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J. Biol. Chem., Vol. 280, Issue 18, 18425-18433, May 6, 2005

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Upstream Stimulatory Factors (USF-1/USF-2) Regulate Human cGMP-dependent Protein Kinase I Gene Expression in Vascular Smooth Muscle Cells^*

Hassan Sellak, ChungSik Choi, Natasha Browner, and Thomas M. Lincoln

From the Department of Physiology, University of South Alabama, College of Medicine, Mobile, Alabama 36688

Cyclic GMP-dependent protein kinase I plays a pivotal role in regulating smooth muscle cell relaxation, growth, and differentiation. Expression of the enzyme varies greatly in smooth muscle and in other tissues and cell types, yet little is known regarding the mechanisms regulating cGMP-dependent protein kinase gene expression. The present work was undertaken to characterize the mechanisms controlling kinase gene expression in vascular smooth muscle cells. A 2-kb human cGMP-dependent protein kinase I 5'-noncoding promoter sequence was characterized by serial deletion, and functional studies demonstrated that a 591-bp 5'-promoter construct possessed the highest activity compared with all other constructs generated from the larger promoter. Analysis of the sequence between -472 and -591 bp from the transcriptional start site revealed the existence of two E-like boxes known to bind upstream stimulatory factors. Electrophoretic mobility shift assays and functional studies using luciferase reporter gene assays identified upstream stimulatory factors as the transcription factors bound to the E-boxes in the 591-bp promoter. Site-directed mutagenesis of the E-boxes abolished the binding of upstream stimulatory factor proteins and decreased the activity of the cGMP-dependent protein kinase I 591-bp promoter, thus confirming the involvement of these transcription factors in mediating gene expression. Cotransfection experiments demonstrated that overexpression of upstream stimulatory factors 1 and 2 increased cGMP-dependent protein kinase I promoter activity. Collectively, these data suggest that the human proximal cGMP-dependent protein kinase I promoter is regulated by tandem E-boxes that bind upstream stimulatory factors.

Received for publication, January 21, 2005 , and in revised form, February 22, 2005.

^* 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.

To whom correspondence should be addressed: Dept. of Physiology, University of South Alabama, Medical Science Bldg. Rm. 3024, Mobile, AL 36688. Tel.: 251-460-6428; Fax: 251-460-6967; E-mail: tlincoln{at}usouthal.edu.

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