TY - JOUR
T1 - Concomitant Nrf2-and ATF4-activation by carnosic acid cooperatively induces expression of cytoprotective genes
AU - Mimura, Junsei
AU - Inose-Maruyama, Atsushi
AU - Taniuchi, Shusuke
AU - Kosaka, Kunio
AU - Yoshida, Hidemi
AU - Yamazaki, Hiromi
AU - Kasai, Shuya
AU - Harada, Nobuhiko
AU - Kaufman, Randal J.
AU - Oyadomari, Seiichi
AU - Itoh, Ken
N1 - Funding Information:
Funding: This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Oxygen Biology: a new criterion for integrated understanding of life” of MEXT, Japan (to K.I., No. 26111010), by a Hirosaki University Institutional Research Grant (to K.I.), and by a grant from the Karoji Memorial Fund for Medical Research of Hirosaki University, Hirosaki University School of Medicine (to J.M.). Portions of this work were supported by NIH grants DK042394, DK110973, DK103185, AG062190 and CA198103 (to R.J.K.). R.J.K. is a member of the UCSD DRC (P30 DK063491) and adjunct professor in the Department of Pharmacology, UCSD.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - ATF4
KW - Antioxidant
KW - Carnosic acid
KW - NGF
KW - Nrf2
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U2 - 10.3390/ijms20071706
DO - 10.3390/ijms20071706
M3 - Article
C2 - 30959808
AN - SCOPUS:85064567643
SN - 1422-0067
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 7
M1 - 1706
ER -