KGF Induction of Human Peroxiredoxin 6 (Prdx6) Gene Expression is Mediated by the Transcription Factor Nrf2

Abstract

Peroxiredoxin 6 (Prdx6), an enzyme that has both phospholipase A2 and peroxidase activities can reduce lipid hydroperoxides by a unique mechanism employing a single conserved cysteine. It is highly expressed in lung, both protecting against oxidative stress and regulating pulmonary surfactant phospholipid metabolism. We reported previously that rodent Prdx6 is up‐regulated in development and by oxidative stress. The goal of our experiments was to identify the mechanism by which keratinocyte growth factor (KGF) induces transcription of the human Prdx6 gene. We had previously found that a consensus Antioxidant Response Element (ARE), located between 357 and 349 nucleotides before the transcriptional start of the human Prdx6 gene was necessary for transcriptional activation of the Prdx6 promoter by KGF in the human lung cell line, A549, and in primary cultures of rat type II cells. We hypothesized that Nrf2, a transcription factor that binds to the ARE might be the activating factor. siRNA directed against Nrf2 blocked the up‐regulation of Prdx6 by KGF; a control siRNA had no effect. KGF increased Prdx6 promoter activity in mouse type II cells, but not in type II cells from Nrf2 null mice. KGF appears to trigger a migration of Nrf2 from cytoplasm to nucleus and an increased binding to the Prdx6 promoter in ChIP assays. We conclude that KGF activation of Prdx6 transcription requires Nrf2. Supported by HL P01‐75587.