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J. Biol. Chem., Vol. 276, Issue 5, 3106-3114, February 2, 2001

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Heterogeneity within Animal Thioredoxin Reductases
EVIDENCE FOR ALTERNATIVE FIRST EXON SPLICING^*

Qi-An Sun, Francesca Zappacosta^§, Valentina M. Factor^¶, Peter J. Wirth^¶, Dolph L. Hatfield, and Vadim N. Gladyshev^**

From the  Department of Biochemistry, University of Nebraska, Lincoln, Nebraska 68588, the ^§ SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, the ^¶ Laboratory of Experimental Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the  Basic Research Laboratory, NCI, National Institutes of Health, Bethesda, Maryland 20892

Animal thioredoxin reductases (TRs) are selenocysteine-containing flavoenzymes that utilize NADPH for reduction of thioredoxins and other protein and nonprotein substrates. Three types of mammalian TRs are known, with TR1 being a cytosolic enzyme, and TR3, a mitochondrial enzyme. Previously characterized TR1 and TR3 occurred as homodimers of 55-57-kDa subunits. We report here that TR1 isolated from mouse liver, mouse liver tumor, and a human T-cell line exhibited extensive heterogeneity as detected by electrophoretic, immunoblot, and mass spectrometry analyses. In particular, a 67-kDa band of TR1 was detected. Furthermore, a novel form of mouse TR1 cDNA encoding a 67-kDa selenoprotein subunit with an additional N-terminal sequence was identified. Subsequent homology analyses revealed three distinct isoforms of mouse and rat TR1 mRNA. These forms differed in 5' sequences that resulted from the alternative use of the first three exons but had common downstream sequences. Similarly, expression of multiple mRNA forms was observed for human TR3 and Drosophila TR. In these genes, alternative first exon splicing resulted in the formation of predicted mitochondrial and cytosolic proteins. In addition, a human TR3 gene overlapped with the gene for catechol-O-methyltransferase (COMT) on a complementary DNA strand, such that mitochondrial TR3 and membrane-bound COMT mRNAs had common first exon sequences; however, transcription start sites for predicted cytosolic TR3 and soluble COMT forms were separated by ~30 kilobases. Thus, this study demonstrates a remarkable heterogeneity within TRs, which, at least in part, results from evolutionary conserved genetic mechanisms employing alternative first exon splicing. Multiple transcription start sites within TR genes may be relevant to complex regulation of expression and/or organelle- and cell type-specific location of animal thioredoxin reductases.

The nucleotide mouse TR1 cDNA sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number AF333036.

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