Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor

Anne Brunet, Azad Bonni, Michael J. Zigmond, Michael Z. Lin, Peter Juo, Linda S. Hu, Michael J. Anderson, Karen C. Arden, John Blenis, Michael E. Greenberg

Research output: Contribution to journalArticlepeer-review

5163 Scopus citations

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.

Original languageEnglish
Pages (from-to)857-868
Number of pages12
JournalCell
Volume96
Issue number6
DOIs
StatePublished - Mar 19 1999

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