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

Abstract

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.

Mutation and genomic deletion status of ataxia telangiectasia mutated ( ATM ) and p53 confer specific gene expression profiles in mantle cell lymphoma

“…For example, both CDK10, a CDC2-related protein kinase involved in regulating the G 2 ͞M phase of the cell cycle, and the proapoptotic BNIP1 transcript are up-regulated in cases with ATM point mutations. Consistent with previous hypotheses of ATM function (21,22), ATM-deficient MCL cases showed differential expression of genes related to oxygen stress response (e.g., a gene related to glutathione peroxidase, CYP4B1, and MAP3K4). Finally, the EEF1A1 gene is down-regulated in ATM mutant cases.…”

Regulation and mechanisms of mammalian double-strand break repair

“…In line with these findings, the AP-1 transcription factor, comprising members of the JUN and FOS families, is constantly active in the brains of ATM-deficient mice not treated with DNA damaging agents (Weizman et al, 2002). Whereas normal mice are capable of responding to IR by activating stress responses such as the AP-1 pathway, ATM-deficient mice show higher basal AP-1 activity but gradually lose their ability to activate AP-1 DNA binding activity in response to IR, suggesting that inactivation of ATM results in a state of constant stress (Weizman et al, 2002). A link between JNK/c-JUN signaling and ATM is provided by c-ABL, which binds to MEKK-1, an upstream kinase in the SEK-1/JNK pathway (Kharbanda et al, 2000).…”

Radiation-induced cell signaling: inside-out and outside-in

“…It has been known for some time that ATM can modulate signaling through the JNK1/2 pathway. ATM knockout mice show elevated MKK4-JNK1/2-c-Jun activation as shown by increased activator protein-1 transcription factor activity and cellular stress, suggesting that ATM regulates the JNK1/2 signaling pathway in a negative fashion (134). Recently, ATM was linked directly to ERK1/2 signaling, which was shown to be necessary in fibroblasts for triggering apoptosis in a p53-independent manner (135).…”