REGULATION OF THE MESSENGER-RNA-BINDING PROTEIN AUF1 BY ACTIVATION OFTHE BETA-ADRENERGIC-RECEPTOR SIGNAL-TRANSDUCTION PATHWAY

In both cell culture based model systems and in the failing human hear t, beta-adrenergic receptors (beta-AR) undergo agonist-mediated down-r egulation. This decrease correlates closely with down-regulation of it s mRNA, an effect regulated in part by changes in mRNA stability. Regu lation of mRNA stability has been associated with mRNA-binding protein s that recognize A + U-rich elements within the 3'-untranslated region s of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonst rate here that the mRNA-binding protein, AUF1, is present in both huma n heart and in hamster DDT1-MF2 smooth muscle cells and that its abund ance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myoc ardial failure, a condition associated with increases in the beta-adre nergic receptor agonist norepinephrine. In the same hearts, there was a significant decrease (similar to 50%) in the abundance of beta(1)-AR mRNA and protein. In DDT1-MFB cells, where agonist-mediated destabili zation of beta(2)-AR mRNA was first described, exposure to beta-AR ago nist resulted in a significant increase in AUF1 mRNA and protein (simi lar to 100%). Conversely, agonist exposure significantly decreased (si milar to 40%) beta(2)-adrenergic receptor mRNA abundance. Last, we dem onstrate that AUF1 can be immunoprecipitated from polysome-derived pro teins following UV cross-linking to the 3'-untranslated region of the human beta(1)-AR mRNA and that purified, recombinant p37(AUF1) protein also binds to beta(1)-AR 3'-untranslated region mRNA.