Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c

Abstract

The forkhead box (FOX) transcription factor FOXM1 is ubiquitously expressed in proliferating cells. FOXM1 expression peaks at the G2/M phase of the cell cycle and its functional deficiency in mice leads to defects in mitosis. To investigate the role of FOXM1 in the cell cycle, we used synchronized hTERT-BJ1 fibroblasts to examine the cell cycle-dependent regulation of FOXM1 function. We observed that FOXM1 is localized mainly in the cytoplasm in cells at late-G1 and S phases. Nuclear translocation occurs just before entry into the G2/M phase and is associated with phosphorylation of FOXM1. Consistent with the dependency of FOXM1 function on mitogenic signals, nuclear translocation of FOXM1 requires activity of the Raf/MEK/MAPK signaling pathway and is enhanced by the MAPK activator aurintricarboxylic acid. This activating effect was suppressed by the MEK1/2 inhibitor U0126. In transient reporter assays, constitutively active MEK1 enhances the transactivating effect of FOXM1c, but not FOXM1b, on the cyclin B1 promoter. RT-PCR analysis confirmed that different cell lines and tissues predominantly express the FOXM1c transcript. Mutations of two ERK1/2 target sequences within FOXM1c completely abolish the MEK1 enhancing effect, suggesting a direct link between Raf/MEK/MAPK signaling and FOXM1 function. Importantly, inhibition of Raf/MEK/MAPK signaling by U0126 led to suppression of FOXM1 target gene expression and delayed progression through G2/M, verifying the functional relevance of FOXM1 activation by MEK1. In summary, we provide the first evidence that Raf/MEK/MAPK signaling exerts its G2/M regulatory effect via FOXM1c.

Overexpression of Forkhead box M1 protein associates with aggressive tumor features and poor prognosis of hepatocellular carcinoma

“…We found that 59.3% of the investigated Hcc samples showed positive FoXM1 expression compared with 23.8% of FoXM1-positive non-tumorous tissues, suggesting that overexpression of FoXM1 occurred in human Hcc tumors. Moreover, nuclear staining pattern of FoXM1 was observed exclusively in Hcc tissues, indicating that FoXM1 signaling was more active in tumor cells since nuclear translocation of FoXM1 is required to maximally exert its transcriptional function (11,26). this interpretation is further supported by our finding that FOXM1 expression in HCC was closely correlated with tumor proliferation reflected by nuclear pcnA expression.…”

Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1

“…FoxM1 expression increases during the G1 to S phase after cyclin E/cyclin-dependent kinase 2-mediated (Major et al, 2004) and Ras/Mek/Erk kinase-mediated phosphorylation (Ma et al, 2005). However, it is unlikely that the increase in G1-phase cells and downregulation of FoxM1 expression in response to OGT knockdown is due to loss of Mek/Erk signaling, as no decrease in Erk activation is observed in OGT knockdown cells.…”

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

“…Therefore, TP53 mutations induce an increase in FOXM1 expression and subsequent abnormal signaling (33). Three isoforms of FOXM1, FOXM1c, FOXM1b and FOXM1s, are involved in cell proliferation and DNA repair (34,35), and the effects of TP53 genetic mutations on these signaling molecules have been hypothesized to cause malignant transformation in cells (36).…”