ATM controls c-Myc and DNA synthesis during postnatal thymocyte development through regulation of redox state.
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.
Yan
Mingshan
M
Science Park-Research Division, The University of Texas M.D. Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
Zhu
Chengming
C
Liu
Na
N
Jiang
Yuhong
Y
Scofield
Virginia L
VL
Riggs
Penny K
PK
Qiang
Wenan
W
Lynn
William S
WS
Wong
Paul K Y
PK
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000502:physiology*; D017931:DNA Primers; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases