Regulaton in Eukaryotic Cells Based on Thio-Redoxin Enzymes
Department of Biological Responses
Institute for Viral Research
53 Shogoin Kawahara-cho
Sakyo-ku, Kyoto 606-8407; JAPAN
Proc. of the International Symposium for Oxidative Stress, Redox Regulation, and Signal Transduction: Clinical Implications, ed. by Junji Yodoi and Lester Packer (November 4-6, 1999) held at Kyodai Kaikan in Kyoto, JAPAN
Growing evidence confirms the importance of Oxidation-Reduction reactions within the cellular components of all living species. In the past decade we have witnessed a remarkable growth of our knowledge regarding redox regulation in signal transduction as well as in the genetic control of eukaryotic cells. Thio-Redoxin -- and other members of this enzymatic family -- have been shown to play multiple roles in eukaryotic as well as prokaryotic cells forming a network with target molecules, including transcription factors, hormone receptors, and other signaling molecules, such as Ref-1 and Ask-1. As a unifying concept covering the entire homeostatic system in countering oxidative stress, we propose the paradigm of Redox Regulation . This involves the anti-oxidant glutathione , as well as the thio-redoxin families, to counter the damaging effects of Oxygen (O) and Nitric Oxide (NO) free-radicals (cross-linking of collagen and lipid peroxidation, leading to loss of membrane fluidity).
Human thio-redoxin, first described as cytokine-like molecules produced by virally-transformed or activated cells, is now known to be a unique stress protein strongly induced by a variety of intracellular and extracellular oxidative stressors in selective tissues and cells.
Recently, chemokine -- as well as the cytokine-like activities of TRX -- have become a more critical issue in various pathophysiological pathways including active viral infection, immuno-inflammatory disorders, and cancer (oncogenesis). A colony of transgenic mice over-expressing TRX [up-regulation of the TRX gene] against UV in the bone marrow have now demonstrated a significant increase in lifespan. Furthermore, recombinant TRX shows a definite cytoprotective activity both in vitro and in vivo, suggesting the utilization of this molecule in protecting against oxidative stress in vivo.
The list of molecules interacting with the "TRX family" is increasing. For example, TBP2 is one of the recently-described TRX targets, identical to Vitamin D3 up-regulated Protein 1, shown to have TRX-inhibitory activity. The role of TRX-family molecules within the cell cycle, in differentiation, and in the control of apoptosis is discussed.