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J. Biol. Chem., Vol. 281, Issue 25, 16951-16961, June 23, 2006

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Regulation of cGMP-dependent Protein Kinase Expression by Rho and Krüppel-like Transcription Factor-4^*

Ying Zeng, Shunhui Zhuang, Jutta Gloddek¹, Chi-Chuan Tseng, Gerry R. Boss, and Renate B. Pilz²

From the Department of Medicine and Cancer Center, University of California at San Diego, La Jolla, California 92093 and the Section of Gastroenterology, Boston University School of Medicine, Boston, Massachusetts 02118

Type I cGMP-dependent protein kinase (PKG I) plays a major role in vascular homeostasis by mediating smooth muscle relaxation in response to nitric oxide, but little is known about the regulation of PKG I expression in smooth muscle cells. We found opposing effects of RhoA and Rac1 on cellular PKG I expression: (i) cell density-dependent changes in PKG I expression varied directly with Rac1 activity and inversely with RhoA activity; (ii) RhoA activation by calpeptin suppressed PKG I, whereas RhoA down-regulation by small interfering RNA increased PKG I expression; and (iii) PKG I promoter activity was suppressed in cells expressing active RhoA or Rho-kinase but was enhanced in cells expressing active Rac1 or a dominant negative RhoA. Sp1 consensus sequences in the PKG I promoter were required for Rho regulation and bound nuclear proteins in a cell density-dependent manner, including the Krüppel-like factor 4 (KLF4). KLF4 was identified as a major trans-acting factor at two proximal Sp1 sites; active RhoA suppressed KLF4 DNA binding and trans-activation potential on the PKG I promoter. Experiments with actin-binding agents suggested that RhoA could regulate KLF4 via its ability to induce actin polymerization. Regulation of PKG I expression by RhoA may explain decreased PKG I levels in vascular smooth muscle cells found in some models of hypertension and vascular injury.

Received for publication, March 6, 2006

^* This work was supported in part by United States Public Health Service Grants GM55586 and AR051300 (to R. B. P.) and CA89828 (to G. R. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by the Deutsche Forschungsgemeinschaft.

² To whom correspondence should be addressed: Dept. of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0652. Tel.: 858-534-8805; Fax: 848-534-1421; E-mail: rpilz{at}ucsd.edu.

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