Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice.
Biochem Biophys Res Commun
; 383(3): 368-72, 2009 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-19364503
ABSTRACT
Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Neoplasias do Timo
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Proteínas de Transporte
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Proteínas Serina-Treonina Quinases
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Fosfotransferases (Aceptor do Grupo Álcool)
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Proteínas de Ciclo Celular
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Proteínas Supressoras de Tumor
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Proteínas de Ligação a DNA
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Linfoma
Limite:
Animals
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos