Role of ATM in Oxidative Stress-mediated c-Jun Phosphorylation in Response to Ionizing Radiation and CdCl2

Lee, Sung A.; Dritschilo, Anatoly; Jung, Mira

doi:10.1074/jbc.m004517200

Cited by 65 publications

(42 citation statements)

References 68 publications

(69 reference statements)

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“…Following this line of thinking, it is possible that prolonged AP-1 induction in Atm-deficient brains is important for neuronal survival. Our results are consistent with several studies (56,63) showing prolonged AP-1 activation in Atm-deficient cells. Whereas wild type fibroblast showed transient induction of c-Jun in response to IR, ATM-deficient fibroblasts responded to IR with prolonged c-Jun expression.…”

Section: Figsupporting

confidence: 83%

Contribution of the Atm Protein to Maintaining Cellular Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in Atm-deficient Brains

Weizman¹,

Shiloh²,

Barzilai³

2003

Journal of Biological Chemistry

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Maintenance of genome stability is essential for keeping cellular homeostasis. The DNA damage response is a central component in maintaining genome integrity. Among of the most cytotoxic DNA lesions are double strand breaks (DSBs) caused by ionizing radiation or radiomimetic chemicals. ATM is missing or inactivated in patients with ataxia-telangiectasia. Ataxia-telangiectasia patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by degeneration of cerebellar Purkinje and granule neurons. Additional features are immunodeficiency, genomic instability, radiation sensitivity, and cancer predisposition. Disruption of the mouse Atm locus creates a murine model of ataxia-telangiectasia that exhibits most of the clinical features of the human disease but very mild neuronal abnormality. The ATM protein is a multifunctional protein kinase, which serves as a master regulator of cellular responses to DSBs. There is growing evidence that ATM may be involved in addition to the DSB response in other processes that maintain processes in cellular homeostasis. For example, mounting evidence points to increased oxidative stress in the absence of ATM. Here we report that the AP-1 pathway is constantly active in the brains of Atm-deficient mice not treated with DNA damaging agents. A canonical activation (increased phosphorylation of mitogen-activated protein kinase kinase-4, c-Jun N-terminal kinase, and c-Jun) of the AP-1 pathway was found in Atm-deficient cerebra, whereas induction of the AP-1 pathway in Atmdeficient cerebella is likely to mediate elevated expression of c-Fos and c-Jun. Although Atm ؉/؉ mice are capable of responding to ionizing radiation by activating stress responses such as the AP-1 pathway, Atm-deficient mice display higher basal AP-1 activity but gradually lose their ability to activate AP-1 DNA-binding activity in response to ionizing radiation. Our results further demonstrate that inactivation of the ATM gene results in a state of constant stress.

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Section: Figsupporting

confidence: 83%

Contribution of the Atm Protein to Maintaining Cellular Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in Atm-deficient Brains

Weizman¹,

Shiloh²,

Barzilai³

2003

Journal of Biological Chemistry

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“…The gene expression data were obtained using Affymetrix DNA microarray (U133A probe set of 14500 human genes) chip assays. The experimental procedures for cell culture and radiation treatment, 2D-gel, MALDI-MS proteomics and microarray have been described elsewhere (Lee et al, 2001;Mewani et al, 2006). Protein identification from MALDI-MS was based on MASCOT search engine using UniProtKB/Swiss-Prot database.…”

Section: Experimental Data Sourcementioning

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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“…Alternatively, ATM has been reported to be a sensor of oxidative damage. Indeed, deregulation of the oxidative stress response is part of the A-T phenotype (16). Some studies have shown reactive oxygen species generated during Cr(VI) reduction; however, the experiments were conducted using extraordinarily high Cr(VI) doses (100 M-2 mM) and already malignant cells (42)(43)(44)(45)(46).…”

Section: Atm-deficient Cells Fail To Exhibit Checkpoint Arrest In Earmentioning

confidence: 99%

“…ATM kinase has been shown to be specifically activated in response to DNA DSBs but not to UVB/UVC or base-damaging agents (7). However, recent reports have demonstrated the activation of ATM by t-butyl-hydroperoxide (15), CdCl 2 (16), UVA (17), heat shock (18), insulin (19), and MNNG (20). Therefore, the function of ATM in the cellular response to DNA damage other than DSBs also needs further investigation.…”

mentioning

confidence: 98%

Chromium (VI) Activates Ataxia Telangiectasia Mutated (ATM) Protein

Ceryak

Patierno

2003

Journal of Biological Chemistry

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The ataxia telangiectasia mutated (ATM) protein plays a central role in early stages of DNA double strand break (DSB) detection and controls cellular responses to this damage. Although hypersensitive to ionizing radiation-induced clonogenic lethality, ataxia telangiectasia cells are paradoxically deficient in their ability to undergo ionizing radiation-induced apoptosis. This contradiction illustrates the complexity of the central role of ATM in DNA damage response and the need for further understanding. Certain hexavalent chromium (Cr(VI)) compounds are implicated as occupational respiratory carcinogens at doses that are both genotoxic and cytotoxic. Cr(VI) induces a broad spectrum of DNA damage, but Cr(VI)-induced DSBs have not been reported. Here, we examined the role of ATM in the cellular response to Cr(VI) and found that Cr(VI) activates ATM. We also show that physiological targets of ATM, p53 Ser-15 and Chk2 Thr-68, were phosphorylated by Cr(VI) exposure in an ATM-dependent fashion. We found that ATM؊/؊ cells were markedly resistant to Cr(VI)-induced apoptosis but considerably more sensitive to Cr(VI)-induced clonogenic lethality than wild type cells, indicating that resistance to Cr(VI)-induced apoptosis did not confer a selective survival advantage. However, analysis of long term growth arrest revealed a striking difference: ATM؊/؊ cells were markedly less able to recover from Cr(VI)-induced growth arrest. This indicates that terminal growth arrest is the fate of these apoptosis-resistant cells. In summary, ATM is involved in cellular response to a complex genotoxin that may not directly induce DSBs. Our data suggest that ATM is a major signal initiator for genotoxin-induced apoptosis but, paradoxically, also contributes to maintenance of cell survival by facilitating recovery/escape from terminal growth arrest. The results also strongly suggest that terminal growth arrest is not merely an extended or even irreversible form of checkpoint arrest, but instead an independent and unique cell fate pathway.

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Role of ATM in Oxidative Stress-mediated c-Jun Phosphorylation in Response to Ionizing Radiation and CdCl2

Cited by 65 publications

References 68 publications

Contribution of the Atm Protein to Maintaining Cellular Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in Atm-deficient Brains

Contribution of the Atm Protein to Maintaining Cellular Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in Atm-deficient Brains

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

Chromium (VI) Activates Ataxia Telangiectasia Mutated (ATM) Protein

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