Self Introduction of Professor Hidenori Ichijo

－Introduction to the Laboratory of Cell Signaling－

My career might be unique among those of the professors in the Graduate School of Pharmaceutical Sciences, the University of Tokyo. In 1985, I graduated from Faculty of Dentistry, Tokyo Medical and Dental University. After a resident of Oral Surgery, the University Hospital, I went on to the Graduate School of the same university as a graduate student at the First Department of Oral Surgery. Since 1990, I worked for 3 years at the Ludwig Institute for Cancer Research at Uppsala, Sweden, as a postdoctoral fellow (Director: Carl-Henrik Heldin, Group Head: Kohei Miyazono; present professor of Faculty of Medicine, the University of Tokyo). After returning to Japan, I worked as a research assistant at Oral Pathology, Tokyo Medical and Dental University. I became an associate, followed by an associate member at Biochemistry, the Cancer Institute, Japanese Foundation for Cancer Research. In February 1998, I was back again to Tokyo Medical and Dental University as a professor at Laboratory of Cell Signaling. Then, in 2002, I moved to the current position in the University of Tokyo.

For the last quarter of a century, I have consistently focused on analysis of intracellular signaling (for the first 10 years, analysis of TGF-β superfamily) since my graduation of the university. In recent years, I have been specifically interested in molecular mechanisms of how physical and chemical stresses are recognized and converted into signaling. The mechanism of stress-induced apoptosis, in which cells die of stress, has been one of big themes in my laboratory.

You may recognize, from the name of our laboratory, cell biology and molecular biology dominate our research. I would like to look for a new direction of pharmaceutical sciences by adopting both pharmacological and physiological approach keeping up the laboratory’s tradition. We keep consciousness of human body, disease, and drug development during the research of target molecules and their molecular mechanisms.

Our research might seem to have nothing to do with pharmacy, but they do deeply have. In fact, much medicine functions as stress in a wider sense for living bodies. It is no exaggeration that our living environment is filled with stress even in ordinary states. Any stimulation around bodies is felt unpleasant if it surpasses some level and length. If you get exposed to the sun too much, you would suffer from burn. Eating too much even healthy food could give you pain. Through tight communication among cells, individuals recognize and make out the quality and quantity of stimulations, think over how to deal with these changes or actually deal with them by reflex action. In a similar manner, each cell of our body is always exposed to changes of circumstance and required to react to them precisely and quickly. Cells have to acknowledge various changes through sensors or receptors located inside and outside of them, and have to decide promptly how to deal with those changes (e.g. by cell proliferation, differentiation etc.).

It is thought that there should be highly-developed intracellular information- processing systems via molecular interactions. Recent research shows that life and death decisions of cells depend on communication system among cellular molecules. Cells are killed by the excess of ultraviolet light, heat, osmotic pressure, oxygen, gravity, and even some medicines. Unless cells cope with the stimulation, various kinds of diseases are caused. It has been clarified that any disorder in stress response plays an extremely important role as causes of several diseases; cancer, immune disease, circulatory organ disease, neurodegenerative disease, etc. Clarification of signal communication systems and molecular mechanism of cell death is important from the view point of selection and assessment for safety of medicine.

We pay attention to the molecule ASK1 (Apoptosis Signal-regulating Kinase1) which is involved in cell signaling of stress response. ASK1 discovered by us in 1997 belongs to MAP Kinase superfamily and is activated by various extracellular stimuli, particularly several stress (e.g. ultraviolet light, osmotic pressure, anticancer drug, deprivation of growth factors), and cytotoxic cytokines (TNF, Fas-L, etc.). Activated ASK1 sends its information downstream (nuclei or other intracellular organs) through cascades of protein phosphorylation. Activation of signaling pathways induces death of cells (apoptosis) in many types of cell. ASK1, therefore, turned to be an important mediator of apoptosis caused by stress.

Molecules which specifically regulate ASK1 activity have been identified by recent studies using yeast two-hybrid screening, pull-down-MS and forward genetics. We intend to clarify the molecular mechanism, in which several stresses eventually activate ASK1-MAP Kinase system. We found that activation of ASK1 sometimes functions as signaling necessary not only for cell death but for cell differentiation or even for cell survival. We are now dedicated to analyze signaling of ASK family and its regulatory molecules which are closely related to life, death, and differentiation of cells by generating knockout animals. We are also doing our research on comprehensive understanding of molecular mechanism of reception and recognition of stresses and of signal transduction and its application to drug discovery.

I feel extremely lucky as a scientist in my research life in two aspects. One is that I have been supported by excellent mentors, friends, rivals, colleagues and students. The other is that every effort has been rewarded as far as scientific research is concerned at least. It may not be the case for those in everyday lives, though. Previously, I thought I have been merely lucky by chance. But after several similar experiences, I began to believe that efforts in the field of bioscience certainly bear fruit. I hope that all the lab members share this same feeling through experiments and discussions.