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Insulin-like growth factor-I induces the phosphorylation and nuclear exclusion of forkhead transcription factors in human neuroblastoma cells

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Akt-mediated phosphorylation of forkhead transcription factors is linked to growth factor-stimulated cell survival. We investigated whether the survival activity of insulin-like growth factor-I (IGF-I) in SH-SY5Y human neuroblastoma (NBL) cells is associated with phosphorylation and/or localization changes in forkhead proteins. IGF-I induced phosphorylation of Erks (p42/p44), FKHR (FOXO1a) (Ser 253), FKHRL1 (FOXO3a) (Ser 256), and Akt (Ser 473). PI3-K inhibitor, LY294002, reduced IGF-I-stimulated phosphorylation of FKHR, FKHRL1, and Akt, but did not affect Erk phosphorylation. Using a GFP-FKHR construct, FKHR imported into the nucleus during growth factor withdrawal-induced apoptosis. In addition, IGF-I rescue from serum withdrawal-induced apoptosis is associated with a rapid export of GFP-FKHR into the cytoplasm. Leptomycin B, an inhibitor of Crm1-mediated nuclear export, decreased the level of FKHRL1 phosphorylation in the presence of IGF-I in vector and FKHR overexpressing cells, but had no effect on the phosphorylation status of FKHR. In addition, leptomycin B prevented IGF-I stimulated nuclear export of GFP-FKHR. These studies show IGF-I phosphorylation of FKHR and FKHRL1 via a PI3-K-dependent pathway in NBL cells.

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  1. Department of Neurology, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI, 48109

    T. S. Schwab, B. B. Madison, A. R. Grauman & E. L. Feldman

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  1. T. S. Schwab
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Schwab, T.S., Madison, B.B., Grauman, A.R. et al. Insulin-like growth factor-I induces the phosphorylation and nuclear exclusion of forkhead transcription factors in human neuroblastoma cells. Apoptosis 10, 831–840 (2005). https://doi.org/10.1007/s10495-005-0429-y

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