CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor

Abstract

The forkhead box O (FOXO) transcription factor FOXO1 functions as a tumor suppressor by regulating expression of genes involved in apoptosis, cell cycle arrest and oxidative detoxification. Here, we demonstrate that cyclin-dependent kinase 1 (CDK1) specifically phosphorylates FOXO1 at serine 249 (S249) in vitro and in vivo. Coimmunoprecipitation assays demonstrate that both endogenous CDK1 and ectopically expressed CDK1 form a protein complex with FOXO1 in prostate cancer (PCa) cells. In vitro protein binding assays reveal that CDK1 interacts directly with FOXO1. Accordingly, overexpression of CDK1 inhibits the transcriptional activity of FOXO1 in PCa cells through S249 phosphorylation on FOXO1. Consistent with the roles of FOXO3a and FOXO4 (two other members of the FOXO family) in cell cycle regulation, forced expression of FOXO1 causes a delay in the transition from G2 to M phase. This effect is blocked completely by overexpression of CDK1 and cyclin B1. Ectopic expression of constitutively active CDK1 also inhibits FOXO1-induced apoptosis in PCa cells. Moreover, we demonstrate that the inhibitory effect of FOXO1 on Ras oncogene-induced colony formation in fibroblasts is diminished by overexpression of CDK1. Given that CDK1 and cyclin B1 are often overexpressed in human cancers including PCa, our findings suggest that aberrant activation of CDK1 may contribute to tumorigenesis by promoting cell proliferation and survival via phosphorylation and inhibition of FOXO1.

Differential Response of Glioma Cells to FOXO1-Directed Therapy

“…CDK2 (47) and, more recently, CDK1 (48,49) were reported to regulate FOXO1 by phosphorylation on S249, which is unaltered in our phosphosite mutant. CDK2 phosphorylation on S249 leads to cytoplasmic localization and decreased activity in both wild-type and FOXO1;AAA in a p53-independent fashion as measured by target gene expression (47).…”

Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells

“…Previous studies found that FOXO1 function was closely related with its phosphorylation and acetylation modification which determined its transcriptional activity (40)(41)(42)(43)(44). Recent studies found that microRNAs, such as miR-96 and miR-370, downregulated FOXO1 expression (28,29).…”

Post-translational modifications of FOXO family proteins

“…Research has demonstrated that, in prostate cancer cells, CDK1 phosphorylates FOXO1 at Ser249, thereby, inhibiting the transcriptional activity of FOXO1 and reducing the effects of FOXO1 on mitosis. FOXO1 phosphorylation induced by CDK1 not only eliminates the effect of FOXO1 on cell death, but also reduces the inhibitory effects of FOXO1 on the proliferation of malignant transformed cells (53). In addition to CDK1 and CDK2, a recent study suggested that the CDK5 can influence the transcriptional activity of FOXO1 directly.…”