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

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

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)640-648
Number of pages9
JournalFree Radical Biology and Medicine
Volume41
Issue number4
DOIs
StatePublished - Aug 15 2006

Keywords

  • ATM
  • Free radicals
  • Reactive oxygen species
  • Thymic lymphoma
  • Thymocyte development
  • c-Myc

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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