Regulation of the human thioredoxin gene promoter and its key substrates: a study of functional and putative regulatory elements

Abstract

Background: The thioredoxin system maintains redox balance through the action of thioredoxin and thioredoxin reductase. Thioredoxin regulates the activity of various substrates, including those that function to counteract cellular oxidative stress. These include the peroxiredoxins, methionine sulfoxide reductase A and specific transcription factors. Of particular relevance is Redox Factor-1, which in turn activates other redox-regulated transcription factors.

Scope of review: Experimentally defined transcription factor binding sites in the human thioredoxin and thioredoxin reductase gene promoters together with promoters of the major thioredoxin system substrates involved in regulating cellular redox status are discussed. An in silico approach was used to identify potential putative binding sites for these transcription factors in all of these promoters.

Major conclusions: Our analysis reveals that many redox gene promoters contain the same transcription factor binding sites. Several of these transcription factors are in turn redox regulated. The ARE is present in several of these promoters and is bound by Nrf2 during various oxidative stress stimuli to upregulate gene expression. Other transcription factors also bind to these promoters during the same oxidative stress stimuli, with this redundancy supporting the importance of the antioxidant response. Putative transcription factor sites were identified in silico, which in combination with specific regulatory knowledge for that gene promoter may inform future experiments.

General significance: Redox proteins are involved in many cellular signalling pathways and aberrant expression can lead to disease or other pathological conditions. Therefore understanding how their expression is regulated is relevant for developing therapeutic agents that target these pathways.

Keywords: AP-1; APE; ARE; Activator protein-1; Antioxidant response element; Antioxidant responsive element; Apurinic/apyrimidinic endonuclease; CRE; CRE binding protein; CREB; ChIP; Chromatin immunoprecipitation; E26 transformation specific; EMSA; Early growth response factor-1; Egr-1; Electrophoretic mobility shift assay; Ets; FOXO; Forkhead O; GSH; Gene promoter; Glutathione; HIF; Hypoxia inducible factor; Keap1; Kelch-like ECH-associated protein 1; MRE; MSR; Metal response element; Methionine sulfoxide reductase; MiTF; Microphthalmia associated transcription factor; NADPH; NF-κB; NGF; Nerve growth factor; Nicotinamide adenine dinucleotide phosphate; Nrf2; Nuclear Factor-κB; Nuclear factor-erythroid 2 p45-related factor 2; Oct-1; Octamer binding protein; Oxidative stress; PPAR; PPAR response element; PPRE; PRDX; Peroxiredoxin; Peroxisome proliferator-activated receptor; RA; RA response element; RAR; RARE; ROS; RXR; Reactive oxygen species; Redox Factor-1; Redox control; Ref-1; Regulatory element; Retinoic acid; Retinoic acid receptor; Retinoid X receptor; Sp1; Specificity protein 1; TSS; Thioredoxin reductase 1; Thioredoxin-1; Transcription factor; Transcription start site; Trx; TrxR; Tumour protein 53; cAMP response element; p53; tBHQ; tert-Butylhydroquinone.