O43524

FOXO3 (forkhead box O3) or FOXO3A, also known as FKHRL1 (forkhead in rhabdomyosarcoma-like 1), is a 673 amino acid transcriptional activator that belongs to the FKHR subfamily of forkhead transcription factors. Transcriptional activation of FKHR proteins is regulated by the serine/threonine kinase Akt1, which phosphorylates FKHRL1 at Threonine 32 and Serine 253. Phosphorylation by Akt1 negatively regulates FKHRL1 by promoting its export from the nucleus. Phosphorylated FKHRL1 associates with 14-3-3 proteins and this complex is retained in the cytoplasm. Growth factor withdrawal stimulates FKHRL1 dephosphorylation and nuclear translocation, leading to FKHR-induced gene-specific transcriptional activation. Within the nucleus, dephosphorylated FKHRL1 triggers apoptosis by inducing the expression of genes that are critical for cell death.