Activation of ATM by DNA Damaging Agents
Abstract
Ataxia-telangiectasia mutated (ATM) is a 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 also have the capacity to induce DNA DSBs, I have investigated the requirement for ATM in the cellular response to these agents. Using human ATM-positive and ATM-negative cell lines, I examined the cellular response to five common chemotherapeutics. Although I observed robust p53-dependent responses with 80% of the agents, only doxorubicin demonstrated a dependence upon AIM. Further characterization of the ATM-dependent response to doxorubicin revealed ATM-dependent p53 nuclear accumulation and phosphorylation of p53 on seven serine residues. I have also investigated doxorubicin-treated cell extracts for ATM autophosphorylation, ATM-dependent changes in p53-DNA binding affinity and alterations in the phosphorylation of downstream signaling molecules. Co-incubation of cells with antioxidants attenuated the doxorubicin-induced effect, suggesting that oxygen radicals may play a role in doxorubicin-induced activation of AIM-dependent pathways. Characterization of a role for AIM in the cellular response to anti-tumor chemotherapeutics could have significant implications for the treatment of breast cancer patients harboring mutations in ATM.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA421136
Entities
People
- Ebba U. Kurz
- Susan P. Lees-miller
Organizations
- University of Calgary