Abstract
CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific alternative splicing and contributes to the pathogenesis of myotonic dystrophy (DM), however the role of CELF6 in cancer cell proliferation is less appreciated. Here, we show that the expression of CELF6 is cell cycle regulated. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-β-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation. Overexpression or depletion of CELF6 modulates p21 gene expression. CELF6 binds to the 3′UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. The effect of CELF6 on cell proliferation is p53 and/or p21 dependent. Collectively, these data demonstrate that CELF6 might be a potential tumor suppressor, CELF6 regulates cell proliferation and cell cycle progression via modulating p21 stability.
Highlights
RNA-binding proteins (RBPs) play crucial role in posttranscriptional regulation in eukaryotes and control multiple aspects of cell behavior
The expression of CELF6 is cell cycle regulated To examine whether the expression of CELF6 is cell cycle regulated, the HCT116 colorectal cancer cells were synchronized at the G1/S boundary by a double-thymidine (DT) block, cells were released and harvested at different time points to perform flow cytometry and immunoblotting analysis
Quantitative RT-PCR demonstrated that the expression patterns of CELF6 protein and mRNA are different, CELF6 mRNA levels increased dramatically 4 h post DT release, indicating that posttranscriptional modifications may regulate the fluctuation of CELF6 protein during the cell cycle (Fig. 1c)
Summary
RNA-binding proteins (RBPs) play crucial role in posttranscriptional regulation in eukaryotes and control multiple aspects of cell behavior. RBPs often bind to mRNAs or noncoding RNAs to regulate all steps of RNA biogenesis, including pre-mRNA splicing, polyadenylation, transport and localization, mRNA stability, and translation[1,2,3]. RBPs bind to specific sequences or secondary structures of target RNAs through RNA-binding domains (RBDs). An RNA-binding protein contains one or more different. RBDs, which allow high flexibility for interaction with different RNA targets[4]. Considering that RBPs coordinate the networks of protein-RNA and protein–protein interactions that control RNA metabolism, aberrant expression of RBPs have been implicated in many human diseases such as cancer[5]. RBPs control the expression of numerous oncogenes or tumor suppressors through posttranscriptional gene regulation. Many RBPs are deregulated in cancer and play critical roles in tumorigenesis and cancer development
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