Cellular responses to DNA damage and other stresses are important determinants of cell viability and mutagenesis and impact the development of a wide range of human diseases. Hypoxic and oxidative stresses are also important in the pathogenesis of many human diseases, ranging from cancer to cardiovascular disease to neurological disorders to aging. Induction of signal transduction pathways is a critical aspect of cellular responses to these stresses and significant advances have been made in recent years elucidating the biochemical steps in such signaling pathways. Clarification of such steps enables modulation of these responses, which can enhance research studies and have the potential to lead to development of new medicines to prevent and treat these diseases. The ATM protein kinase is a central signaling molecule in modulating cellular responses to DNA breakage. Patients with mutated ATM genes have a devastating clinical disorder known as Ataxia-telangiectasia and have a variety of medical problems, including neurodegeneration, immunodeficiency, cancer predisposition, insulin resistance, and telangiectasia development. Arguments are put forth here that the pleiotropic abnormalities in these patients may not simply be due to DNA damage response abnormalities. A novel proposal is made that increased levels of reactive oxygen species, resulting from mitochondrial abnormalities, and abnormalities in cellular responses to hypoxic stresses contribute to or cause many or all of the pathophysiologic states seen in patients with Ataxia-telangiectasia. Preliminary data is presented confirming increased levels of reactive oxygen species in cells lacking ATM function and mitochondrial abnormalities are identified in mouse and human cells and tissues lacking ATM. Interestingly, loss of a single allele of the autophagy-related gene, beclin, partially rescued the abnormalities in reactive oxygen species, mitochondria, and cancer predisposition in mice lacking ATM. Experiments are proposed to further explore the mechanisms by which ATM loss leads to abnormalities in mitochondria and levels of reactive oxygen species and how beclin heterozygosity rescues these abnormalities. Preliminary data also demonstrated abnormal responses to hypoxic stress in cells lacking ATM function. Experiments are proposed to explore the mechanisms by which ATM loss, perhaps through its impact on mitochondria and reactive oxygen species, affects cellular responses to hypoxic stress. The role of ATM in modulating either the Hif-11 or Hif-21 signaling pathways will be investigated. Successful completion of the proposed experiments could lead to new insights into unexpected cellular functions of the ATM protein and establish new paradigms for common mechanisms that contribute to cancer development, neurodegeneration, and metabolic abnormalities.
Patients with Ataxia-telangiectasia, a disease resulting from loss of the ATM gene product, have a wide variety of medical problems, including neurodegeneration, immune deficiencies, premature aging, and cancer predisposition. In experiments proposed here, we will explore why loss of ATM function leads to oxidative stress and damage in cells, with a particular focus on its impact on mitochondrial function and responses to hypoxic stress. New insights gained could be beneficial not only to this patient population, but could also benefit patients with cancer, cardiovascular disease, and neurological disorders.
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