ATM controls c-Myc and DNA synthesis during postnatal thymocyte development through regulation of redox state. Academic Article uri icon

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.

published proceedings

  • Free Radic Biol Med

author list (cited authors)

  • Yan, M., Zhu, C., Liu, N. a., Jiang, Y., Scofield, V. L., Riggs, P. K., ... Wong, P.

citation count

  • 14

complete list of authors

  • Yan, Mingshan||Zhu, Chengming||Liu, Na||Jiang, Yuhong||Scofield, Virginia L||Riggs, Penny K||Qiang, Wenan||Lynn, William S||Wong, Paul KY

publication date

  • January 1, 2006 11:11 AM