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J. Biol. Chem., Vol. 279, Issue 26, 26839-26845, June 25, 2004

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Determinants of Human Plasma Glutathione Peroxidase (GPx-3) Expression^*

Charlene Bierl¶, Barbara Voetsch¶, Richard C. Jin, Diane E. Handy, and Joseph Loscalzo||

From the Whitaker Cardiovascular Institute and the Evans Department of Medicine and the Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118

Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing protein with antioxidant properties. GPx-3 deficiency has been associated with cardiovascular disease and stroke. The regulation of GPx-3 expression remains largely uncharacterized, however, and we studied its transcriptional and translational determinants in a cultured cell system. In transient transfections of a renal cell line (Caki-2), the published sequence cloned upstream of a luciferase reporter gene produced minimal activity (relative luminescence (RL) = 0.6 ± 0.4). Rapid amplification of cDNA ends was used to identify a novel transcription start site that is located 233 bp downstream (3') of the published site and that produced a >25-fold increase in transcriptional activity (RL = 16.8 ± 1.9; p < 0.0001). Analysis of the novel GPx-3 promoter identified Sp-1- and hypoxia-inducible factor-1-binding sites, as well as the redox-sensitive metal response element and antioxidant response element. Hypoxia was identified as a strong transcriptional regulator of GPx-3 expression, in part through the presence of the hypoxia-inducible factor-1-binding site, leading to an almost 3-fold increase in expression levels after 24 h compared with normoxic conditions (normalized RL = 3.5 ± 0.3 versus 1.2 ± 0.1; p < 0.001). We also investigated the role of the translational cofactors tRNA^Sec, SECIS-binding protein-2, and SelD (selenophosphate synthetase D) in GPx-3 protein expression. tRNA^Sec and SelD significantly enhanced GPx-3 expression, whereas SECIS-binding protein-2 showed a trend toward increased expression. These results demonstrate the presence of a novel functional transcription start site for the human GPx-3 gene with a promoter regulated by hypoxia, and identify unique translational determinants of GPx-3 expression.

Received for publication, February 20, 2004 , and in revised form, March 31, 2004.

^* This work was supported in part by National Institutes of Health Grants HL55993, HL58976, and HL61795 (to J. L.). 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) AY552097.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Whitaker Cardiovascular Inst., Boston University School of Medicine, 715 Albany St., W507, Boston, MA 02118. Tel.: 617-638-4890; Fax: 617-638-4066; E-mail: jloscalz{at}bu.edu.

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