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J. Biol. Chem., Vol. 281, Issue 16, 10849-10855, April 21, 2006

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Human Prolyl-4-hydroxylase (I) Transcription Is Mediated by Upstream Stimulatory Factors^*

Li Chen, Ying H. Shen, Xinwen Wang, Jing Wang, Yehua Gan, Nanyue Chen^¶, Jian Wang, Scott A. LeMaire, Joseph S. Coselli, and Xing Li Wang¹

From the Section of Adult Cardiothoracic Service, Texas Heart Institute at St. Luke's Episcopal Hospital and Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030 and ^¶Department of Molecular Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030

Prolyl-4-hydroxylase (I) (P4H(I)) is the rate-limiting subunit for P4H enzyme activity, which is essential for procollagen hydroxylation and secretion. In the current study, we have characterized the human P4H(I) promoter for transcription factors and DNA elements regulating P4H(I) expression. Using a progressive deletion cloning approach, we have constructed pGL3-P4H(I) recombinant plasmids. We have identified a positive regulatory region at the positions of bp –184 to –97 responsible for 80% of the P4H(I) promoter efficiency. Three E-boxes were located within this region, and the E-box at position bp –135 explains most of the regulatory capacity. Upstream stimulatory factors (USF1/USF2) were shown to bind on the E-box using chromatin immunoprecipitation assay. Suppression of USF1 and/or USF2 using specific short interference RNA resulted in a significant reduction in P4H(I) promoter activity, and overexpressed USF1 or USF2 increased P4H(I) promoter activity significantly. Although transforming growth factor 1 increased the USF1/USF2-E-box binding and P4H(I) promoter activity, this up-regulatory effect can be largely prevented by USF1/USF2-specific short interference RNA. On the other hand, cigarette smoking extracts, which have been shown to suppress P4H(I) expression, inhibited the binding between the USF1/USF2 and E-box, resulting in a reduced P4H(I) promoter activity. Furthermore, the E-box on the P4H(I) promoter appeared to indiscriminately bind with either USF1 or USF2, with a similar outcome on the promoter efficiency. In conclusion, our study shows that USF1/USF2 plays a critical role in basal P4H(I) expression, and both positive (transforming growth factor 1) and negative (cigarette smoking extract) regulators appear to influence the USF-E-box interaction and affect P4H(I) expression.

Received for publication, October 16, 2005 , and in revised form, January 23, 2006.

^* This work was supported by American Heart Association Established Investigator Award AHA 0440001N (to X. L. W.) and National Institutes of Health Grants HL066053 and HL71608. 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 To whom correspondence should be addressed: NAB 2010, One Baylor Plaza, Baylor College of Medicine, Houston, TX 77030. Tel.: 713-798-5485; Fax: 713-798-1705; E-mail: xlwang{at}bcm.tmc.edu.

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