Glyceraldehyde-3-Phosphate Dehydrogenase Binds to the AU-Rich 3′ Untranslated Region of Colony-Stimulating Factor–1 (CSF-1) Messenger RNA in Human Ovarian Cancer Cells: Possible Role in CSF-1 Posttranscriptional Regulation and Tumor Phenotype

Abstract

The overexpression of the colony-stimulating factor-1(CSF-1) by epithelial ovarian cancer cells enhances invasiveness and metastatic properties, contributing to the poor prognosis of the patients. It has been suggested that CSF-1 3Vuntranslated region containing AU-rich elements (ARE) could regulate CSF-1 posttranscriptional expression and be responsible for its aberrant abundance in such cancer cells. In this study, normal (NOSE.1) and malignant (Hey) ovarian epithelial cells were used to examine CSF-1 expression and regulation. CSF-1 overexpression in Hey cells was found to associate with increased invasiveness, motility, urokinase activity, and virulence of tumorigenicity, compared with NOSE.1 cells, which expressed little CSF-1. CSF-1 ARE was further found to serve as an mRNA decay element that correlates with downregulation of protein translation. Moreover, such downregulation was found more prominent in NOSE.1 than in Hey cells, suggesting differences in posttranscriptional regulation. As a variety of trans-acting factors [AU-binding protein (AUBP)] are known to modulate messenger stability through binding to such elements, we examined the protein content of both cell lines for their ability to bind the CSF-1 ARE. Our results strongly suggested the abundance of such AUBP activity in Hey cells. We isolated a 37-kDa AUBP, which was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To summarize, our study identified GAPDH as an AUBP abundant in Hey cells, where it binds to CSF-1 ARE that imparts mRNA decay. These data suggest that GAPDH binding to CSF-1 ARE sequence prevents CSF-1 mRNA decay and subsequent down-regulation of CSF-1 protein translation, leading to CSF-1 overexpression and increased metastatic properties seen in ovarian cancer. (Cancer Res 2005; 65(9): 3762-71)

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces cancer cell senescence by interacting with telomerase RNA component

“…24), we examined whether an interaction between GAPDH and the telomerase RNA moiety hTERC exists. As a positive control for GAPDH RNA binding, an AU-rich RNA molecule (4× AUUUA) was used, as has been previously demonstrated to interact with GAPDH (26). As shown in Fig.…”

“…In the nucleus, GAPDH is the key component of a gene transcriptosome for cell division (6). Binding to nucleic acids, GAPDH is implicated in mediating RNA nuclear export (22), protecting mRNA from degradation through interaction with AU-rich elements (AREs) (26) and the repair of DNA (27). Moreover, studies have shown that GAPDH binds to telomeres directly (8,9).…”

Radiation-Induced Changes in Gene Expression Involve Recruitment of Existing Messenger RNAs to and away from Polysomes

“…Interestingly, the only pathway that was overrepresented by genes whose translation was decreased after irradiation was monosaccharide catabolism, specifically glycolysis. Whereas GAPDH is a glycolytic enzyme and yet was increased in the polysome fraction after irradiation, recent reports indicate that it has additional activities, including RNA binding (23).…”

Significance of the glycolytic pathway and glycolysis related-genes in tumorigenesis of human colorectal cancers

“…Consequently, high carbohydrates, through the up-regulation of a series of glycolysis-related genes, may subsequently activate the glycolytic pathway and is closely related to the tumorigenesis of CRC. GAPD is overexpressed in both ovarian and prostate cancers, and is proved to be crucial in metastatic properties (31)(32)(33). In addition, GAPD is associated with the proliferation and aggressiveness of breast cancer cells (34).…”