Hemin-induced activation of the thioredoxin gene by Nrf2: A differential regulation of the antioxidant responsive element by a switch of its binding factors

Yong Chul Kim, Hiroshi Masutani, Yoshimi Yamaguchi, Ken Itoh, Masayuki Yamamoto, Junji Yodoi

Research output: Contribution to journalArticlepeer-review

251 Citations (Scopus)

Abstract

Thioredoxin plays an important role in various cellular processes through redox regulation. Here, we have demonstrated that thioredoxin expression is transcriptionally induced in K562 cells by hemin (ferriprotoporphyrin IX) through activation of a regulatory region positioned from -452 to -420 bp of the thioredoxin gene. Insertion of a mutation in the antioxidant responsive element (ARE)/AP-1 consensus binding sequence in this region abolished the response to hemin. With electrophoretic mobility shift and DNA affinity assays, we have shown that the NF-E2p45/small Maf complex constitutively binds to the ARE. The binding of the Nrf2/small Maf complex to ARE was induced by hemin, whereas the binding of Jun/Fos proteins to ARE was induced by phorbol 12-myristate 13-acetate, but not hemin. Hemin induced nuclear translocation of Nrf2 but did not affect nuclear expression of Jun/Fos proteins. Overexpression of Nrf2 augmented the response to hemin in a dose-dependent manner. In contrast, overexpression of the dominant negative mutant of Nrf2 suppressed hemin-induced activation through the ARE. We show here hemin-induced activation of the thioredoxin gene by Nrf2 through the ARE and propose a novel mechanism of the regulation of the ARE through a switch of its binding factors.

Original languageEnglish
Pages (from-to)18399-18406
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number21
DOIs
Publication statusPublished - 2001 Jan 25
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Hemin-induced activation of the thioredoxin gene by Nrf2: A differential regulation of the antioxidant responsive element by a switch of its binding factors'. Together they form a unique fingerprint.

Cite this