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Regulation of the extracellular antioxidant selenoprotein plasma glutathione peroxidase (GPx-3) in mammalian cells

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Abstract

Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing extracellular antioxidant protein that catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides. Selenoprotein expression involves the alternate recognition of a UGA codon as a selenocysteine codon and requires signals in the 3′-untranslated region (UTR), including a selenocysteine insertion sequence (SECIS), as well as specific translational cofactors. To ascertain regulatory determinants of GPx-3 expression and function, we generated recombinant GPx-3 (rGPX-3) constructs with various 3′-UTR, as well as a Sec73Cys mutant. In transfected Cos7 cells, the Sec73Cys mutant was expressed at higher levels than the wild type rGPx-3, although the wild type rGPx-3 had higher specific activity, similar to plasma purified GPx-3. A 3′-UTR with only the SECIS was insufficient for wild type rGPx-3 protein expression. Selenocompound supplementation and co-transfection with SECIS binding protein 2 increased wild type rGPx-3 expression. These results demonstrate the importance of translational mechanisms in GPx-3 expression.

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Abbreviations

GPx-3:

Plasma glutathione peroxidase

UTR:

3′-Untranslated region

SECIS:

Selenocysteine insertion sequence

rGPx-3:

Recombinant GPx-3

GPx:

Glutathione peroxidase

GSH:

Glutathione

Sec:

Selenocysteine

eEFSec:

Sec-elongation factor

SBP2:

SECIS binding protein 2

qRT-PCR:

Qualitative real-time polymerase chain reaction

SelD:

Human selenophosphate synthetase D

G3PDH:

Glyceraldehyde-3-phosphate dehydrogenase

rLacZ:

Recombinant Lac Z

TRx:

Thioredoxin

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Acknowledgments

This work is supported by the National Institutes of Health grants HL61795, HL58976, HL28178, and HL81587. The authors would like to acknowledge and thank Barbara Voestch and Ying-Yi Zhang for their helpful advice and suggestions, and Stephanie Tribuna for excellent secretarial assistance.

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Authors and Affiliations

  1. Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Filomena G. Ottaviano

  2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Rm 630, Boston, MA, 02115, USA

    Filomena G. Ottaviano, Shiow-Shih Tang, Diane E. Handy & Joseph Loscalzo

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  1. Filomena G. Ottaviano
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  2. Shiow-Shih Tang
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Correspondence to Joseph Loscalzo.

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This work was submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Boston University School of Medicine for Filomena G. Ottaviano.

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Ottaviano, F.G., Tang, SS., Handy, D.E. et al. Regulation of the extracellular antioxidant selenoprotein plasma glutathione peroxidase (GPx-3) in mammalian cells. Mol Cell Biochem 327, 111–126 (2009). https://doi.org/10.1007/s11010-009-0049-x

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