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AKT-phosphorylated FOXO1 suppresses ERK activation and chemoresistance by disrupting IQGAP1- MAPK interaction.
- Source :
-
EMBO Journal . 4/13/2017, Vol. 36 Issue 8, p995-1010. 16p. - Publication Year :
- 2017
-
Abstract
- Nuclear FOXO proteins act as tumor suppressors by transcriptionally activating genes involved in apoptosis and cell cycle arrest, and these anticancer functions are inhibited by AKT-induced phosphorylation and cytoplasmic sequestration of FOXOs. We found that, after AKT-mediated phosphorylation at serine 319, FOXO1 binds to IQGAP1, a hub for activation of the MAPK pathway, and impedes IQGAP1-dependent phosphorylation of ERK1/2 ( pERK1/2). Conversely, decreased FOXO1 expression increases pERK1/2 in cancer cell lines and correlates with increased pERK1/2 levels in patient specimens and disease progression. Treatment of cancer cells with PI3K inhibitors or taxane causes FOXO1 localization in the nucleus, increased expression of pERK1/2, and drug resistance. These effects are reversed by administering a small FOXO1-derived phospho-mimicking peptide inhibitor in vitro and in mice. Our results show a tumor suppressor role of AKT-phosphorylated FOXO1 in the cytoplasm and suggest that this function of FOXO1 can be harnessed to overcome chemoresistance in cancer. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PROTEOMICS
*MOLECULAR genetics
*DNA
*APOPTOSIS
*HEREDITY
Subjects
Details
- Language :
- English
- ISSN :
- 02614189
- Volume :
- 36
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- EMBO Journal
- Publication Type :
- Academic Journal
- Accession number :
- 122458331
- Full Text :
- https://doi.org/10.15252/embj.201695534