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J. Biol. Chem., Vol. 281, Issue 26, 18043-18050, June 30, 2006

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Sp1 and Sp3 Mediate Constitutive Transcription of the Human Hyaluronan Synthase 2 Gene^*

Jamie Monslow¹, John D. Williams, Donald J. Fraser, Daryn R. Michael, Pelagia Foka^¶, Ann P. Kift-Morgan, Dong Dong Luo, Ceri A. Fielding, Kathrine J. Craig, Nicholas Topley, Simon A. Jones^||, Dipak P. Ramji^¶, and Timothy Bowen²

From the Institute of Nephrology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, Cardiff Institute of Tissue Engineering and Repair, Cardiff Medicentre, Heath Park, Cardiff, CF14 4UJ, ^||School of Biosciences, Cardiff University, Museum Avenue, P. O. Box 911, Cardiff CF10 3US, and ^¶Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom

The linear glycosaminoglycan hyaluronan (HA) is synthesized at the plasma membrane by the HA synthase (HAS) enzymes HAS1, -2, and -3 and performs multiple functions as part of the vertebrate extracellular matrix. Up-regulation of HA synthesis in the renal corticointerstitium, and the resultant extracellular matrix expansion, is a common feature of renal fibrosis. However, the regulation of expression of these HAS isoforms at transcriptional and translational levels is poorly understood. We have recently described the genomic structures of the human HAS genes, thereby identifying putative promoter regions for each isoform. Further analysis of the HAS2 gene identified the transcription initiation site and showed that region F3, comprising the proximal 121 bp of promoter sequence, mediated full constitutive transcription. In the present study, we have analyzed this region in the human renal proximal tubular epithelial cell line HK-2. Electrophoretic mobility shift and promoter assay data demonstrated that transcription factors Sp1 and Sp3 bound to three sites immediately upstream of the HAS2 transcription initiation site and that mutation of the consensus recognition sequences within these sites ablated their transcriptional response. Furthermore, subsequent knockdown of Sp1 or Sp3 using small interfering RNAs decreased constitutive HAS2 mRNA synthesis. In contrast, significant binding of HK-2 nuclear proteins by putative upstream NF-Y, CCAAT, and NF-B recognition sites was not observed. The identification of Sp1 and Sp3 as principal mediators of HAS2 constitutive transcription augments recent findings identifying upstream promoter elements and provides further insights into the mechanism of HAS2 transcriptional activation.

Received for publication, September 23, 2005 , and in revised form, February 21, 2006.

^* This work was funded by Project Grant 057503 from the Wellcome Trust. 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 The recipient of a Ph.D. studentship from the Kidney Wales Foundation.

² To whom correspondence should be addressed. Tel.: 44-29-2074-8389; Fax: 44-29-2074-8470; E-mail: bowent{at}cf.ac.uk.

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