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J Cell Biochem ; 115(2): 261-70, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24038283

RESUMEN

Mitogen-activated kinase activating death domain containing protein (MADD) is abundantly expressed in cancer cells and necessary for maintaining cancer cell survival. However, this survival function of MADD is dependent upon its phosphorylation by protein kinase B (Akt). The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. The downstream targets of PTEN in triggering apoptosis have not yet been completely identified. Here, we report that MADD can act as a pro-apoptotic factor to initiate TRAIL-induced apoptosis when its phosphorylation is attenuated by PTEN. Our data show that tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) induced a reduction in MADD phosphorylation with a concomitant up-regulation of PTEN. Knock down of PTEN using a specific siRNA prevented TRAIL-induced reduction in pMADD levels. Surprisingly, Akt non-phosphorylated MADD translocated from the plasma membrane to cytoplasm where it bound to 14-3-3 and displaced 14-3-3 associated Bax, which translocated to mitochondria resulting in cytochrome c release. Taken together, our data reveal that PTEN can convey the death signal by preventing MADD phosphorylation by Akt.


Asunto(s)
Apoptosis/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Fosfohidrolasa PTEN/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas 14-3-3/metabolismo , Línea Celular Tumoral , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Mitocondrias/metabolismo , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño , Factor de Necrosis Tumoral alfa/genética
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