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Vol. 62, Issue 2, 225-233, August 2002
Departments of Psychiatry, and Pharmacology and Therapeutics,
Douglas Hospital Research Center, McGill University,
Montreal, Quebec, Canada
Insulin-like growth factor-1 (IGF-1) is a trophic factor promoting cell
survival by activating phosphatidylinositol 3-kinase (PI3K)/Akt kinase
pathway. FKHRL1, a member of the Forkhead family of transcription
factors possibly involved in cell cycle and apoptosis, is a downstream
target of Akt in fibroblasts. However, very little information is
available concerning neurons. We report herein that IGF-1 rapidly
induced the phosphorylation of endogenous FKHRL1 in hippocampal
neurons. The PI3K/Akt kinase pathway mediates this action, as evidenced
by the use of different kinase inhibitors, the expression of
constitutively active Akt, and in vitro kinase assay. IGF-1 blocked the
nuclear translocation of FKHRL1 in hippocampal neurons and promoted
survival in parallel to the phosphorylation of Akt and FKHRL1.
Similarly, the expression of constitutively active Akt in PC-12 cells
increased the phosphorylation of FKHRL1 and promoted survival, whereas
the expression of kinase dead Akt attenuated IGF-1-mediated survival
of PC-12 cells. Moreover, the overexpression of wild-type FKHRL1 and
its nonphosphorylated mutant induced apoptosis in cultured hippocampal
neurons. Interestingly, IGF-1 and PI3-kinase inhibitors have no
significant effect on the cell cycle inhibitor p27kip1 in hippocampal
neurons. This finding suggests that in contrast to fibroblasts, FKHRL1
is unlikely to be involved in cell cycle in neurons. Taken together,
these data reveal that endogenous FKHRL1 is a downstream substrate of PI3K/Akt in IGF-1 receptor signaling in hippocampal neurons and suggest
that the phosphorylation of this transcription factor may play an
important role in the neuronal survival properties of IGF-1.
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