Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression

Hiromi Sasaki, Hideyo Sato, Kazumi Kuriyama-Matsumura, Kanako Sato, Kanako Maebara, Hongyu Wang, Miehiko Tamba, Ken Itoh, Masayuki Yamamoto, Shiro Bannai

Research output: Contribution to journalArticlepeer-review

377 Citations (Scopus)


In mammalian cultured cells, the cystine/glutamate exchange transport mediated by system xc- is important to maintain intracellular GSH levels. System xc- consists of two protein components, xCT and the heavy chain of 4F2 antigen. The activity of system xc- is induced by various stimuli, including electrophilic agents like diethyl maleate. In the present study, we have investigated the mechanism of the transcriptional regulation of xCT mRNA by diethyl maleate. The xCT gene consisted of twelve exons and sequence analysis identified four electrophile response element (EpRE)-like sequences between -230 and -1 in the 5′-flanking region, designated EpRE-1 to EpRE-4. To identify sequences mediating the constitutive and induced expression of xCT, a series of 5′-deletion mutants created from the 5′-flanking region were cloned into a luciferase reproter vector and transfected into BHK21 cells. The 5′-deletion analysis revealed that the sequence between -116 and -82 is essential for the basal expression and the sequence between -226 and -116 containing EpRE-1 is essential in response to diethyl maleate. Mutational analysis demonstrated that EpRE-1 is critically involved in the response to diethyl maleate. Other stress agents like arsenite, cadmium, and hydroquinone seemed to induce system xc- activity via the same sequence. Furthermore, the experiments using the mouse embryonic fibroblasts derived from the Nrf2-deficient mice revealed that the induction of xCT gene by electrophilic agents is mediated by Nrf2. EpRE occurs in a broad spectrum of genes for the proteins that are involved in the defense against xenobiotics and regulates their expression. The present results have demonstrated that xCT is a novel member of this protein family.

Original languageEnglish
Pages (from-to)44765-44771
Number of pages7
JournalJournal of Biological Chemistry
Issue number47
Publication statusPublished - 2002 Nov 22
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression'. Together they form a unique fingerprint.

Cite this