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, Expression and mRNA Stability and Increases AUF1 Expression in Cardiomyocytes
1 Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, United States
2 Anesthesiology and Medicine, UCLA School of Medicine, Los Angeles, California, United States
3 Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, United States; Institute of Molecular Cardiology, University of Maryland Biotechnology Institute, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: trogers{at}umaryland.edu.
A central feature of heart disease is a molecular remodeling of signaling pathways in cardiac myocytes. This study focused on novel molecular elements of MAP kinase-mediated alterations in the pattern of gene expression of the protein phosphatase, PP2A. In an established model of sustained JNK activation a 70% decrease in expression of the targeting subunit of PP2A, B56
, was observed in either neonatal or adult cardiomyocytes. This loss in protein abundance was accompanied by a decrease of 69% in B56 mRNA steady-state levels. Given that the 3 prime untranslated region of this transcript contains AU-rich elements known to regulate mRNA degradation, experiments explored the notion that instability of B56 mRNA accounts for the response. mRNA time course analyses with real time PCR methods showed that B56 transcript was transformed from a stable (no decay over 1 hr) to a labile form that rapidly degraded within minutes. These results were supported by complementary experiments revealing that the RNA-binding protein AUF1, known to destabilize target mRNA, was increased 4-fold in JNK-activated cells. A variety of other stress-related stimuli, such as p38 MAP kinase activation and phorbol ester, upregulated AUF1 and decreased B56 expression in cultured cardiac cells as well. In addition, gel mobility shift assays demonstrated that p37AUF1 binds with nanomolar affinity to segments of the B56 3 prime untranslated region. Thus, these studies provide new evidence that signaling-induced mRNA instability is an important mechanism that underlies the changes in the pattern of gene expression evoked by stress-activated pathways in cardiac cells.
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