Immediate-early MEK-1-dependent stabilization of rat smooth muscle cell cyclooxygenase-2 mRNA by G alpha(q)-coupled receptor signaling

Activation of G alpha(q)-coupled P2Y nucleotide receptors strongly (>100-fo ld) induces the rat vascular smooth muscle cell cyclooxygenase-2 (COX-2) mR NA, yet transcription is induced only similar to 3-fold over 1 h. Intact ce ll decay analysis of tetracycline-suppressible luciferase chimera mRNAs sho ws that regulated stabilization of the intrinsically unstable mRNA contribu tes to this response. Deletion mapping of the 2468-base COX-2 mRNA 3'-untra nslated region (UTR) shows that a distal, 130 base AU-rich region functions as a cis-acting regulated stabilization response element, which under basa l conditions serves as the dominant instability determinant for the 3'-UTR. Regulation of this response is through the p42/44 MAP kinases, whereas the p38 MAP kinases are not involved. The stabilization response element binds avidly and specifically to a prominent nuclear-enriched similar to 90-kDa factor and several less abundantly labeled mRNA binding proteins that are u naffected by P2Y receptor signaling. Although other instability determinant s are located throughout the rat COX-2 mRNA 3'-UTR, mitogen signaling only interferes with rapid decay mediated by its most distal 130 bases. A comple x of nuclear factors that bind this mRNA region specifically may include ca ndidate targets for regulatory modulation, These observations support the g eneral notion that the rapid induction of immediate-early gene expression t hrough mitogenic receptors involves simultaneous activation of transcriptio nal and post-transcriptional mechanisms.