Winner of FAOBMB Award for Research Excellence 2020

Professor Masayuki Yamamoto

Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Japan

Masayuki Yamamoto graduated from the Tohoku University School of Medicine in Sendai, Japan, in 1979 and received his PhD from the Graduate School of Medicine in 1983.  In 1983-1986, Yamamoto was a postdoctoral fellow at Northwestern University, USA, with Professor Doug Engel.  As a doctoral and postdoctoral fellow, he studied the metabolic regulation of heme biosynthesis and cloned cDNA encoding erythroid-type 5-aminolevulinate synthase (ALAS2).  This finding for the first time revealed that there are erythroid-specific and house-keeping isozymes in heme biosynthesis in animals.

In order to clarify how erythroid-specific gene expression is attained, in 1989, Yamamoto revisited the Engel laboratory and in collaboration identified the GATA family of transcription factors.  These are now widely studied, having been recognized as one of the prototype transcription factor families regulating lineage commitment and cell differentiation.  In 1991, Yamamoto returned to Japan and starts a series of analyses on the Gata1 and Gata2 genes.  He clarified unique structure of Gata1 and Gata2 genes, and identified hematopoietic enhancer of Gata1, leukemia due to Gata1 knockdown.  He thereby developed the notion GATA1-related leukemia.

In 1995, Yamamoto started analyses on NF-E2 transcription factors and recognized that a critical cis­regulatory element for erythroid-specific gene expression by NF-E2 also affects the manifestation of a newly described cytoprotective response in cells. This is now known as NRF2-regulated cytoprotective response.  In 1997, his team described the consequences of Nrf2 gene disruption.  Since then, the Nrf2-knockout mice have been contributing widely to our appreciation of the roles that NRF2 target genes play in many disease states.

In addition to jumpstarting this dynamic and exciting area integral to the role of redox biology in cell signaling, maintenance of health and to disease processes, his team has been using the tools of molecular biology, mouse genetics and structural biology to lead the unveiling of the intricate details how chemical signals are transduced through a sensor protein to allow NRF2 to accumulate in the nucleus and activate or repress its target genes.  In 1999, Yamamoto isolated and characterized a repressor protein, KEAP1, that serves as a sensor for oxidative and electrophilic signals through cysteine oxidation or adduction.

The use of small molecule activators of the NRF2 pathway has been realized for disease prevention through impeding KEAP1 repression of the pathway.  One such NRF2-targeted molecule has already been approved by the FDA for management of relapsing multiple sclerosis.  Other KEAP1-targeting molecules, either as drugs or as bioactive natural products in foods, are in advanced clinical trials to prevent or mitigate the progression of several chronic diseases.  In 2006, his team also identified mutations in KEAP1 and NRF2 in cancers.  This has therapeutic implications, as constitutive activation of the pathway leads to chemo-resistance and radio-resistance.

The KEAP1-NRF2 field has exploded to more than 15,000 publications and Yamamoto has been selected as the highly cited researcher by Clarivate Analytics in 2018 and 2019.  His work has been recognized internationally in multiple prizes, such as the Thomson Scientific Research Front Award 2004 (Thomson Scientific Co.), Nissan Science Award (2008), Leading Edge in Basic Science Award (Society of Toxicology, 2011), Toray Science and Technology Prize (2011), Uehara Prize (2012), Medal of Honor with Purple Ribbon (The Emperor of Japan; 2012), the Japan Academy Prize (the Japan Academy, 2014) and Kakiuchi Samuro Prize (The Japanese Society of Biochemistry, 2017).

Yamamoto was the Dean of the School of Medicine at Tohoku University at the time of the Great East Japan Earthquake and Tsunami in 2011.  He has been serving as the Founding Executive Director of The Tohoku Medical Megabank Organization.  This body established a cutting-edge integrated biobank that combined medical and genome information during the process of rebuilding the community medical system, in order to best support health and welfare in the Tsunami-damaged Tohoku area.

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