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 CK2␣ overexpression. TGF-␤1 increased the expressions of CK2 and TTP and the TTP function. The siRNA against CK2␣ or TTP reversed TGF-␤1-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-␤1 enhances the activity of CK2. 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). TTP also regulates the stability of VEGF transcripts (2), indicating a possible role for TTP in angiogenesis and tumor growth (3, 4). Up-regulation of TTP mRNA can be induced by 12-Otetradecanoylphorbol-13-acetate (5), insulin (6), lipopolysaccharide (LPS) (7, 8), GM-CSF (9), TGF-␤ (10), IL-10 (11), and glucocorticoid (12). TTP mRNA contains AREs, and its stability is regulated by TTP itself (8).TTP is highly phosphorylated both in vitro and in vivo, and its phosphorylation is regulated by p42 MAPK (13), p38 MAPK (13, 14), c-Jun N-terminal kinase (JNK) (13), and MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2) (7,15,16). Among these protein kinases, the p38 MAPK/MK-2 pathway has been reported to be a crucial regulator of the expression, stability, and function of TTP (7,17,18). Phosphorylation of TTP by MK2 increases the binding of 14-3-3 proteins, thereby excluding TTP from stress granules, inactivating TTP, and increasing the stabilities of target mRNAs (15,16,19). The TTP protein is unstable and is rapidly degraded by proteasomes (17, 20); however, phosphorylation of TTP by p38 MAPK protects TTP from proteasomal degradation (17). 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.Casein kinase 2 (CK2), a highly conserved and ubiquitously expressed serine/threonine kinase, is a tetramer composed of two catalytic subunits (␣ and ␣Ј) and two regulatory subunits (␤) in an ␣ 2 ␤ 2 , ␣␣Ј␤ 2 , or ␣Ј 2...

Compared with EMR, ESMR-L is a safe and effective method for histologic complete resection of small rectal carcinoid tumors, especially in patients with previously biopsied carcinoid tumors.