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      Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor

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          Abstract

          Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.

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          Most cited references 35

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          Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.

          Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt. However, the mechanism by which Akt functions to promote survival is not understood. We show that growth factor activation of the PI3'K/Akt signaling pathway culminates in the phosphorylation of the BCL-2 family member BAD, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner. These findings define a mechanism by which growth factors directly inactivate a critical component of the cell-intrinsic death machinery.
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            Death receptors: signaling and modulation.

            Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.
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              Apoptosis by death factor.

               S Nagata (1997)
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                Author and article information

                Journal
                Cell
                Cell
                Elsevier BV
                00928674
                March 1999
                March 1999
                : 96
                : 6
                : 857-868
                10.1016/S0092-8674(00)80595-4
                10102273
                © 1999

                https://www.elsevier.com/tdm/userlicense/1.0/

                https://www.elsevier.com/open-access/userlicense/1.0/

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