1. Regulation of the mRNA-binding protein AUF1 by activation of the beta-adrenergic receptor signal transduction pathway.
- Author
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Pende A, Tremmel KD, DeMaria CT, Blaxall BC, Minobe WA, Sherman JA, Bisognano JD, Bristow MR, Brewer G, and Port J
- Subjects
- Base Sequence, DNA Primers chemistry, GTP-Binding Proteins physiology, Heart Failure metabolism, Heterogeneous Nuclear Ribonucleoprotein D0, Humans, Molecular Sequence Data, Muscle, Smooth metabolism, Polyribosomes metabolism, Polyribosomes radiation effects, Proto-Oncogene Mas, RNA, Messenger chemistry, Recombinant Proteins, Signal Transduction, Ultraviolet Rays, Gene Expression Regulation, Heterogeneous-Nuclear Ribonucleoprotein D, Myocardium metabolism, RNA, Messenger metabolism, RNA-Binding Proteins metabolism, Receptors, Adrenergic, beta physiology
- Abstract
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 (approximately 50%) in the abundance of beta1-AR mRNA and protein. In DDT1-MF2 cells, where agonist-mediated destabilization of beta2-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (approximately 100%). Conversely, agonist exposure significantly decreased (approximately 40%) beta2-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 beta1-AR mRNA and that purified, recombinant p37AUF1 protein also binds to beta1-AR 3'-untranslated region mRNA.
- Published
- 1996
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