Brunet A, Bonni A, Zigmond M J, Lin M Z, Juo P, Hu L S, Anderson M J, Arden K C, Blenis J, Greenberg M E
Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell. 1999 Mar 19;96(6):857-68. doi: 10.1016/s0092-8674(00)80595-4.
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.
存活因子可通过激活丝氨酸/苏氨酸激酶Akt以转录非依赖的方式抑制细胞凋亡，Akt随后磷酸化并使凋亡机制的组分失活，包括BAD和半胱天冬酶9。在本研究中，我们证明Akt还调节叉头转录因子家族成员FKHRL1的活性。在存活因子存在的情况下，Akt使FKHRL1磷酸化，导致FKHRL1与14-3-3蛋白结合并保留在细胞质中。存活因子撤除导致FKHRL1去磷酸化、核转位和靶基因激活。在细胞核内，FKHRL1最有可能通过诱导对细胞死亡至关重要的基因（如Fas配体基因）的表达来触发细胞凋亡。
