Basic Medicine, Genomics, Genetics and Epigenetics, Oncology
Gene Expression Regulation
Metabolic and Transcriptional Response to Redox Disturbance in Aging-related Disorders
Medical Sciences Course
- Master / Doctoral Degree
- MOTOHASHI, Hozumi
Professor, M.D. Ph.D.
hozumim*med.tohoku.ac.jp (Please convert "*" into "@".)
- Regulatory mechanisms of stress response system during carcinogenesis
- Roles of stress response system in hematopoietic stem cell aging
- Functional interaction between intranuclear redox homeostasis and regulation of gene expression
response to oxidative stress and xenobiotics, transcription factors, metabolic regulation
transgenic mice & knockout mice, metabolomic analysis, flow cytometry
Transcriptional regulation of gene expression is the key process in the stress response to extrinsic and intrinsic insults, which is one of the critical determinants of organismal aging process. The KEAP1-NRF2 system plays a central role in the protection from various stresses, including reactive oxygen species and xenobiotics. It has been shown that NRF2-activating chemicals, either naturally occurring or artificially synthesized, are beneficial for our health. On the other hand, our recent work revealed that NRF2 contributes to the malignant evolution of cancer cells by modulating cellular metabolic activity. Based on this result, we are focusing on the function of NRF2 in carcinogenesis and malignant evolution of cancers, especially in relation with epigenetic regulations. Our goal is to clarify specific molecular mechanisms of NRF2 function in cancer cells that are distinguished from those in normal cells, which we believe would make an ideal molecular target of anti-cancer therapy for patients with NRF2-positive cancers. Considering that disturbance of intranuclear redox balance often causes genome instability resulting in carcinogenesis and progeria, we are also interested in the relation among aging processes, intranuclear redox balance and NRF2-mediated antioxidant capacity. Thus, we are cultivating a new field of intranuclear redox metabolism and its effect on gene expression via genetic and epigenetic alterations.
Figure 1. NRF2 mediates malignant evolution and proliferation of cancers
- Honkura Y. et al. NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea. Sci Rep in press
- Sekine H. et al. The mediator subunit MED16 transduces NRF2-activating signals into antioxidant gene expression. Mol Cell Biol in press.
- Shirasaki K, et al. Nrf2 promotes compensatory liver hypertrophy after portal vein branch ligation in mice. Hepatology 59(6), 2371-2382, 2014.
- Taguchi K, et al. Nrf2 enhances cholangiocyte expansion in Pten-deficient livers. Mol Cell Biol 34(5), 900-913, 2014.
- Mitsuishi Y, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22(1), 66-79, 2012.