ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome

Schneider, Jochen G.; Finck, Brian N.; Ren, Jie; Standley, Kara N.; Takagi, Motoki; Maclean, Kirsteen H.; Bernal‐Mizrachi, Carlos; Muslin, Anthony J.; Kastan, Michael B.; Semenkovich, Clay F.

doi:10.1016/j.cmet.2006.10.002

Cited by 219 publications

(235 citation statements)

References 59 publications

(65 reference statements)

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“…ATM, the gene mutated in the cancer-prone human disease ataxiatelangiectasia (AT), is a protein kinase that serves as a critical mediator of signaling pathways that facilitate the response of mammalian cells to ionizing radiation (IR) and other agents that induce DNA double-strand breaks (4). Recently, however, ataxiatelangiectasia mutated (ATM) has been implicated in metabolic pathways unrelated to DNA damage (5).…”

mentioning

confidence: 99%

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Alexander

Cai

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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644

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Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm -deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.

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mentioning

confidence: 99%

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Alexander

Cai

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

644

562

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“…On the other hand, diets that are rich in antioxidant components may prevent oxidative DNA lesions and the development of senescent adipocytes, which may prevent the development of obesity and the metabolic syndrome in response to proinflammatory diets and environmental toxins. These findings, together with other DNA repair enzyme-defective mouse models (3,4,(6)(7)(8), suggest that reduction of genome integrity, regardless of whether it is induced by defective DNA repair or exogenous agents, contributes causatively to the development of the metabolic syndrome. Given that most people become overweight or moderately obese with age rather than severely obese (48), the mechanistic relationship between loss of genome integrity and development of the metabolic syndrome with age needs to be further studied.…”

Section: Impact Of Pol η On Cellular Senescence and Adipogenesis Usingmentioning

confidence: 94%

“…In addition, defective DNA repair enzymes are associated with the metabolic symptom; for example, DNA glycosylase (Neil1)-and OGG1-deficient mice are obese (3)(4)(5), and nucleotide excision repair protein ERCC1-XPF deficiency causes lipodystrophy (6). Furthermore, DNA damage response protein ataxia telangiectasia mutated (ATM) suppresses JNK activity through p53 signaling and mediates an antioxidant action that has been suggested to be relevant to the metabolic syndrome (7). Nucleotide excision repair XP-A protein may affect metabolism by altering mitochondrial function (8).…”

mentioning

confidence: 99%

Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

Chen

Harris

Hatahet

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Obesity and the metabolic syndrome have evolved to be major health issues throughout the world. Whether loss of genome integrity contributes to this epidemic is an open question. DNA polymerase η (pol η), encoded by the xeroderma pigmentosum (XP-V) gene, plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage. Herein, we demonstrate that pol η deficiency in mice (pol η −/− ) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. In comparison to WT mice, adipose tissue from pol η −/− mice exhibits increased DNA damage and a greater DNA damage response, indicated by upregulation and/or phosphorylation of ataxia telangiectasia mutated (ATM), phosphorylated H 2 AX (γH 2 AX), and poly[ADP-ribose] polymerase 1 (PARP-1). Concomitantly, increased cellular senescence in the adipose tissue from pol η −/− mice was observed and measured by up-regulation of senescence markers, including p53, p16 Ink4a , p21, senescence-associated (SA) β-gal activity, and SA secretion of proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) as early as 4 wk of age. Treatment of pol η −/− mice with a p53 inhibitor, pifithrin-α, reduced adipocyte senescence and attenuated the metabolic abnormalities. Furthermore, elevation of adipocyte DNA damage with a high-fat diet or sodium arsenite exacerbated adipocyte senescence and metabolic abnormalities in pol η −/− mice. In contrast, reduction of adipose DNA damage with N-acetylcysteine or metformin ameliorated cellular senescence and metabolic abnormalities. These studies indicate that elevated DNA damage is a root cause of adipocyte senescence, which plays a determining role in the development of obesity and insulin resistance.T he human genome is constantly challenged by exogenous and endogenous DNA damaging agents. To ensure genome integrity, human cells have faithful DNA replication machinery and DNA repair systems that are coordinated by DNA damage response networks. In response to different extents or types of DNA lesions, the DNA damage response activates appropriate cellular responses, including transient or permanent (senescence) cell cycle arrest, or apoptosis, to minimize the detrimental effects of DNA lesions (1). Reduction or deficiency in DNA repair/replication enzyme activity is well documented to increase vulnerability for the development of cancer, neurodegenerative diseases, and aging (2). In addition, defective DNA repair enzymes are associated with the metabolic symptom; for example, DNA glycosylase (Neil1)-and OGG1-deficient mice are obese (3-5), and nucleotide excision repair protein ERCC1-XPF deficiency causes lipodystrophy (6). Furthermore, DNA damage response protein ataxia telangiectasia mutated (ATM) suppresses JNK activity through p53 signaling and mediates an antioxidant action that has been suggested to be relevant to the metabolic syndrome (7). Nucleotide excision repair XP-A protein may affect metabolism by altering mitochondrial...

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“…Interestingly, recent studies suggested that human ATM regulates mTORC1 pathway either positively or negatively depending on the presence or absence of stresses 44,45,[50][51][52] . Given that TCTP makes a complex with ATM and functions in both nucleus and cytoplasm, it could be possible that TCTP and ATM might share a function for modulating mTORC1 pathway.…”

Section: Identification Of Datm As a Direct Binding Partner For Dtctpmentioning

confidence: 99%

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

Hong

Choi

2013

Nat Commun

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Translationally controlled tumour protein (TCTP) is implicated in growth regulation and cancer. Recently, human TCTP has been suggested to play a role in the DNA damage response by forming a complex with ataxia telangiectasia-mutated (ATM) kinase . However, the exact nature of this interaction and its roles in vivo remained unclear. Here, we utilize Drosophila as an animal model to study the nuclear function of Drosophila TCTP (dTCTP). dTCTP mutants show increased radiation sensitivity during development as well as strong genetic interaction with dATM mutations, resulting in severe defects in developmental timing, organ size and chromosome stability. We identify Drosophila ATM (dATM) as a direct binding partner of dTCTP and describe a mechanistic basis for dATM activation by dTCTP. Altogether, this study provides the first in vivo evidence for direct modulation of dATM activity by dTCTP in the control of genome stability and organ development.

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ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome

Cited by 219 publications

References 59 publications

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster

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