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Papers In Press, published online ahead of print December 19, 2002
Department of Neurobiochemistry, Tel Aviv University, Tel Aviv 69978
Corresponding Author: barzilai{at}post.tau.ac.il
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 chmeicals ATM is missing or inactivated in patients with ataxia telangiectasia (A-T). A-T 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 A-T 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 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 MKK4, JNK and c-Jun) of the AP-1 pathway was found in Atm-deficient cerebra, whereas induction of the AP-1 pathway in Atm-deficient cerebella is likely to be mediate elevated expression of c-Fos and c-Jun . Whereas Atm+/+ mice are capable of responding to ionizing radiation (IR) 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 IR. Our results further demonstrate that inactivation of the ATM gene results in a state of constant stress.
J. Biol. Chem, 10.1074/jbc.M211168200
Submitted on October 31, 2002
Revised on December 18, 2002
Accepted on December 19, 2002
Contribution of the Atm protein to maintaining cellular homeostasis evidenced by continuous activation of the AP-1 pathway in Atm-deficient brains
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