2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces binding of a 50 kDa protein on the 3 ' untranslated region of urokinase-type plasminogen activatormRNA

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic compound that ha s recently attracted much attention as an environmental contaminant, elicit s a variety of toxic responses. Most, if not all, of the toxic effects of T CDD are thought to result from alteration of gene expression. TCDD acts thr ough both transcriptional and posttranscriptional mechanisms to alter gene expression of many genes. Transforming growth factor (TGF)-alpha and urokin ase-type plasminogen activator (uPA) are examples of the genes up-regulated posttranscriptionally by TCDD by mRNA stabilization. While effects of TCDD on transcription have been extensively studied, the molecular mechanisms u nderlying the TCDD-induced changes in mRNA stability are poorly understood. In this study, we investigated the trans-acting factors involved in TCDD-d ependent mRNA stabilization. UV-crosslinking study showed that a liver cyto plasmic protein of 50 kDa (p50) selectively recognized the 3' UTR of the uP A mRNA in a TCDD-dependent manner. We also showed that the activation of p5 0 by TCDD is mediated through a protein phosphorylation cascade but not via de novo protein synthesis. This is the first study to show the presence of the TCDD-dependent RNA binding activity which may be involved in TCDD-depe ndent stabilization of mRNA. (C) 2000 Academic Press.