Phosphorylated P68 RNA Helicase Activates Snail1 Transcription by Promoting HDAC1 Dissociation from the Snail1 Promoter

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Oncogene (Impact Factor: 8.46). 09/2010; 29(39):5427-36. DOI: 10.1038/onc.2010.276
Source: PubMed


The nuclear p68 RNA helicase is a prototypical member of the DEAD-box family of RNA helicases. p68 RNA helicase has been implicated in cell proliferation and early organ development and maturation. However, the functional role of p68 RNA helicase in these biological processes at the molecular level is not well understood. We previously reported that tyrosine phosphorylation of p68 RNA helicase mediates the effects of platelet-derived growth factor (PDGF) in induction of epithelial mesenchymal transition by promoting β-catenin nuclear translocation. Here, we report that phosphorylation of p68 RNA helicase at Y593 upregulates transcription of the Snail1 gene. The phosphorylated p68 activates transcription of the Snail1 gene by promoting histone deacetylase (HDAC)1 dissociation from the Snail1 promoter. Our results showed that p68 interacted with the nuclear remodeling and deacetylation complex MBD3:Mi-2/NuRD. Thus, our data suggested that a DEAD-box RNA unwindase could potentially regulate gene expression by functioning as a protein 'displacer' to modulate protein-protein interactions at the chromatin-remodeling complex.

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    • "It is combinated with the microtubules as a α-tubulin deacetylase. It is found that a lot of protein can be acetylated, and HDAC6 plays an important role in the physiological and pathological processes such as transcriptional regulation, signal transduction, cell differentiation and apoptosis, growth and development, and occurrence of metabolic diseases and tumors (Barnes et al., 2009; Husain et al., 2009; Carter et al., 2010). "
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    ABSTRACT: Objective: To study the effects of down-regulation of HDAC6 expression on proliferation, cell cycling and migration of esophageal squamous cell carcinoma (ESCC) cells and related molecular mechanisms. Methods: ESCC cell line EC9706 cells were randomly divided into untreated (with no transfection), control siRNA (transfected with control siRNA) and HDAC6 siRNA (transfected with HDAC6 small interfering RNA) groups. Effects of HDAC6 siRNA interference on expression of HDAC6 mRNA and protein in EC9706 cells were investigated by semi-quantitative RT-PCR, Western blotting and immunocytochemistry methods. Effects of down-regulation of HDAC6 expression on cell proliferation, cell cycle, and cell migration were studied using a CCK-8 kit, flow cytometry and Boyden chambers, respectively. Changes of mRNA and protein expression levels of cell cycle related factor (p21) and cell migration related factor (E-cadherin) were investigated by semi- quantitative RT-PCR and Western blotting methods. Results: After transfection of HDAC6 siRNA, the expression of HDAC6 mRNA and protein in EC9706 cells was significantly downregulated. In the HDAC6 siRNA group, cell proliferation was markedly inhibited, the percentage of cells in G0/G1 phase evidently increased and the percentage of cells in S phase decreased, and the number of migrating cells significantly and obviously decreased. The mRNA and protein expression levels of p21 and E-cadherin in the HDAC6 siRNA group were significantly higher than those in the untreated group and the control siRNA group, respectively. Conclusions: HDAC6 siRNA can effectively downregulate the expression of HDAC6 mRNA and protein in EC9706 cells. Down-regulation of HDAC6 expression can obviously inhibit cell proliferation, arrest cell cycling in the G0/G1 phase and reduce cell migration. The latter two functions may be closely related with the elevation of mRNA and protein expression of p21 and E-cadherin.
    Preview · Article · Feb 2013 · Asian Pacific journal of cancer prevention: APJCP
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    • "This DEAD box RNA helicase acts as a transcriptional co-regulator of several transcription factors, including the estrogen receptor (ER) (15–18). Ddx5, when recruited to target promoters by transcription factors, can in turn recruit or displace histone modifying enzymes, like CBP/p300 and HDACs, and/or recruit RNAPII, which ddx5 also binds to (19,20). Furthermore, ddx5 is a component of the spliceosome and facilitates the pre-spliceosome to spliceosome transition by unwinding the U1 snRNA/5′ splice site base-pairs thanks to its RNA helicase activity (21). "
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    ABSTRACT: It is widely accepted that pre-mRNA maturation, including splicing, is tightly coupled to both transcription and mRNA export, but factors linking the three processes are less understood. By analysing the estrogen-regulated expression of the c-fos mRNA that is processed during transcription, we show that the ddx5 RNA helicase, is required throughout the major nuclear steps of the expression of the c-fos gene, from transcription to mRNA export. Indeed, ddx5, whose recruitment on the c-fos gene was increased upon estrogen treatment, was required for the full transcriptional activation of the c-fos gene. In addition, ddx5 was required for c-fos co-transcriptional RNA splicing. When splicing occurred post-transcriptionally in the absence of ddx5, the c-fos mRNA was poorly exported into the cytosol because of inefficient recruitment of the TAP mRNA export receptor. Finally, ddx5 was present in the c-fos messenger ribonucleoprotein together with mRNA export factors, which further supports that ddx5 is a key operator in the c-fos ‘mRNA factory’.
    Full-text · Article · Nov 2012 · Nucleic Acids Research
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    ABSTRACT: The DEAD box RNA helicases p68 (DDX5) and p72 (DDX17) play important roles in multiple cellular processes that are commonly dysregulated in cancers, including transcription, pre-mRNA processing/alternative splicing and miRNA processing. Although p68 and p72 appear to have some overlapping functions, they clearly also have distinct, nonredundant functions. Furthermore, their ability to interact with a variety of different factors and act as multifunctional proteins has the potential to impact on several different processes, and alterations in expression or function of p68 and/or p72 could have profound implications for cancer development. However, their roles are likely to be context-dependent and both proteins have been reported to have pro-proliferation or even oncogenic functions as well as antiproliferative or tumor cosuppressor roles. Therefore, eludicating the precise role of these proteins in cancer is likely to be complex and to depend on the cellular environment and interacting factors. In this article, we review the many functions that have been attributed to p68 and p72 and discuss their potential roles in cancer development.
    No preview · Article · Feb 2011 · Future Oncology
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