1. IKBKE Phosphorylation and Inhibition of FOXO3a: A Mechanism of IKBKE Oncogenic Function
- Author
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Guo, Jian-Ping, Tian, Wei, Shu, Shaokun, Xin, Yu, Shou, Chengchao, and Cheng, Jin Q.
- Subjects
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PHOSPHORYLATION , *FORKHEAD transcription factors , *CELLULAR control mechanisms , *REGULATION of cell growth , *GENE expression , *BREAST tumors , *LUNG tumors - Abstract
Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival and growth. The transcriptional activity and subcellular localization of FOXO are tightly regulated by post-translational modifications. Here we report that IKBKE regulates FOXO3a through phosphorylation of FOXO3a-Ser644. The phosphorylation of FOXO3a resulted in its degradation and nuclear-cytoplasmic translocation. Previous studies have shown that IKBKE directly activates Akt and that Akt inhibits FOXO3a by phosphorylation of Ser32, Ser253 and Ser315. However, the activity of Akt-nonphosphorytable FOXO3a-A3 (i.e., converting 3 serine residues to alanine) was inhibited by IKBKE. Furthermore, overexpression of IKBKE correlates with elevated levels of pFOXO3a-S644 in primary lung and breast tumors. IKBKE inhibits cellular function of FOXO3a and FOXO3a-A3 but, to a much less extent, of FOXO3a-S644A. These findings suggest that IKBKE regulates FOXO3a primarily through phosphorylation of SerS644 and that IKBKE exerts its cellular function, at least to some extent, through regulation of FOXO3a. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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