TY - JOUR
T1 - Insulin-like growth factor-I induces the phosphorylation and nuclear exclusion of forkhead transcription factors in human neuroblastoma cells
AU - Schwab, T. S.
AU - Madison, B. B.
AU - Grauman, A. R.
AU - Feldman, E. L.
N1 - Funding Information:
The authors would like to thank Drs. Cynthia M. van Golen and Phillip S. Leventhal for assistance in writing and editing of this manuscript and Dr. Eric D. Schwab for assistance in figure preparation, and Ms. Judy Boldt for secretarial assistance. This work was supported in part by the UM-Comprehensive Cancer Center NIH CA46592, NIH T32 NS07222, NIH RO1 NS36778, NIH RO1 NS38849 and the Program for Understanding Neurological Diseases (PFUND).
PY - 2005/8
Y1 - 2005/8
N2 - 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.
AB - 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.
KW - FKHR
KW - FKHRL1
KW - Forkhead
KW - IGF-I
KW - IGF-IR
KW - Neuroblastoma
UR - http://www.scopus.com/inward/record.url?scp=23944475155&partnerID=8YFLogxK
U2 - 10.1007/s10495-005-0429-y
DO - 10.1007/s10495-005-0429-y
M3 - Article
C2 - 16133873
AN - SCOPUS:23944475155
VL - 10
SP - 831
EP - 840
JO - Apoptosis
JF - Apoptosis
SN - 1360-8185
IS - 4
ER -