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Nuclear/cytoplasmic shuttling of the transcription factor FoxO1 is regulated by neurotrophic factors
Author(s) -
Gan Lixia,
Zheng Wenhua,
Chabot JeanGuy,
Unterman Terry G.,
Quirion Remi
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03108.x
Subject(s) - foxo1 , neurotrophin , neurotrophic factors , transcription factor , protein kinase b , biology , microbiology and biotechnology , pi3k/akt/mtor pathway , brain derived neurotrophic factor , growth factor , nerve growth factor , insulin like growth factor , tropomyosin receptor kinase b , phosphorylation , endocrinology , medicine , signal transduction , receptor , biochemistry , gene
Abstract FoxO1, a member of the FoxO subfamily of forkhead transcription factors, is an important target for insulin and growth factor signaling in the regulation of metabolism, cell cycle and proliferation, and survival in peripheral tissues. However, its role in the central nervous system is mostly unknown. In this study, we examined the effect of neurotrophic factors on nuclear/cytoplasmic shuttling of FoxO1. We showed that insulin‐like growth factor‐1 (IGF‐1) and nerve growth factor (NGF) potently induced the nuclear exclusion of FoxO1‐green fluorescent protein (GFP) while neurotrophin (NT)‐3 and NT‐4 were much weaker and brain‐derived neurotrophic factor (BDNF) failed to induce FoxO1 translocation in PC12 cells. FoxO1 translocation was inhibited by LY294002, a well‐established PI3K/Akt kinase inhibitor. Moreover, FoxO1 was phosphorylated at Thr24 and Ser256 residues by the above neurotrophic factors, with the exception of BDNF. Triple mutant FoxO1, in which three Akt/PKB phosphorylation sites (Thr24, Ser256 and Ser319) were mutated to alanine, resulted in the complete nuclear targeting of the expressed FoxO1‐GFP fusion protein in the presence of the above neurotrophic factors in both PC12 cells and cultured hippocampal and cortical neurons. Taken together, these findings demonstrate that neurotrophic factors are able to regulate nuclear/cytoplasmic shuttling of FoxO1 via the PI3K/Akt pathway in neuronal cells.