Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
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.
Brunet
A
A
Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bonni
A
A
Zigmond
M J
MJ
Lin
M Z
MZ
Juo
P
P
Hu
L S
LS
Anderson
M J
MJ
Arden
K C
KC
Blenis
J
J
Greenberg
M E
ME
D048948:14-3-3 Proteins; D017209:Apoptosis; D001665:Binding Sites; D002461:Cell Line, Transformed; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008562:Membrane Glycoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt