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J. Biol. Chem., Vol. 282, Issue 13, 9505-9516, March 30, 2007

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Protein Kinase C Regulates Internal Initiation of Translation of the GATA-4 mRNA following Vasopressin-induced Hypertrophy of Cardiac Myocytes^*

Anushree Sharma¹, Janine Masri, Oak D. Jo, Andrew Bernath, Jheralyn Martin, Alexander Funk, and Joseph Gera²

From the Department of Research & Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 91343 and the Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90048

GATA-4 is a key member of the GATA family of transcription factors involved in cardiac development and growth as well as in cardiac hypertrophy and heart failure. Our previous studies suggest that GATA-4 protein synthesis may be translationally regulated. We report here that the 518-nt long 5'-untranslated region (5'-UTR) of the GATA-4 mRNA, which is predicted to form stable secondary structures (–65 kcal/mol) such as to be inhibitory to cap-dependent initiation, confers efficient translation to monocistronic reporter mRNAs in cell-free extracts. Moreover, uncapped GATA-4 5'-UTR containing monocistronic reporter mRNAs continue to be well translated while capped reporters are insensitive to the inhibition of initiation by cap-analog, suggesting a cap-independent mechanism of initiation. Utilizing a dicistronic luciferase mRNA reporter containing the GATA-4 5'-UTR within the intercistronic region, we demonstrate that this leader sequence confers functional internal ribosome entry site (IRES) activity. The activity of the GATA-4 IRES is unaffected in trans-differentiating P19CL6 cells, however, is strongly stimulated immediately following arginine-vasopressin exposure of H9c2 ventricular myocytes. IRES activity is then maintained at submaximal levels during hypertrophic growth of these cells. Supraphysiological Ca²⁺ levels diminished stimulation of IRES activity immediately following exposure to vasopressin and inhibition of protein kinase C activity utilizing a pseudosubstrate peptide sequence blocked IRES activity during hypertrophy. Thus, our data suggest a mechanism for GATA-4 protein synthesis under conditions of reduced global cap-dependent translation, which is maintained at a submaximal level during hypertrophic growth and point to the regulation of GATA-4 IRES activity by sarco(ER)-reticular Ca²⁺ stores and PKC.

Received for publication, September 15, 2006 , and in revised form, January 24, 2007.

^* This work was supported in part by Grant CA109312 from the National Institutes of Health and by an award from the Veterans Administration. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO.

² To whom correspondence should be addressed. Tel.: 818-895-9416; Fax: 818-895-9554; E-mail: gera{at}ucla.edu.

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