Regulation of the mRNA-binding protein AUF1 by activation of the beta-adrenergic receptor signal transduction pathway

In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors (beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonstrate here that the mRNA-binding protein, AUF1, is present in both human heart and in hamster DDT1-MF2 smooth muscle cells and that its abundance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myocardial failure, a condition associated with increases in the beta-adrenergic 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 destabilization of beta(2)-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (similar to 100%). Conversely, agonist exposure significantly decreased (similar to 40%) beta(2)-adrenergic receptor mRNA abundance. Last, we demonstrate that AUF1 can be immunoprecipitated from polysome-derived proteins 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.