POSTTRANSCRIPTIONAL REGULATION OF UROKINASE PLASMINOGEN-ACTIVATOR RECEPTOR MESSENGER-RNA LEVELS BY LEUKOCYTE INTEGRIN ENGAGEMENT

As an adhesion receptor, the beta(2) integrin lymphocyte function-asso ciated antigen-1 (LFA-1) contributes a strong adhesive force to promot e T lymphocyte recirculation and interaction with antigen-presenting c ells. As a signaling molecule, LFA-1-mediates transmembrane signaling, which leads to the generation of second messengers and costimulation resulting in T cell activation. We recently have demonstrated that, in costimulatory fashion, LFA-1 activation promotes the induction of T c ell membrane urokinase plasminogen activator receptor (uPAR) and that this induced uPAR is functional. To investigate the mechanism(s) of th is induction, we used the RNA polymerase II inhibitor 5,6-dichloro-1-b eta-D-ribobenzimidazole and determined that uPAR mRNA degradation is d elayed by LFA-1 activation. Cloning of the wild-type, deleted and muta ted 3'-untranslated region of the uPAR cDNA into a serum-inducible rab bit beta-globin cDNA reporter construct revealed that the AU-rich elem ents and, in particular the nonameric UUAUUUAUU sequence, are crucial cis-acting elements in uPAR mRNA degradation. Experiments in which Jur kat T cells were transfected with reporter constructs demonstrated tha t LFA-1 engagement was able to stabilize the unstable reporter mRNA co ntaining the uPAR 3'-untranslated region. Our study reveals a conseque nce of adhesion receptor-mediated signaling in T cells, which is poten tially important in the regulation of T cell activation, including pro duction of cytokines and expression of protooncogenes, many of which a re controlled through 3' AU-rich elements.