AGONIST-MEDIATED DESTABILIZATION OF HUMAN BETA(1)-ADRENERGIC RECEPTORMESSENGER-RNA - ROLE OF THE 3'-UNTRANSLATED TRANSLATED REGION

For proto-oncogenes and cytokines, regulation of gene expression at th e level of mRNA stability is well established. In contrast, there is c omparatively limited knowledge regarding this mechanism of regulation for G-protein-coupled receptors. To explore this process further, the human beta(1)-adrenergic receptor (AR) was stably expressed in tsAF8 c ells. Treatment with beta-agonist decreased the half-life of beta(1)-A R mRNA by similar to 50%. Removal of the 3'UTR from the beta(1)-AR (co ding region only) dramatically stabilized mRNA. Additionally, in a chi meric mRNA, the beta(1)-AR 3'UTR was able to target the normally highl y stable beta-globin mRNA for accelerated decay. However, the chimera did not undergo agonist-mediated destabilization indicating that the 3 'UTR may be ''necessary but not sufficient'' for agonist-mediated mRNA destabilization. Inhibition of translation significantly stabilized b eta(1)-AR mRNA (similar to 2-fold); however, pretreatment of cells wit h beta-agonist prior to translational arrest produced the same degree of mRNA destabilization indicating that agonist-mediated destabilizati on may be independent of the translation process. Conversely, translat ional inhibition simultaneous with beta-agonist exposure abrogated ago nist-mediated destabilization indicating a dependence on de novo prote in synthesis. (C) 1998 Academic Press.