Abstract
Akt is a common mediator of cell survival in a variety of circumstances. Although some candidate Akt targets have been described, the function of Akt is not fully understood, particularly because of the cell type- and context-dependent apoptosis regulation. In this study, we demonstrate that one of the mechanisms by which Akt antagonizes apoptosis involves the inhibition of Nur77, a transcription factor implicated in T-cell receptor-mediated apoptosis. It has been suggested that Akt phosphorylates Nur77 directly, but whether Akt suppresses biological functions of Nur77 remains unknown. We found that Akt inhibited the DNA binding activity of Nur77 and stimulated its association with 14-3-3 in a phosphorylation site-dependent manner. Moreover, we found that expression of Akt suppressed Nur77-induced apoptosis in fibroblasts and activation-induced cell death of T-cell hybridomas. The inhibition of Nur77 by Akt suggests a mechanism that explains how T-cell receptor activation can promote survival in some instances even when Nur77 is induced. Collectively, these results may suggest that Akt is a negative regulator of Nur77 in T-cell apoptosis.
Highlights
The regulation of survival versus apoptosis is a central issue during T-cell development and activation
We demonstrate that one of the mechanisms by which Akt antagonizes apoptosis involves the inhibition of Nur77, a transcription factor implicated in T-cell receptor-mediated apoptosis
Thymocytes derived from mice deficient in p110␥, a catalytic subunit of phosphatidylinositol 3-kinase (PI3-K), exhibited enhanced apoptosis [18], whereas those derived from ptenϪ/Ϫ mice, in which the PI3-K-Akt pathway is constitutively active, were more resistant to T-cell receptor (TCR)-mediated cell death and resulted in a defect in thymic negative selection [19, 20]
Summary
The regulation of survival versus apoptosis is a central issue during T-cell development and activation. We found that expression of Akt suppressed Nur77-induced apoptosis in fibroblasts and activation-induced cell death of T-cell hybridomas.
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