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Activation of ATM by DNA Damaging Agents

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Annual summary rept. 1 Sep 2002-31 Aug 2005

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Ataxia-telangiectasia mutated ATM is a serinethreonine protein kinase that acts as a master switch controlling the cell cycle in response to ionizing radiation-induced DNA double-strand breaks DSBs. Carriers of ATM mutations are at increased risk for breast cancer. Since many anti-tumor chemotherapeutics used in breast cancer treatment have the capacity to induce DSBs, I have investigated the requirement for ATM in the cellular response to these agents. I have previously identified doxorubicin as an agent that stimulates ATM autophosphorylation and the ATM-dependent phosphorylation of multiple downstream effectors of ATM in part through the generation of hydroxyl radicals. I have now expanded these studies to examine the functionally related topoisomerase II poison, etoposide. In contrast to doxorubicin, etoposide induces the phosphorylation of several downstream effectors in an ATM-independent manner despite stimulating ATM autophosphorylation, and etoposide appears to stimulate a signaling cascade initiated by the ATM-related protein kinase, ATR. Studies are now underway to identify proteins that interact with ATM following drug treatment. Characterization of a role for ATM in the cellular response to anti-tumor chemotherapeutics could have significant implications for the treatment of breast cancer patients harboring mutations in ATM.

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  • Biochemistry
  • Medicine and Medical Research

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