Shetty Sreerama, Idell Steven
Associate Professor of Medicine, University of Texas Health Center at Tyler, Tyler, TX, 75708, USA.
Am J Respir Cell Mol Biol. 2004 Jan;30(1):69-75. doi: 10.1165/rcmb.2002-0305OC. Epub 2003 Jun 19.
Interaction between urokinase-type plasminogen activator (uPA) and its receptor (uPAR) localizes cellular proteolysis and promotes cellular proliferation and migration, effects that may contribute to the pathogenesis of lung inflammation and neoplasia. Enhanced uPAR expression as well as stabilization of uPAR mRNA by transforming growth factor-beta and phorbol myristate acetate (PMA) shares a common mechanism involving phosphorylation and dephosphorylation of a uPAR mRNA-binding protein (uPAR mRNABp). PMA-induced tyrosine phosphorylation of the uPAR mRNABp inhibited the uPAR mRNA-uPAR mRNABp interaction, stabilized uPAR mRNA and enhanced uPAR protein expression. Downregulation of the uPAR mRNA and uPAR mRNABp interaction by PMA and transforming growth factor-beta can be reversed by pretreatment of cells with herbimycin which in turn inhibits expression of uPAR protein via a decrease in uPAR mRNA stability. Our experiments indicate that post-transcriptional regulation of uPAR expression requires activation of tyrosine kinases. Cytokines can regulate uPAR expression of lung-derived epithelial cells at the post-transcriptional level by tyrosine phosphorylation of the uPAR mRNA binding protein and may thereby influence tissue remodeling in lung injury or neoplasia.
尿激酶型纤溶酶原激活剂（uPA）与其受体（uPAR）之间的相互作用可使细胞内蛋白水解定位，并促进细胞增殖和迁移，这些作用可能与肺部炎症和肿瘤形成的发病机制有关。转化生长因子-β和佛波酯肉豆蔻酸酯（PMA）可增强uPAR的表达以及uPAR mRNA的稳定性，这一过程涉及一种uPAR mRNA结合蛋白（uPAR mRNABp）的磷酸化和去磷酸化的共同机制。PMA诱导的uPAR mRNABp酪氨酸磷酸化抑制了uPAR mRNA与uPAR mRNABp的相互作用，稳定了uPAR mRNA并增强了uPAR蛋白的表达。PMA和转化生长因子-β对uPAR mRNA与uPAR mRNABp相互作用的下调作用可通过用赫曲霉素预处理细胞来逆转，而赫曲霉素又通过降低uPAR mRNA的稳定性来抑制uPAR蛋白的表达。我们的实验表明，uPAR表达的转录后调控需要酪氨酸激酶的激活。细胞因子可通过uPAR mRNA结合蛋白的酪氨酸磷酸化在转录后水平调节肺源性上皮细胞的uPAR表达，从而可能影响肺损伤或肿瘤形成中的组织重塑。
