Our Reserch Projects

Functional Analysis and Utilization of the Environmental Transcription Factor NRF1

We have been studying the transcription factors Nrf1 (NF-E2 related factor 1) and Nrf2 (NF-E2 related factor 2). Those are involved in the regulation of oxidative stress. Especially, we try to understanding the physiological function of those transcriptional factor function using genetically modified animals. It becomes to elucidate the relationship between Nrf1 and Nrf2.

Is more antioxidant protein better for health?

Although retaining high levels of antioxidant proteins is thought to do many good things, such as making you less likely to get drunk or develop cancer. However, some certain cancers have reversed this trend and acquired resistance to anti-cancer drugs. Antioxidant proteins need to be induced at the right time and in the right organ or place in response to stimuli, and disappear quickly once the marignant cells are dealt with.

Transcription Factor Nrf1 Represses Antioxidant Enzymes Expression

It has long been thought that Nrf1, like Nrf2, which induces the expression of antioxidant proteins, is stabilized by external stimuli. Like Nrf2, the Nrf1 also induces the expression of antioxidant proteins through the antioxidative response element, ARE or electrophile response element, EpRE (TGA[G/C]NNNGC). Nrf1 is similar to Nrf2, as was clear from the EMSA analysis of in vitro. However, mice lacking the Nrf1 gene die soon after birth, whereas Nrf2 mice have a completely different phenotype, not only being born normally but also having the ability to reproduce.

The establishment of antibodies recognizing the Nrf1 protein apparently revealed the presence of Nrf1 protein in the mouse liver under normal conditions, suggesting that Nrf1 is involved in transcriptional regulation even in the unstimulated state.

When we established new drug-induced liver-specific Nrf1-deficient mice and observed their liver phenotype, we found a marked accumulation of fat and an increase in glutathione, the main antioxidant, compared to wild-type mice. We found that this was caused by ectopic upregulation of xCT (a receptor for cystine uptake from outside the cell). Since xCT is used as a cancer marker, it is thought that changes in Nrf1 expression may also be related to lesions.

What's the substance that regulates Nrf1?

While research on Nrf2 is exploding, research on Nrf1 has been slow. We believed that this was due to the fact that the substance that specifically induces Nrf1 is unknown. We established reporter cells that can detect Nrf1 stabilization with high sensitivity and obtained specific activators (T1-20) from tens of thousands of compounds. Currently, we are working on scrutinizing hit compounds other than T1-20 and identifying target proteins.

We want more substances that regulate Nrf1!

Substances that can regulate Nrf1 may be found in food and other products. Therefore, we are proceeding with the evaluation of agricultural and other products, mainly from Saga Prefecture. Through a series of functional evaluation, we believe we can contribute to branding of locally produced products. In the future, we would like to promote research that contributes to a healthier and longer-lived society from the field of agriculture by utilizing the functional ingredients we have acquired to conduct applied research not only in the field of drug discovery, but also in the field of health foods and cosmetics.

Evaluation Methods

Until now, we have mainly used genetically engineered mice for analysis, but for easier evaluation, we have introduced an experimental system using small fish. I have introduced small fish because of my love of fish, and I am always looking forward to your interest and collaboration.