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J. Biol. Chem., Vol. 278, Issue 47, 46494-46505, November 21, 2003

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Differences in the Function of Three Conserved E-boxes of the Muscle Creatine Kinase Gene in Cultured Myocytes and in Transgenic Mouse Skeletal and Cardiac Muscle^*

Quynh-Giao V. Nguyen, Jean N. Buskin, Charis L. Himeda, Margaret A. Shield, and Stephen D. Hauschka

From the Department of Biochemistry, University of Washington, Seattle, Washington 98195-7350

The 1256-base pair enhancer-promoter of the mouse muscle creatine kinase gene includes three CAnnTG E-boxes that are conserved among mammals and have flanking and middle sequences conforming to consensus muscle regulatory factor binding sites. This study seeks to determine whether these E-boxes are critical for muscle creatine kinase expression in physiologically distinct muscles. Mutations of the "right" and "left" E-boxes in the enhancer decreased expression in cultured skeletal myocytes 10- and 2-fold, respectively, whereas a "promoter" E-box mutation had little effect. In neonatal myocardiocytes, the left E-box mutation decreased expression 3-fold, whereas right or promoter E-box mutations had no effect. Very different effects were seen in transgenic mice, where the promoter E-box mutation decreased expression in quadriceps, extensor digitorum longus, and soleus 10-fold, and 100-fold in distal tongue, diaphragm, and ventricle. The right E-box mutation, tested in the presence of the other two mutations, caused a significant decrease in distal tongue, but not in quadriceps, extensor digitorum longus, soleus, or ventricle. Mutation of the left E-box actually raised expression in soleus, suggesting a possible repressor role for this control element. The discrepancies between mutation effects in differentiating skeletal muscle cultures, neonatal myocardiocytes, and adult mice suggested that the E-boxes might play different roles during muscle development and adult steady-state function. However, transgenic analysis of embryonic and early postnatal mice indicated no positive role for these three E-boxes in early development, implying that differences in E-box function between adult muscle and cultured cells are the result of physiological signals.

Received for publication, July 28, 2003 , and in revised form, September 8, 2003.

^* This work was supported by National Institutes of Health Grants AR 18860 and HL 64387, by a grant from the Muscular Dystrophy Association, and by National Science Foundation Grant EEC9529161 (to the University of Washington Engineered Biomaterials National Bioengineering Research Center). 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.

Present address: Northwest Center for Public Health Practice, University of Washington, Seattle, WA 98195-4809.

To whom correspondence should be addressed: Dept. of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195-7350. Tel.: 206-543-1797; Fax: 206-685-1792; E-mail: haus{at}u.washington.edu.

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