Abstract
Tristetraprolin (TTP) is an AU-rich element-binding protein that regulates mRNA stability. We previously showed that TTP acts as a negative regulator of VEGF gene expression in colon cancer cells. The p38 MAPK pathway is known to suppress the TTP activity. However, until now the signaling pathway to enhance TTP function is not well known. Here, we show that casein kinase 2 (CK2) enhances the TTP function in the regulation of the VEGF expression in colon cancer cells. CK2 increased TTP protein levels and enhanced VEGF mRNA decaying activity of TTP. TTP was not a direct target of CK2. Instead, CK2 increased the phosphorylation of MKP-1, which led to a decrease in the phosphorylation of p38 MAPK. Inhibition of MKP-1 by siRNA attenuated the increase in TTP function and the decrease of p38 phosphorylation induced by CK2α overexpression. TGF-β1 increased the expressions of CK2 and TTP and the TTP function. The siRNA against CK2α or TTP reversed TGF-β1-induced increases in the expression of CK2 and TTP and the TTP function. Our data suggest that CK2 enhances the protein level and activity of TTP via the modulation of the MKP-1-p38 MAPK signaling pathway and that TGF-β1 enhances the activity of CK2.
Highlights
Tristetraprolin (TTP)3 is an AU-rich element (ARE)-binding protein that mediates the decay of ARE-containing mRNAs such as those encoding cytokines and proto-oncogenes [1]
We demonstrate that Casein kinase 2 (CK2) increases the VEGF mRNA decaying activity of TTP in human colon cancer cells by protecting the TTP protein from phosphorylation and proteasomal degradation
CK2 Inhibition via CK2 Inhibitors or siRNA Decreases the VEGF mRNA Decaying Activity of TTP—TTP has been reported to be phosphorylated by various kinds of protein kinases [39]
Summary
Tristetraprolin (TTP) is an AU-rich element (ARE)-binding protein that mediates the decay of ARE-containing mRNAs such as those encoding cytokines and proto-oncogenes [1]. Recent evidence suggests that phosphorylation-induced inhibition of TTP can be reversed by protein phosphatase 2A (PP2A) through the inactivation of p38 MAPK and MK2 [21] Despite these studies on TTP phosphorylation, the signaling pathways responsible for the induction of TTP activity are not well known. We previously reported that TTP down-regulates the expression of VEGF and inhibits the growth of human colon cancer cells in vitro and in vivo [37]. We demonstrate that CK2 increases the VEGF mRNA decaying activity of TTP in human colon cancer cells by protecting the TTP protein from phosphorylation and proteasomal degradation.
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