Abstract IA08: Ataxia-telangiectasia: Broad implications from the study of a rare disease

Abstract

Abstract DNA damage signaling pathways are critical mediators of both tumor development and tumor responses to chemotherapy and radiation therapy. Significant progress has been made in recent years in elucidating the molecular controls of cellular responses to DNA damage in mammalian cells. Much of what we have learned about damage signaling pathways has come from the study of human diseases, particularly cancer predisposition syndromes. Ataxia-Telangiectasia (A-T) is a pleiotropic disorder with multiple phenotypic abnormalities, including progressive neurodegeneration, immunodeficiencies, cancer predisposition, insulin resistance, telangiectasia development, infertility, and extreme radiosensitivity. ATM, the gene mutated in A-T, is a central mediator of responses to DNA double strand breaks in cells. Once activated, ATM phosphorylates numerous substrates in the cell that modulate the cell's response to the DNA damage. Though ATM clearly plays a central role in mediating cellular responses to DNA breakage, some of the clinical abnormalities in A-T are difficult to attribute directly to alterations in DNA damage signaling. The broad-based symptoms in A-T and recently acquired data suggest that ATM may have roles that extend beyond its regulation of DNA damage responses. In particular, ATM appears to affect insulin signaling pathways and evidence has been generated supporting a direct role for ATM in mitochondrial function. These new insights suggest that Ataxia-Telangiectasia should be considered, at least in part, as a mitochondrial dysfunction disease and provide links between cancer-related DNA damage signaling and more general metabolic signaling pathways. Some of these new insights are also providing opportunities for considerations of novel ways to modulate ATM function for clinical benefit. Citation Format: Michael B. Kastan. Ataxia-telangiectasia: Broad implications from the study of a rare disease. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA08.