Phosphorylation of p68 RNA Helicase Plays a Role in Platelet-derived Growth Factor-induced Cell Proliferation by Up-regulating Cyclin D1 and c-Myc Expression

Abstract

p68 RNA helicase is a protypical member of DEAD box family RNA helicase. The protein plays an important role in the cell developmental program and organ maturation. We demonstrated previously that, in response to growth factor platelet-derived growth factor (PDGF)-BB stimulation, p68 is phosphorylated at Tyr(593), and the phosphorylation of p68 promotes epithelial-mesenchymal transition via promoting beta-catenin nuclear translocation (Yang, L., Lin, C., and Liu, Z. R. (2006) Cell 127, 139-155). We show here that the tyrosine phosphorylation of p68 also mediates the effects of PDGF in stimulating cell proliferation. The phosphorylated p68 (referred to as phospho-p68) promotes cell proliferation by activating the transcription of cyclin D1 and c-Myc genes. We show that the ATPase/helicase activities of p68 are required for the activation of cyclin D1 transcription. The phospho-p68 participates in the complex assembled at the cyclin D1 and c-Myc promoters, which strongly suggests a direct role in transcriptional regulation. Furthermore, our data demonstrated that the phosphorylation of p68 at Tyr(593) plays a role in mediating the autocrine loop effects of PDGF, suggesting an important role for p68 phosphorylation in cell proliferation.

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

“…LCN2 can enhance tumor growth and metastasis by protecting matrix metalloproteinase-9 from degradation and by increasing angiogenesis and/ or by promoting the epithelial to mesenchymal transition, which is associated with breast cancer progression (Leng et al, 2009;Yang et al, 2009). Therefore, this study identified a novel gene regulatory pathway (NFAT5 stimulation of S100A4 and LCN2 genes) that is coactivated by ddx5/ddx17 and that, together with previously reported ddx5 and ddx17 target genes like cyclin D1 and Snail (Shin et al, 2007;Yang et al, 2007;Carter et al, 2010), strengthens the role of ddx5 and ddx17 in tumor progression.…”

“…One intriguing possibility is that, depending on the cellular context, ddx5/ddx17-splicing activity or their transcriptional activity could dominate each other and this could participate in the dual function of ddx5 and ddx17 in cancer. In this context, several reports have indicated that the splicing and transcriptional activities of ddx5 and ddx17 can be modulated by different post-translational modifications that depend on cellular signaling pathways (Yang et al, 2006(Yang et al, , 2007Jacobs et al, 2007;Carter et al, 2010;Mooney et al, 2010a, b). In addition, several post-translational modifications of ddx5 or ddx17 have been shown to be altered in different cancers (Causevic et al, 2001;Yang et al, 2005).…”

Oncogenic role of DDX3 in breast cancer biogenesis

“…For example, human DDX5 has been shown to be overexpressed at the protein level in colorectal tumors as well as in the hepatic tumor cell lines, HT-29 and HCT116, which have undergone an epithelial-mesenchymal transition (Yang et al, 2005(Yang et al, , 2006. In addition, DDX5 has been shown to upregulate the expression of cyclin D1 along with c-myc genes, which promoted cell proliferation in a series of mammalian cell lines (Yang et al, 2007). Along these lines, the activity of oncoprotein EWS-FLI1 has been shown to be enhanced by RNA helicase H in the Ewing's sarcoma family of tumors (Toretsky et al, 2006).…”

Reciprocal Regulation of Protein Kinase and Pyruvate Kinase Activities of Pyruvate Kinase M2 by Growth Signals

“…For instance, we previously demonstrated that platelet-derived growth factor (PDGF) or EGF stimulation led to tyrosine phosphorylation of p68 RNA helicase in SW480 cells (16,19). Presently, our experiments demonstrated that binding to tyrosine phosphoprotein converted PKM2 from tetramer to dimer and therefore activated the protein kinase activity.…”