CD28-COSTIMULATION ACTIVATES CYCLIC AMP-RESPONSIVE ELEMENT-BINDING PROTEIN IN T-LYMPHOCYTES

Cyclic AMP-responsive element binding protein (CREB) mediates gene exp ression in response to cAMP stimulation. The transcriptional activity of CREB depends on both the phosphorylation of Ser(133) and the recrui tment of cofactor for assembly of transcriptional complex, Extensive S er(133) phosphorylation of CREB was induced during T cell activation. This phosphorylation event is essential for IL-2 gene expression, Howe ver, phosphorylation of CREB at Ser(133) was not sufficient for transc riptional activity by CREB, The presence of a second signal from CD28, a potent costimulatory molecule on T cells, stimulated CREB-mediated gene expression. CD28, an effective costimulator of T cell activation and IL-2 gene expression, is shown to induce CREB activation in the pr esence of anti-CDS or O-tetradecanoylphorbol 13-acetate. These two sig nals together stimulated a CRE-dependent reporter gene, the proliferat ing cell nuclear Ag promoter, and transactivation by the GAL4-CREB fus ion protein, Thus optimal induction of CREB, similar to the full activ ation of T lymphocytes, may be mediated by two distinct signal transdu ctions. Using the specific kinase inhibitor, one of the two pathways a ppeared to involve mitogen-activated protein kinase kinase but not pro tein kinase C, protein kinase A, or p70 S6 kinase.