Regulation of FOXO transcription factor

Abstract

It is well known that the FOXO subfamily of forkhead transcription factors play a critical role in cell cycle, apoptosis, and energy metabolism, and are important for mediating effects of insulin and growth factors on gene expression as a downstream target of phosphatidylinositol 3-kinase (PI3K) and Akt. Here, I found a novel regulator of FOXO transcription factor, CRK, through genetic screening. Through coimmunoprecipitation analyses, I demonstrated that FKHR directly interacts with CRK in vivo, and that the C-terminal of CRK is needed for interaction with FKHR. Furthermore, I examined the regulation of CRK on FKHR; I revealed that CRK phosphorylates and thus, inhibits FKHR-dependent transcription in a kinase-activity-dependent manner, and that CRK induces the nuclear exclusion of FKHR by export mechanism using immunocytochemical analyses. Collectively, these findings establish CRK as a new regulator of FKHR.