Concomitant Nrf2-and ATF4-activation by carnosic acid cooperatively induces expression of cytoprotective genes

Junsei Mimura, Atsushi Inose-Maruyama, Shusuke Taniuchi, Kunio Kosaka, Hidemi Yoshida, Hiromi Yamazaki, Shuya Kasai, Nobuhiko Harada, Randal J. Kaufman, Seiichi Oyadomari, Ken Itoh

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Carnosic acid (CA) is a phytochemical found in some dietary herbs, such as Rosmarinus officinalis L., and possesses antioxidative and anti-microbial properties. We previously demonstrated that CA functions as an activator of nuclear factor, erythroid 2 (NF-E2)-related factor 2 (Nrf2), an oxidative stress-responsive transcription factor in human and rodent cells. CA enhances the expression of nerve growth factor (NGF) and antioxidant genes, such as HO-1 in an Nrf2-dependent manner in U373MG human astrocytoma cells. However, CA also induces NGF gene expression in an Nrf2-independent manner, since 50 µM of CA administration showed striking NGF gene induction compared with the classical Nrf2 inducer tert-butylhydroquinone (tBHQ) in U373MG cells. By comparative transcriptome analysis, we found that CA activates activating transcription factor 4 (ATF4) in addition to Nrf2 at high doses. CA activated ATF4 in phospho-eIF2α-and heme-regulated inhibitor kinase (HRI)-dependent manners, indicating that CA activates ATF4 through the integrated stress response (ISR) pathway. Furthermore, CA activated Nrf2 and ATF4 cooperatively enhanced the expression of NGF and many antioxidant genes while acting independently to certain client genes. Taken together, these results represent a novel mechanism of CA-mediated gene regulation evoked by Nrf2 and ATF4 cooperation.

Original languageEnglish
Article number1706
JournalInternational journal of molecular sciences
Issue number7
Publication statusPublished - 2019 Apr 1
Externally publishedYes


  • ATF4
  • Antioxidant
  • Carnosic acid
  • NGF
  • Nrf2

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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