative cell-culture RNA interference (RNAi) assay of Drosophila kinases and phosphatases to identify key regulators of stress response pathways that reac...

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Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

et al. 2020

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Increasing evidence suggests that interference with growth factor receptor tyrosine kinase (RTK) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA-damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity-based phosphoproteomic discovery survey, we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using invivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene-driven proliferation and genomic stability.Abbreviations ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; CDK, cell cycle-dependent kinase; CHEK1, checkpoint kinase 1; CHEK2, checkpoint kinase 2; DDA, DNA-damaging agent; DDR, DNA damage response; DNA-PKcs, catalytic subunit of the DNA-dependent protein kinase

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The ATM protein kinase: regulating the cellular response to genotoxic stress, and more

Cited by 1,354 publications

References 197 publications

Tissue damage control in disease tolerance

Tissue damage control in disease tolerance

The Hippo pathway promotes cell survival in response to chemical stress

Deciphering MET‐dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics

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