ATM controls c-Myc and DNA synthesis during postnatal thymocyte development through regulation of redox state

Abstract

The oncoprotein c-Myc is essential for thymocyte development, and its dysregulation causes lymphoid malignancies. We have demonstrated previously that spontaneous DNA synthesis in Atm −/− thymocytes is markedly increased over that of Atm +/+ thymocytes and that glucocorticoid dexamethasone suppresses thymocyte DNA synthesis and prevents the ultimate development of thymic lymphoma in Atm −/− mice. Recently, we reported that in Atm −/− thymic lymphoma cells c-Myc is overexpressed compared with the levels of c-Myc in primary thymocytes from wild-type or Atm −/− mice. In this study, we show that c-Myc expression progressively increases with age in primary thymocytes from Atm −/− mice and that the upregulation of c-Myc parallels the elevated DNA synthesis in the cells, suggesting that deregulation of c-Myc may drive the uncontrolled proliferation of thymocytes in Atm −/− mice. Here we also demonstrate that Atm −/− thymocytes exhibit increased levels of hydrogen peroxide, NF-E2-related factor (Nrf-2), peroxiredoxin-1, and intracellular glutathione relative to thymocytes from Atm +/+ mice. Importantly, reduction of hydrogen peroxide by administration of the antioxidant N-acetylcysteine to Atm −/− mice attenuates the elevation of Nrf-2, c-Myc, and DNA synthesis in their thymocytes, suggesting that ATM may control c-Myc and DNA synthesis during postnatal thymocyte development by preventing accumulation of reactive oxygen species.