Control of lymphomagenesis by ATM through ROS, mTOR and PP2A signaling

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DESCRIPTION (provided by applicant): Ataxia telangiectasia (A-T) is a human autosomal recessive disease characterized in part by lymphoid tumorigenesis. A-T is caused by mutations within the Atm gene, resulting in a loss of function of the gene product, ATM. Recent studies have shown that inactivation of Atm is also associated with sporadic lymphoid tumors in non-A-T patients. Therefore, it is of broad significance for lymphoid tumor chemoprevention to study the role of ATM in suppressing lymphoid tumorigenesis. ATM is a serine/threonine kinase that regulates a variety of responses required for DNA damage repair. ATM becomes activated via autophosphorylation and subsequently initiates phosphorylation of multiple substrates important for cell cycle regulation. In particular, work in our laboratory has focused on the role of ATM in regulation of immature thymocyte proliferation and differentiation, and on prevention of thymic lymphoma development by glucocorticoids and antioxidants using Atm knockout cell lines and mice. Our current findings demonstrate that in the absence of ATM, DNA synthesis and c-Myc levels are increased and phosphorylation of 4E-BPI, a downstream molecule of mammalian target of rapamycin (mTOR), is increased, suggesting that ATM may regulate thymocyte development through the mTOR signaling pathway. In addition, recent evidence suggests that ATM may activate PP2A, a known tumor suppressor, either through the mTOR pathway or by changing reactive oxygen species (ROS) levels. We therefore hypothesize that ATM prevents lymphomagenesis during thymocyte development by regulating cell cycle related molecules and oncogenic transcriptional regulators. We propose that this regulation occurs through the mTOR and/or PP2A signaling pathways, either directly or through thiol redox mechanisms. To test this hypothesis we will identify the role of ATM in controlling mTOR signaling pathways by examining ATM kinase targeted molecules and protein levels in Atm-/- thymocytes. We will also identify the role of ATM in regulating PP2A activity as being direct or indirect, through balancing the redox state in thymocytes and monitoring protein levels and activities. The rationale for this research application is that identification of ATM-targeted molecules in thymocyte development will allow us to regulate their activities pharmacologically. These studies will significantly advance us towards our long-term goal of understanding how ATM regulates lymphocyte development, how ATM prevents lympoid tumorigenesis, and ultimately finding ways to treat or prevent lymphoid tumors caused by Atm inactivation.