Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug response

Sulfiredoxin is an AP-1 target gene that is required for transformation and shows elevated expression in human skin malignancies

“…In yeast, activation of Tpx1 (yeast homologue of Prx I) by Srx facilitated reduction of oxidized cysteine in PAP1 (yeast homologue of c-Jun) and activated PAP1-dependent gene transcription (33,38). Furthermore, Srx also plays a positive role in the deglutathionylation of multiple proteins, including PTP 1B, and thus promotes cell proliferation (39,40), which may also contribute to tumorigenesis.…”

Sulfiredoxin Protein Is Critical for Redox Balance and Survival of Cells Exposed to Low Steady-state Levels of H2O2*

“…Indeed, we show here that Srx is a novel component to maintain the redox balance in cells exposed to low steady-state levels of H 2 O 2 by using Srxdepleted cell lines and Srx Ϫ/Ϫ MEF cells. In this study, the expression of Srx gene was depleted by an RNA interference system, but this approach has sometimes been found to silence nontargeted genes (26) Recent findings demonstrate that phorbol ester, a tumorpromoting agent, induces Srx expression in wild-type mice (27) and that Srx is highly expressed in certain human skin malignancies (28), breast adenocarcinoma (29), and lung adenocarcinoma (30), implicating a role for Srx in the regulation of cancer maintenance and metastasis via lowering sensitivity to ROS-generating anticancer drugs or enhancing cell proliferation rates. These results suggest that Srx is a functionally novel target in cancer prevention and treatment.…”

A Role for Glutathione Transferase Omega 1 (GSTO1-1) in the Glutathionylation Cycle

“…The substrate specificity suggested by the immunoblot in Fig. 2C is not surprising as glutathionylation is known to regulate the activity of specific proteins and metabolic pathways (3,8,12), and substrate specificity may be an important differentiating factor between the actions of glutaredoxin, thioredoxin, sulfiredoxin, and GSTP1-1 that have all been reported to catalyze glutathionylation cycle reactions. As a regulatory mechanism, glutathionylation has been likened to phosphorylation that is dependent on the actions of a plethora of specific kinases and phosphatases.…”

“…Glutathionylation is also important in other physiological roles as there is mounting evidence that even in the absence of oxidative stress the selective glutathionylation/deglutathionylation of specific protein thiols can contribute to cell signaling and the regulation of some metabolic pathways (2,3). Glutathionylation has been shown to have an impact on several cellular processes including regulation of the cell cycle (4), apoptosis (5-7), and drug response in cancer (8) and in the progression of neurodegeneration (9). The cohort of proteins that are structurally and functionally modified by glutathionylation is collectively known as the "disulfide proteome" or "glutathionome" and have been recently reviewed (3,10).…”

“…In addition, sulfiredoxin and glutathione transferase Pi have been shown to catalyze the deglutathionylation and glutathionylation of specific proteins, respectively (8,13). The Omega class GSTs (GSTO1-1 2 and GSTO2-2) were discovered by bioinformatics (14 -16), and immunohistochemical studies identified GSTO1-1 in a diverse range of tissues with varied expression levels (17).…”