Evidence for intriguingly complex transcription of human thioredoxin reductase 1.

Human thioredoxin reductase 1 (TrxR1, the TXNRD1 gene product) is a ubiquitously expressed selenoprotein with many important redox regulatory functions. In this study, we have further characterized the recently identified core promoter region of TXNRD1. One critical Sp1/Sp3 site was found to be important in A549 and HeLa cells, whereas another Sp1/Sp3 site and one Oct1 site bound transcription factors but were, nonetheless, dispensable for transcription. We also experimentally identified several 5'-region TXNRD1 transcript variants using 5'-RACE with cDNA derived from different tissues, and we analyzed all available TXNRD1-derived EST sequences. The results show that the core promoter governs transcription of the clear majority of TXNRD1 transcripts but also that alternative promoters may be activated under rare conditions or in specific cell types. Furthermore, extensive alternative splicing occured in the 5' region of TXNRD1. In total, 21 different transcripts were identified, potentially encoding five isoforms of TrxR1 carrying alternative N-terminal domains. One isoform encompassed a glutaredoxin domain, whereas another encoded a predicted mitochondrial localization signal. These results reveal that the human thioredoxin system is intriguingly complex. Cell-specific transcription of the TXNRD1 gene encoding different isoforms of TrxR1 must be taken into account to fully understand the functions of the human thioredoxin system.