Medical Science

Shigetsugu Hatakeyama

When Are Proteins Degraded in Our Body?

Shigetsugu Hatakeyama , Professor

Graduate School of Medicine (School of Medicine)

High school : Hokkaido Prefectural Asahikawa East High School

Academic background : Doctoral program of Hokkaido University

Research areas
medical chemistry (biochemistry, molecular biology, and cellular biology)
Research keywords
medical science, biochemistry, protein degradation, cancer, mass spectrometer, knockout mice, ES cells

What made you conduct this research?

The objective of biochemistry is to separate substances in the body down to molecular levels, thereby determining the substances existing in the body, along with the amount, function, and causal effect thereof. The purpose of my field of research is to understand the mechanism that causes the degradation of protein (known as the main component of muscles and hair). Prior to this research, I was working in immunology, studying how leukocytes (lymphocytes) counterattack microorganisms (bacteria and viruses). Subsequently, in the process of exploring the types of proteins functioning in leukocyte cells, I started this current research in the field of “protein degradation.” Protein degradation is a phenomenon occurring inside your body every day of your life. When you eat meat, enzymes such as pepsin and trypsin are activated in the gastro-intestine, breaking them down into amino acids. Amino acids are absorbed in the intestines, after which they become the components forming various cells and organs in the body. At the same time, the cells in our bodies are degrading some protein components and discarding them at a certain rate on a daily basis. By keeping this balance, the homeostasis of our body is maintained. In fact, though your appearance today may appear the same as last year, in terms of substances, almost everything has been replaced (Figure 1). Going to extremes, the protein components forming your nails today may become body components of someone nice next to you in a year.

Figure 1. In terms of substances, will you be the same “you” in one year?

What kind of experiments do you perform?

We use materials such as cells, mice, other animals, and human-derived tissues in some cases, and analyze live cells or purified molecules. It is known that when cancer cells develop in the body, a large number of oncogenes are activated or tumor-suppressing proteins are inactivated (degraded). Therefore, it is important to identify the enzymes related to the synthesis and degradation of cancer-related proteins. In addition, in Japan’s aging society, Alzheimer’s disease and Parkinson’s disease are significant diseases in the field of medicine. It was revealed that with these diseases, abnormal virulent proteins are accumulated in the nerve cells. Here again, it is important to identify the enzymes that degrade the virulent proteins. In order to identify them, it is beneficial to use a mass spectrometer, which is able to detect and identify proteins even if their amounts are extremely small (Figure 2). Moreover, in order to determine whether the identified protein is a real enzyme, it is necessary to prepare mice in which the corresponding gene is sufficiently expressed (or other lower organisms such as insects in some cases) as well as mice in which the corresponding gene is disrupted (gene knockout mice) (Figure 3-7). Thus, experiments using ES cells are necessary. We are studying the mechanism of protein degradation by combining these experiment methods. 

Figure 2. Mass Spectrometer
Detects minor proteins.

Figure 3. Developmental Engineering Laboratory
Creates gene-disrupted mice.

Figure 4. ES Cell

Figure 5. Gene Disrupted Mouse.

Figure 6. Green Glowing Silkworms (GFP)
It is obvious even without a fluorescent microscope.

Figure 7. Green Glowing Silkworms (GFP)
Observation using a stereoscopic fluorescent microscope.

What will this be useful for?

My dream is to discover the proteases associated with the cause of developing cancers and neurodegenerative diseases. In the past, I have discovered some disease-related genes; however, regarding body control, it is extremely complicated with numerous systems spread out as a network. While the human genome (gene sequence) has been decoded, as scientists, we still have a lot of work to do in order to clarify the functions of each one. As of the present moment, although we have the blueprint for the human genome, nobody can yet create a human in the laboratory. We cannot still create even simple organisms.


Hatakeyama, Shigetsugu. “Ubiquitin Proteasome Systems.” Co-author of “The Science of Neurodegenerative Diseases.” Nanzando; 36-48 (2007)