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JNK activation decreases PP2A regulatory subunit B56 expression and mRNA stability and increases AUF1 expression in cardiomyocytes

¹Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland; ²Departments of Anesthesiology and Medicine, University of California at Los Angeles, California; and ³Institute of Molecular Cardiology, Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland

Submitted 2 November 2005 ; accepted in final form 23 March 2006

A central feature of heart disease is a molecular remodeling of signaling pathways in cardiac myocytes. This study focused on novel molecular elements of MAPK-mediated alterations in the pattern of gene expression of the protein phosphatase 2A (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'-untranslated region of this transcript contains adenylate-uridylate-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 significant decay over 1 h) to a labile form that rapidly degraded within minutes. These results were supported by complementary experiments that revealed that the RNA-binding protein AUF1, known to destabilize target mRNA, was increased fourfold in JNK-activated cells. A variety of other stress-related stimuli, such as p38 MAPK activation and phorbol ester, upregulated AUF1 expression in cultured cardiac cells as well. In addition, gel mobility shift assays demonstrated that p37^AUF1 binds with nanomolar affinity to segments of the B56 3'-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.

protein phosphatase 2A; mitogen-activated protein kinase; gene expression; AUF1

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