Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation.
J Exp Med
; 194(8): 1097-110, 2001 Oct 15.
Article
en En
| MEDLINE
| ID: mdl-11602639
ABSTRACT
Syncytia arising from the fusion of cells expressing a lymphotropic human immunodeficiency virus (HIV)-1-encoded envelope glycoprotein complex (Env) gene with cells expressing the CD4/CXCR4 complex undergo apoptosis through a mitochondrion-controlled pathway initiated by the upregulation of Bax. In syncytial apoptosis, phosphorylation of p53 on serine 15 (p53S15) precedes Bax upregulation, the apoptosis-linked conformational change of Bax, the insertion of Bax in mitochondrial membranes, subsequent release of cytochrome c, caspase activation, and apoptosis. p53S15 phosphorylation also occurs in vivo, in HIV-1(+) donors, where it can be detected in preapoptotic and apoptotic syncytia in lymph nodes, as well as in peripheral blood mononuclear cells, correlating with viral load. Syncytium-induced p53S15 phosphorylation is mediated by the upregulation/activation of mammalian target of rapamycin (mTOR), also called FKBP12-rapamycin-associated protein (FRAP), which coimmunoprecipitates with p53. Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in primary CD4(+) lymphoblasts infected by HIV-1. Concomitantly, rapamycin inhibits p53S15 phosphorylation, mitochondrial translocation of Bax, loss of the mitochondrial transmembrane potential, mitochondrial release of cytochrome c, and nuclear chromatin condensation. Transfection with dominant negative p53 has a similar antiapoptotic action as rapamycin, upstream of the Bax upregulation/translocation. In summary, we demonstrate that phosphorylation of p53S15 by mTOR/FRAP plays a critical role in syncytial apoptosis driven by HIV-1 Env.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Portadoras
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Proteína gp41 de Envoltorio del VIH
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Proteína gp120 de Envoltorio del VIH
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Proteína p53 Supresora de Tumor
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VIH-1
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Apoptosis
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Fosfotransferasas (Aceptor de Grupo Alcohol)
/
Inmunofilinas
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Año:
2001
Tipo del documento:
Article
País de afiliación:
Francia