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Insulin-like growth factor-1-induced phosphorylation of the Forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells
Zheng W.-H.1; Kar S.1; Quirion R.1
2000-12-15
Source PublicationJournal of Biological Chemistry
ISSN00219258
Volume275Issue:50Pages:39152-39158
Abstract

The Forkhead family transcription factor FKHRL1, a mammalian homolog of DAF16 in the nematode Caenorhabditis elegans, is an inducer of apoptosis in its unphosphorylated form and was recently reported as a substrate of Akt kinases. Insulin-like growth factor (IGF-1) is a potent stimulant of Akt kinase, leading to inhibition of the apoptotic pathway. In this study, we characterized the phosphorylation of FKHRL1 induced by IGF-1 in PC12 cells and various neuronal cell types and examined the potential role of Akt in this regard. IGF-1 rapidly induced the phosphorylation of Akt and FKHRL1 in PC12 cells. The phosphorylation of Akt and FKHRL1 induced by 10 nM IGF-1 was inhibited by the phosphatidylinositide 3-kinase (PI3K) inhibitors wortmannin (0.25-2 μM) and LY294002 (12.5-100 μM), but not by the MEK inhibitor PD98059 (50 μM) or the p70 S6 kinase pathway inhibitor rapamycin (50 nM), suggesting that the phosphorylation of FKHRL1 induced by IGF-1 is mediated by the PI3K pathway. As observed for IGF-1, an in vitro kinase assay with purified active Akt kinase demonstrated that the kinase is capable of directly phosphorylating FKHRL1 at Thr and Ser , leading to inhibition of its pro-apoptotic properties. Moreover, transient expression of constitutively active Akt (MS-Akt, where MS is a myristylation signal) increased the phosphorylation of FKHRL1, whereas the expression of kinase-dead Akt (M179A Akt) attenuated the phosphorylation of FKHRL1 induced by 10 nM IGF-1 in PC12 cells. Interestingly, FKHRL1 co-immunoprecipitated with Akt in PC12 cells, indicating that these two proteins can associate in these cells. As IGF-1 also induced the phosphorylation of FKHRL1 in primary cortical and cerebellar neuronal cultures, these data, taken together, demonstrate that IGF-1, acting via the PI3K/Akt kinase pathway, can regulate the phosphorylation of FKHRL1, leading to inhibition of this apoptotic transcription factor in neuronal cells.

DOI10.1074/jbc.M002417200
URLView the original
Indexed BySCI
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000165953100030
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Cited Times [WOS]:123   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Douglas Hospital Research Center
2.Fonds de la Recherche en Sante du Quebec
Recommended Citation
GB/T 7714
Zheng W.-H.,Kar S.,Quirion R.. Insulin-like growth factor-1-induced phosphorylation of the Forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells[J]. Journal of Biological Chemistry,2000,275(50):39152-39158.
APA Zheng W.-H.,Kar S.,&Quirion R..(2000).Insulin-like growth factor-1-induced phosphorylation of the Forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells.Journal of Biological Chemistry,275(50),39152-39158.
MLA Zheng W.-H.,et al."Insulin-like growth factor-1-induced phosphorylation of the Forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells".Journal of Biological Chemistry 275.50(2000):39152-39158.
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