Posttranscriptional regulation of urokinase plasminogen activator receptor messenger RNA levels by leukocyte integrin engagement.
As an adhesion receptor, the beta2 integrin lymphocyte function-associated antigen-1 (LFA-1) contributes a strong adhesive force to promote T lymphocyte recirculation and interaction with antigen-presenting cells. 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 cell membrane urokinase plasminogen activator receptor (uPAR) and that this induced uPAR is functional. To investigate the mechanism(s) of this induction, we used the RNA polymerase II inhibitor 5, 6-dichloro-1-beta-D-ribobenzimidazole and determined that uPAR mRNA degradation is delayed by LFA-1 activation. Cloning of the wild-type, deleted and mutated 3'-untranslated region of the uPAR cDNA into a serum-inducible rabbit beta-globin cDNA reporter construct revealed that the AU-rich elements and, in particular the nonameric UUAUUUAUU sequence, are crucial cis-acting elements in uPAR mRNA degradation. Experiments in which Jurkat T cells were transfected with reporter constructs demonstrated that LFA-1 engagement was able to stabilize the unstable reporter mRNA containing the uPAR 3'-untranslated region. Our study reveals a consequence of adhesion receptor-mediated signaling in T cells, which is potentially important in the regulation of T cell activation, including production of cytokines and expression of proto-oncogenes, many of which are controlled through 3' AU-rich elements.
Wang
G J
GJ
Section of Immunobiology, Molecular Cardiobiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Collinge
M
M
Blasi
F
F
Pardi
R
R
Bender
J R
JR
D000595:Amino Acid Sequence; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000276:immunology*; D019169:Jurkat Cells; D007962:Leukocytes / Q000276:immunology*; D008969:Molecular Sequence Data; D012323:RNA Processing, Post-Transcriptional / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D055293:Receptors, Urokinase Plasminogen Activator; D013601:T-Lymphocytes / Q000276:immunology*; D014568:Urokinase-Type Plasminogen Activator / Q000276:immunology
D016023:Integrins; C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator