Biol. Pharm. Bull. 29(3) 543—546 (2006)

نویسندگان

  • Michie NISHIMOTO
  • Motoharu SAKAUE
  • Shuntaro HARA
چکیده

it is known to be a highly toxic metal. The level of cadmium in the environment has risen with advances in industrialization, and the role of cadmium in human diseases is of increasing concern. The mechanisms of cadmium toxicity are poorly understood. However, cadmium is thought to cause harmful effects in multiple ways, including production of reactive oxygen species (ROS). The thioredoxin (Trx) system, which consists of Trx and Trx reductase (TrxR), is one of the major enzymatic systems modulating intracellular ROS levels. Trx is a small redox-active protein that reduces a wide range of substrates by reversible oxidation of its active center dithiol to a disulfide. The Trx system is involved in many cellular functions. Oxidized Trx, which does not exert its biological effects, can be reduced by receiving electrons from NADPH via TrxR. Since TrxR is the only class of enzymes known to reduce oxidized Trx, activity of this enzyme is thought to be an important factor in regulating the activity of the Trx system. Mammalian TrxR is a selenoprotein containing a penultimate Cterminal selenocysteine residue essential for its catalytic activity. To date, three mammalian TrxR isozymes have been identified: cytosolic form (TrxR1), mitochondrial form (TrxR2), and testis-specific form (TrxR3). Among these three isozymes, TrxR1 is the most well characterized and is known to be inducible in response to various stimuli, including peroxynitrite, phorbol ester, interleukin 1b , and tumor necrosis factor a . We have recently reported that cadmium also up-regulates the TrxR1 mRNA level in bovine arterial endothelial cells by activating NF-E2-related factor 2 (Nrf2), a stress-responsive transcriptional factor. Nrf2 is activated by cadmium and is shown to be involved in hemin-induced Trx gene expression as well as TrxR1 gene expression. However, physiological or pathological roles of the induction of TrxR1 gene expression have not been fully elucidated. In the present study, we attempted to clarify the biological meaning of this induction, that is, to determine whether cadmium-induced TrxR1 plays an important role in cellular defense against cadmium toxicity. It is known to be difficult to overexpress enzymatically active selenoproteins such as TrxR in mammalian cells. Therefore, knockdown of TrxR1 by antisense or small interfering RNA (siRNA) seems to be more sound way to examine its intracellular function. Very recently, Seemann and Hainaut reported that transfection of TrxR1 siRNA led to a downregulation of TrxR1 protein with a decrease of over 90% at 48 h after transfection. We here silenced the expression of TrxR1 in HeLa cells by using siRNA and examined the effect of gene silencing of TrxR1 on the sensitivity of the cells toward cadmium-induced cell death.

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تاریخ انتشار 2006