ENGLISH
Professor Hiroyasu Nakano
1. Curriculum Vitae
Business address
Department of Biochemistry Toho University School of Medicine 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540 Japan
E-mail: hiroyasu.nakano@med.toho-u.ac.jp
Tel: 81-3-3762-4151 Ext. 2351
FAX: 81-3-5493-5412
Education
- 1978-84
- MD, Chiba University School of Medicine, Chiba, Japan
- 1984-86
- Residency, Department of Medicine,
Chiba University School of Medicine, Chiba - 1986-89
- Research Fellow, Department of Medicine,
The Research Institute of Lung Cancer,
Chiba University School of Medicine, Chiba - 1991-95
- PhD, Division of Molecular Genetics (Prof. Takashi Saito),
Chiba University Graduate School of Medicine
Professional experience
- 1995-2001
- Assistant Professor, Department of Immunology,
Juntendo University Graduate School of Medicine - 2000-2003
- An investigator, Precursory Research for Embryonic Science
and Technology (PRESTO), Japan Science and Technology
Corporation (JST) - 2001-2014
- Associate Professor, Department of Immunology,
Juntendo University Graduate School of Medicine - 2014-present
- Professor, Department of Biochemistry
Toho University School of Medicine
Honors and Awards
- 1999
- Inohana young investigators’ award,
Chiba University Graduate School of Medicine - 2001
- Young Investigators’ grants award,
Human Frontier Science Program (HFSP) - 2008
- Medical Research Encouragement Prize of
The Japan Medical Association
Academic activities
- 1990-present
- Member, Japanese Society for Immunology
- 1992-present
- Member, Japanese Society for Oncology
- 1994-present
- Member, Japanese Society for Molecular Biology
- 2002-2012
- Member, American Society for Biochemistry and Molecular Biology
- 2003-present
- Member, Japanese Society for Biochemistry
- 2003-present
- Board of Councilors, Japanese Society for Immunology
- 2010-2014
- Board of Councilors, Japanese Society for Cell Death
- 2015-present
- Board of Councilors, Japanese Society for Biochemistry
- 2015-present
- Board of Directors, Japanese Society for Cell Death
Editorial Board Members
- 2007-2012
- Editorial Board Member, Journal of Biological Chemistry
- 2011-present
- Editorial Board Member, PLoS ONE
- 2015-present
- Editorial Board Member, Journal of Biochemistry
2. Team
Staff members
Soh Yamazaki, PhD, Associated Professor
Sanae Miyake, PhD, Assistant Professor
Yuichi Tsuchiya, PhD, Assistant Professor
Yutaka Deguchi, PhD, Assistant Professor
Shin Murai, PhD, Assistant Professor
Osamu Nakabayashi, PhD, Assistant Professor
Takashi Nishina, PhD, Assistant Professor
Graduate Students
Ryodai Shindo, PhD student
Takeyuki Kurosawa, MD, PhD student
Shoji Katagiri, MD, PhD student
Ryosuke Miura, PhD student
Hiroomi Miyoshi, MD, PhD student
Technical Staff
Sachiko Komazawa-Sakon
Assistant
Wakako Osanai
3. Research Projects
Our lab is interesting in the mechanism how regulated cell death maintains tissue homeostasis under physiological conditions, and also dysregulated cell death contributes to the development of many pathological conditions, and acute and chronic inflammatory diseases. To achieve these goals, we have been working on the function of cellular FLICE-inhibitory protein (cFLIP) and interleukin (IL)-11.
(1) Necroptosis and cFLIP
Apoptosis is a prototype of programmed cell death and plays a crucial role in the development of various organs and elimination of unwanted cells. Recent studies have revealed another type of programmed cell death, which is referred to as necroptosis (Nakano, Curr Top Microbiol Immunol 2015). Necroptosis is executed by two related kinases, receptor-interacting kinase (RIPK)1 and RIPK3, and a downstream effector molecule, mixed lineage kinase domain-like (MLKL). Cellular FLICE-inhibitory protein (cFLIP) is a catalytically inactive homolog of the initiator caspase, caspase-8. CFLAR gene encodes two proteins, designated a long form cFLIP (cFLIPL) and a short from cFLIP (cFLIPs) due to an alternative splicing. Since Cflar-deficient mice exhibits embryonic lethality by enhanced apoptosis and necroptosis, it has been unclear whether cFLIP plays a role in maintaining tissue homeostasis. We previously reported that cFLIP is a very unstable protein and degraded rapidly in NF-kB-deficient cells upon TNFa stimulation (Nakajima, EMBO J 2006; Oncogene 2008). Moreover, we recently generated conditional Cflar-deficient mice such as hepatocytes, intestinal epithelial cells, and epidermal cells, and reported that cFLIP plays a crucial role in preventing various types of cells from apoptosis and necroptosis (Piao, Sci Signal 2012). Using TNFa-induced acute liver injury in hepatocyte-specific cFLIP-deficient mice as a model, we have very recently reported that depletion of myeloid cells exacerbated liver injury along with aberrant increase in serum histone H3 in mouse serum (Piao, Hepatology 2016).
To further investigate a role for cFLIP in necroptosis, we have generated cFLIPs transgenic mice. We are currently determining whether overexpression of cFLIPs might block or promote apoptosis or necroptosis in vivo and investigating the mechanism.
cFLIP is an unstable protein that is degraded by the proteasome/ubiquitin pathway. Although a previous study reported that an E3 ligase, ITCH might be responsible for degradation of cFLIP, we are currently working on a newly identified candidate that is responsible for degradation of cFLIP.
Since there has been no probe to detect necroptosis in living cells, we are currently working on developing a probe to detect necroptosis in living cells. Development of the probe to monitor necroptosis and generation of transgenic mice expressing the probe might be useful to investigate biological consequences and significances of necroptosis in vitro and in vivo.
(2) Oxidative stress and IL-11
Interleukin-11 (IL-11) is a member of the IL-6 family cytokines, and controls various cellular responses, including hematopoiesis, bone development, tissue repair, and carcinogenesis. IL-11 binds to the IL-11 receptor 1 (IL-11R1) and gp130 complex and activates the family of signal transducer and activator of transcription (STAT) proteins. We previously reported that IL-11 is produced by hepatocytes in an oxidative stress-dependent manner and ameliorates acetaminophen-induced liver injury (Nishina, Sci Signal 2012). Moreover, oxidative stress-dependent IL-11 production largely depends on a transcription factor, Fra-1 that is upregulated by ERK-dependent phosphorylation of Fra-1.
We have very recently reported that one electrophile, 1,2-Naphthoquinone (1,2-NQ), induces IL-11 production in vitro and in vivo. We also have found that IL-11 counteracts 1,2-NQ-induced intestinal toxicity through inducing proliferation of intestinal epithelial cells. Further analyses have revealed that NRF2, a critical transcription factor for oxidative stress, promotes translation of Fra-1 gene, thereby upregulating Fra-1 that subsequently induces IL-11 production (Nishina, J Biol Chem 2016). Thus, our present study has revealed an unexpected role for NRF2 in IL-11 production through upregulating Fra-1.
While accumulating studies have shown that IL-11 plays a crucial role in the development of gastric and colon cancer in human and mice. However, the detailed characters of IL-11-producing cells have not been determined yet. To address this issue, we have generated IL-11-GFP reporter mice and are determining which cells can produce IL-11 upon oxidative stress or along with tumor development. Through these studies, we would like to develop a novel strategy to treat gastric and colon cancer by specifically depleting IL-11-producing cells.
4. Selected Publications
- 1. Piao X, Yamazaki S, Komazawa-Sakon S, Miyake S, Nakabayashi O, Kurosawa T, Mikami T, Tanaka M, Van Rooijen N, Ohmuraya M, Oikawa A, Kojima Y, Kakuta S, Uchiyama Y, Tanaka M, Nakano H. Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum. Hepatology 2016, 10.1002/hep.28878
- 2. Nishina T, Deguchi Y, Miura R, Yamazaki S, Shinkai Y, Kojima Y, Okumura K, Kumagai Y, Nakano H. Critical contribution of NRF2 to an electrophile-induced interleukin-11 production. J Biol Chem 2016, 10.1074/jbc.M116.744755.
- 3. Nakano H, Piao X, Shindo R, Komazawa-Sakon S. Cellular FLICE-Inhibitory Protein Regulates Tissue Homeostasis. Curr Top Microbiol Immunol 2015, 10.1007/82_2015_448.
- 4. Piao X, Komazawa-Sakon S, Nishina T, Koike M, Piao JH, Ehlken H, Kurihara H, Hara M, Van Rooijen N, Schutz G, Ohmuraya M, Uchiyama Y, Yagita H, Okumura K, He YW, Nakano H. c-FLIP Maintains Tissue Homeostasis by Preventing Apoptosis and Programmed Necrosis. Sci Signal 2012;5:ra93.
- 5. Nishina T, Komazawa-Sakon S, Yanaka S, Piao X, Zheng DM, Piao JH, Kojima Y, Yamashina S, Sano E, Putoczki T, Doi T, Ueno T, Ezaki J, Ushio H, Ernst M, Tsumoto K, Okumura K, Nakano H. Interleukin-11 links oxidative stress and compensatory proliferation. Sci Signal 2012;5:ra5.
- 6. Ushio H, Ueno T, Kojima Y, Komatsu M, Tanaka S, Yamamoto A, Ichimura Y, Ezaki J, Nishida K, Komazawa-Sakon S, Niyonsaba F, Ishii T, Yanagawa T, Kominami E, Ogawa H, Okumura K, Nakano H. Crucial role for autophagy in degranulation of mast cells. J Allergy Clin Immunol 2011;127:1267-1276 e1266.
- 7. Tokunaga F, Nakagawa T, Nakahara M, Saeki Y, Taniguchi M, Sakata S, Tanaka K, Nakano H, Iwai K. SHARPIN is a component of the NF-kB-activating linear ubiquitin chain assembly complex. Nature 2011;471:633-636.
- 8. Nakajima A, Kojima Y, Nakayama M, Yagita H, Okumura K, Nakano H. Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactive oxygen species accumulation in tumor cells. Oncogene 2008;27:76-84.
- 9. Nakano H, Nakajima A, Sakon-Komazawa S, Piao JH, Xue X, Okumura K. Reactive oxygen species mediate crosstalk between NF-kB and JNK. Cell Death Differ 2006;13:730-737.
- 10. Nakajima A, Komazawa-Sakon S, Takekawa M, Sasazuki T, Yeh WC, Yagita H, Okumura K, Nakano H. An antiapoptotic protein, c-FLIP(L), directly binds to MKK7 and inhibits the JNK pathway. EMBO J 2006;25:5549-5559.
- 11. Nakano H. Signaling crosstalk between NF-kappaB and JNK. Trends Immunol 2004;25:402-405.
- 12. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T, Nakano H. NF-kB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 2003;22:3898-3909.
- 13. Honda K, Nakano H, Yoshida H, Nishikawa S, Rennert P, Ikuta K, Tamechika M, Yamaguchi K, Fukumoto T, Chiba T, Nishikawa SI. Molecular basis for hematopoietic/mesenchymal interaction during initiation of Peyer's patch organogenesis. J Exp Med 2001;193:621-630.
- 14. Nakano H, Sakon S, Koseki H, Takemori T, Tada K, Matsumoto M, Munechika E, Sakai T, Shirasawa T, Akiba H, Kobata T, Santee SM, Ware CF, Rennert PD, Taniguchi M, Yagita H, Okumura K. Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation. Proc Natl Acad Sci U S A 1999;96:9803-9808.
- 15. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura K. Differential regulation of IkB kinase alpha and beta by two upstream kinases, NF-kB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc Natl Acad Sci U S A 1998;95:3537-3542.
- 16. Nakano H, Oshima H, Chung W, Williams-Abbott L, Ware CF, Yagita H, Okumura K. TRAF5, an activator of NF-kB and putative signal transducer for the lymphotoxin-beta receptor. J Biol Chem 1996;271:14661-14664.
