Regulated expression of certain genes in the intestinal epithelial cells is controlled at the posttranscriptional levels of mRNA stability and mRNA translation. Dysregulation in either one could lead to various pathophysiological conditions including colon cancer and inflammatory bowel disease. An important cis-acting element controlling these functions is the AU-rich sequence elements, which is present in the 3'untranslated region of many tightly regulated genes. We have recently identified a novel AU-rich RNA binding protein, CUGBP2, which is induced in intestinal epithelial cells after radiation injury, coincident with the cells undergoing apoptosis. Furthermore COX-2 mRNA rapidly accumulates in the intestine after radiation injury, however, COX-2 mRNA translation is inhibited. We have now determined that CUGBP2 binds 3' untranslated region of COX-2 mRNA and stabilizes the mRNA, but inhibits its translation. Accordingly, the three aims of the current application are (a) to investigate the mechanism by which CUGBP2 binds and stabilizes AU-rich mRNAs, (b) to determine the mechanism by which CUGBP2 affects mRNA translation, and (c) to determine the effects of CUGBP2 expression on intestinal epithelial cell apoptosis. These experimental approaches should lead to a better understanding and significance of mucosal gene expression induced by injury, and advance our knowledge of posttranscriptional control of gene expression in intestine.
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