TY - JOUR
T1 - ATM controls c-Myc and DNA synthesis during postnatal thymocyte development through regulation of redox state
AU - Yan, Mingshan
AU - Zhu, Chengming
AU - Liu, Na
AU - Jiang, Yuhong
AU - Scofield, Virginia L.
AU - Riggs, Penny K.
AU - Qiang, Wenan
AU - Lynn, William S.
AU - Wong, Paul K.Y.
N1 - Funding Information:
We thank Walter J. Pagel, Shawna Johnson, and Joi Holcomb for their assistance in preparing the manuscript; Kent Claypool, Lifang Zhang, and Shoufeng Wang for their technical assistance; and David G. Johnson for his comments on the manuscript. This work was supported in part by grants from the A-T Children’s Project (Deerfield Beach, FL, USA), the Longevity Foundation (formerly the Ataxia Telangiectasia Project) (Austin, TX, USA), the Leukemia Research Foundation, National Cancer Institute Core Grant CA16672, and NIEHS Center Grant ES07784.
PY - 2006/8/15
Y1 - 2006/8/15
N2 - 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.
AB - 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.
KW - ATM
KW - Free radicals
KW - Reactive oxygen species
KW - Thymic lymphoma
KW - Thymocyte development
KW - c-Myc
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U2 - 10.1016/j.freeradbiomed.2006.05.008
DO - 10.1016/j.freeradbiomed.2006.05.008
M3 - Article
C2 - 16863997
AN - SCOPUS:33746046363
VL - 41
SP - 640
EP - 648
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 4
ER -