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J. Biol. Chem., Vol. 279, Issue 20, 20576-20581, May 14, 2004

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Identification and Analysis of the Promoter Region of the Human Hyaluronan Synthase 2 Gene^*

Jamie Monslow¶, John D. Williams, Carol A. Guy||, Iain K. Price, Kathrine J. Craig, Hywel J. Williams||, Nigel M. Williams||, John Martin, Sharon L. Coleman, Nicholas Topley, Andrew P. Spicer**, Paul R. Buckland||, Malcolm Davies, and Timothy Bowen

From the Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom, Cardiff Institute of Tissue Engineering and Repair, Cardiff Medicentre, Heath Park, Cardiff, CF14 4UJ, United Kingdom, ^||Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom, and ^**Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas 77030

Hyaluronan (HA) is a linear glycosaminoglycan of the vertebrate extracellular matrix that is synthesized at the plasma membrane by the HA synthase (HAS) enzymes HAS1, -2 and -3. The regulation of HA synthesis has been implicated in a variety of extracellular matrix-mediated and pathological processes, including renal fibrosis. We have recently described the genomic structures of each of the human HAS genes. In the present study, we analyzed the HAS2 promoter region. In 5'-rapid amplification of cDNA ends analysis of purified mRNA from human renal epithelial proximal tubular cells, we detected an extended sequence for HAS2 exon 1, relocating the transcription initiation site 130 nucleotides upstream of the reference HAS2 mRNA sequence, GenBank^TM accession number NM_005328. A luciferase reporter gene assay of nested fragments spanning the 5' terminus of NM_005328 demonstrated the constitutive promoter activity of sequences directly upstream of the repositioned transcription initiation site but not of the newly designated exonic nucleotides. Using reverse transcription-PCR, expression of this extended HAS2 mRNA was demonstrated in a variety of human cell types, and orthologous sequences were detected in mouse and rat kidney. Alignment of human, murine, and equine genomic DNA sequences upstream of the repositioned HAS2 exon 1 provided evidence for the evolutionary conservation of specific transcription factor binding sites. The location of the HAS2 promoter will facilitate analysis of the transcriptional regulation of this gene in a variety of pathological contexts as well as in developmental models in which HAS2 null animals have an embryonic lethal phenotype.

Received for publication, November 19, 2003 , and in revised form, February 24, 2004.

^* This work was funded by Project Grant J1146W25K 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ604570.

^¶ Recipient of a Ph.D. studentship from the Kidney Research Unit for Wales Foundation.

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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