Prevention of thymic lymphoma development in Atm-/- mice by dexamethasone.
We have reported (M. Yan et al., FASEB J., 15: 1132-1138, 2001) that spontaneous DNA synthesisis markedly increased in the thymocytes from the atrophied thymi of young Atm-/- mice. We, therefore, set out to determine whether this elevated DNA synthesis is responsible for the development of thymic lymphomas in all Atm-/- mice by 4-5 months of age. We show here that in Atm-/- mice: (a) increased DNA synthesis occurs, especially in the immature CD4(-) CD8(-) (dominant negative) and CD8(+) thymocyte populations; (b) the relative percentage of dominant negative cells increases significantly during postnatal development, with a sharp peak at 4 weeks of age; and (c) dexamethasone suppresses DNA synthesis in these thymocytes and prevents thymic lymphoma development. These observations suggest that ataxia telangiectasia mutated (ATM) down-regulates the proliferation of thymocytes, allowing T-cell development and differentiation. The results also show that dexamethasone, like ATM, checks DNA synthesis in developing thymocytes. Finally, the data document for the first time that dexamethasone prevents or slows thymic lymphoma development in Atm-/- mice.
Yan
Mingshan
M
The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA.
Kuang
Xianghong
X
Qiang
Wenan
W
Shen
Jianjun
J
Claypool
Kent
K
Lynn
William S
WS
Wong
Paul K Y
PK
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D008223:Lymphoma / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013953:Thymus Neoplasms / Q000235:genetics / Q000517:prevention & control*; D025521:Tumor Suppressor Proteins
D016588:Anticarcinogenic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases