| Summary: | Carnosic acid (CA) is a phytochemical found in some dietary herbs, such as <i>Rosmarinus officinalis</i> 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 <i>HO-1</i> in an Nrf2-dependent manner in U373MG human astrocytoma cells. However, CA also induces <i>NGF</i> gene expression in an Nrf2-independent manner, since 50 μM of CA administration showed striking <i>NGF</i> gene induction compared with the classical Nrf2 inducer <i>tert</i>-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 <i>NGF</i> 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.
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