Function
This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein is ubiquitously expressed in all prokaryotic and eukaryotic organisms, but demonstrates especially high expression in tissues with heavy metabolic activity, including the stomach, testis, ovary, liver, heart, neurons, and adrenal gland. It may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis. Specifically, the ability of TXN2 to reduce disulfide bonds enables the protein to regulate mitochondrial redox and, thus, the production of reactive oxygen species (ROS). By extension, downregulation of TXN2 can lead to increased ROS generation and cell death. The antiapoptotic function of TXN2 is attributed to its involvement in GSH-dependent mechanisms to scavenge ROS, or its interaction with, and thus regulation of, thiols in the mitochondrial permeability transition pore component adenine nucleotide translocator (ANT).
Overexpression of TXN2 was shown to have attenuated hypoxia-induced HIF-1alpha accumulation, which is in direct opposition of the cytosolic TXN1, which enhanced HIF-1alpha levels. Moreover, although both TXN2 and TXN1 are able to reduce insulin, TXN2 does not depend on the oxidative status of the protein for this activity, a quality which may contribute to their difference in function.
Clinical significance
It has been demonstrated that genetic polymorphisms in the TXN2 gene may be associated with the risk of spina bifida.
TXN2 is known to inhibit transforming growth factor (TGF)-β-stimulated ROS generation independent of Smad signaling. TGF-β is a pro-oncogenic cytokine that induces epithelial–mesenchymal transition (EMT), which is a crucial event in metastatic progression. In particular, TXN2 inhibits TGF-β-mediated induction of HMGA2, a central EMT mediator, and fibronectin, an EMT marker.
