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Message from Professor
Our laboratory is investigating the cellular stress response mechanisms against the environmental stress, especially the oxidative stress, amino acid starvation, and mitochondrial stress1-4). The above-mentioned stresses play an important role in degenerative diseases associated with aging such as heart failure and neurodegenerative diseases. We consider that the reinforcement of the stress response against these stresses could delay the onset of these diseases or even prevent the diseases by restoring homeostasis. Regarding the molecular mechanisms, we are focusing on the Keap1-Nrf2 system5) and GCN1-GCN2-ATF4 pathway6). GCN1-GCN2-ATF4 pathway is more ancient mechanism against oxidative stress than Keap1-Nrf2 system as GCN1-GCN2-ATF4 pathway, but not Keap1-Nrf2 system, exists in the single cell eukaryote yeast7). We consider that Keap1-Nrf2 system has evolved after the appearance of metazoan and interact with GCN1-GCN2-ATF4 pathway to cooperatively regulate oxidative stress response8, 9). 1. Emerging regulatory role of Nrf2 in iron, heme and hemoglobin metabolism in physiology and disease. Kasai S, Mimura J, Ozaki T, Itoh K. Front. Vet Sci 5:242, 2018. 2. Role of ISR-ATF4 pathway and its cross talk with Nrf2 in mitochondrial quality control. Kasai S, Yamazaki H, Tanji K, Máté János Engler, Matsumiya, Itoh K. J Clin Biochem Nutr 64, 1-12, 2019. 3. Emerging evidence for crosstalk between Nrf2 and mitochondria in physiological homeostasis and in heart disease.Tsushima M, Liu J, Hirao W, Yamazaki H, Tomita H, Itoh K. Arch Pharm Res 2019. 4. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Kasai S, Shimizu S, Tatara Y, Mimura J, Itoh K. Biomolecules 10(2), 2020. 5. Itoh K, Mimura J, Yamamoto M. Discovery of the negative regulator of Nrf2, Keap1: A historical overview. Antioxid Redox Signal. 120, 145-154, 2010. 6. Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice. Yamazaki H, Kasai S, Mimura J, Ye P, Inose-Maruyama A, Tanji K, Wakabayashi K, Mizuno S, Sugiyama F, Takahashi S, Sato T, Ozaki T, Cavener DR, Yamamoto M, Itoh K. PLoS Genet. 2020 Apr 23;16(4):e1008693. 7. Rising levels of atmospheric oxygen and evolution of Nrf2. Gacesa R, Dunlap WC, Barlow DJ, Laskowski RA, Long PF. Sci Rep. 6:27740, 2016. 8. Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition. Ye P, Mimura J, Okada T, Sato H, Liu T, Maruyama A, Ohyama C, Itoh K. Mol Cell Biol 34, 3421-3434, 2014. 9. Concomitant Nrf2- and ATF4-activation by carnosic acid cooperatively induces expression of cytoprotective genes. Mimura J, Inose-Maruyama A, Taniuchi S, Kosaka K, Yoshida H, Yamazaki H, Kasai S, Harada N, Kaufman RJ, Oyadomari S, Itoh K. Int J Mol Sci. 20(7), 2019.
