ABSTRACT
Prdx6, a unique member of the peroxiredoxin family of antioxidants, is highly expressed in liver and protects cells from oxidative damage by reducing H2O2 and various lipid peroxides. We investigated the transcriptional regulation of Prdx6 in the H2.35 mouse hepatocyte cell line and sought to determine the mechanism of basal and induced expression. We found that Prdx6 expression is down-regulated upon serum deprivation and subsequently induced in a time-dependent manner in response to KGF, TNF-alpha, dexamethasone, and H2O2. Inhibitors of both PKC and MEK largely prevented Prdx6 induction by KGF and, to a lesser extent, TNF-alpha. Interestingly, inhibition of NF-kappaB led to a marked increase in Prdx6 regulation in the absence or presence of inducers, suggesting a normal role for NF-kappaB in Prdx6 suppression. Using reporter constructs from the mouse gene, we found that the first 160 bp of the proximal promoter was sufficient for low levels of expression, and expression increased sixfold with 1200 bp of the proximal promoter. These regions were not, however, sufficient to mediate up-regulation by the known Prdx6 inducers in our system. Together, these data support multiple pathways of Prdx6 regulation and reveal important promoter regions that mediate its transcriptional regulation.
