Mammalian Peroxiredoxin Isoforms Can Reduce Hydrogen Peroxide Generated in Response to Growth Factors and Tumor Necrosis Factor-α

Abstract

Mammalian tissues express three immunologically distinct peroxiredoxin (Prx) proteins (Prx I, II, and III), which are the products of distinct genes. With the use of recombinant proteins Prx I, II, and III, all have now been shown to possess peroxidase activity and to rely on Trx as a source of reducing equivalents for the reduction of H 2 O 2 . Prx I and II are cytosolic proteins, whereas Prx III is localized in mitochondria. Transient overexpression of Prx I or II in cultured cells showed that they were able to eliminate the intracellular H 2 O 2 generated in response to growth factors. Moreover, the activation of nuclear factor B (NF B) induced by extracellularly added H 2 O 2 or tumor necrosis factor-␣ was blocked by overproduction of Prx II. These results suggest that, together with glutathione peroxidase and catalase, Prx enzymes likely play an important role in eliminating peroxides generated during metabolism. In addition, Prx I and II might participate in the signaling cascades of growth factors and tumor necrosis factor-␣ by regulating the intracellular concentration of H 2 O 2 .We have previously purified a 25-kDa thioredoxin peroxidase (TPx) 1 from Saccharomyces cerevisiae that reduces hydroperoxides with thioredoxin (Trx) as an immediate electron donor (1-7). A data base search revealed more than 40 proteins from a wide variety of species that show sequence similarity to yeast TPx (8,9). These homologous proteins were named the peroxiredoxin (Prx) family (8, 9). They were not termed the TPx family because not all members use Trx as the hydrogen donor (10, 11). 2 The Prx family includes 12 mammalian proteins that were identified without reference to peroxidase activity but rather in association with a variety of diverse cellular functions including proliferation, differentiation, and immune response (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Whether any of these mammalian Prx proteins possess peroxidase activity and, if so, the identity of the immediate electron donors both remain unknown. As will be published elsewhere, the mammalian Prx members can be divided into three distinct groups (Prx I, II, and III) on the basis of their amino acid sequences and immunological properties. 3

Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells

“…Peroxiredoxins are in different subcellular compartments. While Prx III is localized to mitochondria [12,22,54,55], Prx I and Prx II are found in the cytoplasm [15,23,32,43]. Furthermore Prx I is thought to be translocated into the nucleus by association with other proteins such as tyrosine kinase c-Abl, though given its small size it could enter passively [34].…”

“…Prx enzymes have been identified in association with various cellular functions apparently unrelated to peroxidase activity. Several lines of evidence support the concept that peroxiredoxins can influence cell proliferation and differentiation, immunological defence, receptor signalling and apoptosis [10,23,26,27,28,29]. This is reflected by the numerous synonyms used.…”

“…19] and catalyse reduction of both hydrogen peroxide and alkyl peroxides to water or to the corresponding alcohol using thioredoxin (Tx) as their physiological hydrogen donor [20,21,22,23,24]. Additionally it has been shown that the bacterial peroxiredoxin AhpC (alkylhydroperoxide reductase subunit C) is able to protect against nitrogen radicals [25].…”

“…Prx II is important in erythroid cell differentiation [11,26] and protects red blood cell membranes from peroxidation [20,45]. It also regulates signal transduction pathways that directly relate to apoptotic cell death [23,27,28,29,46]. Prx II is thought to protect neuronal cells against destruction by hypoxia and ischaemia [11,47] and tumour cells against X-ray treatment and chemotherapy [48].…”

Histone deacetylase inhibitors: molecular mechanisms of action

“…Overexpression of Bcl-2 blocks HDACi-induced transformed cell death (Mitsiades et al, 2003). Peroxiredoxins reduce ROS generation (Kang et al, 1998) and may protect transformed cells from HDACi-induced cell death, which is strongly associated with ROS production (Rosato and Grant, 2005). Resistance to FK228 has been associated with multiple drug resistance, upregulation of and efflux by P-gp (MDR1) (Glaser, 2006).…”