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J. Biol. Chem., Vol. 278, Issue 9, 6741-6747, February 28, 2003
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From the 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
Atm-deficient 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.
Contribution of the Atm Protein to Maintaining Cellular
Homeostasis Evidenced by Continuous Activation of the AP-1 Pathway in
Atm-deficient Brains*
,¶
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, and the § Department of Human
Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv
University, Tel Aviv 69978 Israel
*
This work was supported by grants from the
Ataxia-Telangiectasia Children's Project (to A. B. and Y. S.), a
grant from the Ataxia-Telangiectasia Medical Research Foundation (to
Y. S.), and the Israel Science Foundation Grant 502/00-1 (to A. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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