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Regulation of T-cell survival and mitochondrial homeostasis by TSC1.
O'Brien, Thomas F; Gorentla, Balachandra K; Xie, Danli; Srivatsan, Sruti; McLeod, Ian X; He, You-Wen; Zhong, Xiao-Ping.
Afiliação
  • O'Brien TF; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Eur J Immunol ; 41(11): 3361-70, 2011 Nov.
Article em En | MEDLINE | ID: mdl-21805467
ABSTRACT
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T-cell activation and responses to microbial infection. However, the importance of mTOR regulation in T cells has yet to be explored. The TSC1/TSC2 complex has been shown to inhibit mTORC1 signaling in cell line models. We show here that deletion of TSC1 in the murine T-cell lineage results in a dramatic reduction of the peripheral T-cell pool, correlating with increased cell death. While mTORC1 is constitutively activated, mTORC2 signaling, reflected by Akt phosphorylation and activity, is decreased in TSC1-deficient T cells. Furthermore, TSC1-deficient T cells contain elevated reactive oxygen species (ROS) and exhibit decreased mitochondrial content and membrane potential, which is correlated with the activation of the intrinsic death pathway. Overall, our results demonstrate that TSC1 differentially regulates mTORC1 and mTORC2 activity, promotes T-cell survival, and is critical for normal mitochondrial homeostasis in T cells.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Linfócitos T / Transdução de Sinais / Proteínas Supressoras de Tumor / Homeostase / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Linfócitos T / Transdução de Sinais / Proteínas Supressoras de Tumor / Homeostase / Mitocôndrias Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2011 Tipo de documento: Article