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Kazumi Nakano / Associate Professor / Biosciences
Department of Computational Biology and Medical Sciences / / Viral oncogenesis
http://uchimaru.umin.jp/

Career Summary
1994 (B.Sc.) Japan Womenfs University and National Institute of Polar Research, Japan

1996 (M.Sc.) Faculty of Science, The University of Tokyo, Japan

2000 (Ph.D.) Faculty of Agricultural Sciences, The University of British Columbia (UBC), Vancouver, Canada

2000 (Postdoctoral fellowship) Faculty of Agricultural Sciences, UBC, Vancouver, Canada

Feb.-July 2003 (Postdoctoral fellowship) Department of Biology and Chemistry, City University of Hong Kong, Hong Kong

Oct. 2003 (Researcher) Food Processing and Preservation Division, National Research Institute of Fisheries Science, Japan

2004 (Research Associate) RIKEN Genome Science Center, Japan

2007 (Research resident) Department of Medical Genome Sciences, Graduate
School of Frontier Sciences, The University of Tokyo, Japan

2009 (Research Associate) Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan

2016 (Research Associate) Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan

2017 (Associate Professor) Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan
Educational Activities
(1) MGS Fundamental Exercise II
(2) MGS Fundamental Exercise IV
(3) Research experience seminar for undergraduate students
(4) The International Alliance Research Internship (IARI)
Research Activities
Adult T-cell leukemia/lymphoma (ATL) [JW1]is one of the most aggressive malignancies caused by infection of the human retrovirus, Human T-cell Leukemia Virus type-1 (HTLV-1), to T cells. HTLV-1 is mainly transmitted to infants from infected mothers through breastfeeding and leads to malignant transformation of infected T cells 60?70 years after the infection. My research goal is to clarify the underlying molecular mechanisms of HTLV-1 pathogenesis and the molecular disorders responsible for the onset of ATL.

After the HTLV-1 entry, the viral genomic RNA is reverse-transcribed and immediately integrated into the host human genome (provirus). Then, transcription and translation from the HTLV-1 provirus occur through the host cell machinery. I am particularly interested in the function of a viral protein, Rex, which is known to nuclear-export unspliced and partially spliced viral mRNAs. Recently, we have found that Rex inhibits cellular nonsense-mediated mRNA decay (NMD) to protect viral mRNAs and enhances the production of viral proteins. We continue to investigate how Rex hijacks the cellular environment beneficial for viral replication, and thus how to trigger[JW2] immortalization and leukemogenesis of HTLV-1 infected T cells.

In order to clarify molecular dysregulation, which is accumulated in HTLV-1 infected cells for several decades and triggers the ATL onset, we have been investigating the gene expression profiles of ATL cells in detail. Thus far, we have revealed abnormal overexpression of various genes including oncogenic transcription factors, c-Myb, and FoxM1, of which dysregulation may cause malignant transformation and proliferative/metastatic phenotypes of ATL cells.

Literature
1. Nakano K., Uchimaru K., Utsunomiya A., Yamaguchi K., and Watanabe T. (2016). Dysregulation of c-Myb pathway by aberrant expression of proto-oncogene MYB provides the basis for malignancy in adult T-cell leukemia/lymphoma cells. Clin Cancer Res. 22: 5915-5928.

2. Nakano K. and Watanabe T. (2016). HTLV-1 Rex Tunes the Cellular Environment Favorable for Viral Replication. Viruses 8: 58; doi:10.3390/v8030058.

3. Aoki S., Firouzi S., L?pez Y., Yamochi T., Nakano K., Uchimaru K., Utusnomiya A., Iwanaga M., and Watanabe T. (2016). Transition of adult T-cell leukemia/lymphoma clones during clinical progression. Int. J. Hematol. 2016 Jul 6. [Epub ahead of print]

4. Fujikawa D., Nakagawa S., Hori M., Kurokawa N., Soejima A., Nakano K., Yamochi T., Nakashima M., Kobayashi S., Tanaka Y., Iwanaga I., Utsunomiya A., Uchimaru K., Yamagishi M., and Watanabe T. (2016). Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood 127: 1790-1802.

5. Ochiya T., Takenaga K., Asagiri M., Nakano K., Satoh H., Watanabe T., Imajoh-Ohmi S., and Endo, H. (2015). Efficient inhibition of tumor angiogenesis and growth by asynthetic peptide blocking S100A4-methionine aminopeptidase interaction. Methods Clin. Dev. 2: 15008; doi:10.1038/mtm.2015.8

6. Takahashi R., Yamagishi M., Nakano K., Yamochi T., and Yamochi T, et al. (2014) Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia. Cancer Sci. 1?10.

7. Kobayashi S., Nakano K., Watanabe E., Ishigaki T., and Ohno N., et al. (2014) CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult t-cell leukemia/lymphoma. Clin Cancer Res. 20: 2851?2861.

8. Nakano K., Ando T., Yamagishi M., Yokoyama K., Ishida T., Ohsugi T., Tanaka Y., Brighty D. W., and Watanabe T. (2013). Viral interference with host mRNA surveillance, the nonsense-mediated mRNA decay (NMD) pathway, through a new function of HTLV-1 Rex: implications for retroviral replication. Microbes Infect. 15:491-505.

9. Asanuma S., Yamagishi M., Kawanami K., Nakano K., Sato-Otsubo A., Muto S., Sanada M., Yamochi T., Kobayashi S., Utsunomiya A., Iwanaga M., Yamaguchi K., Uchimaru K., Ogawa S., and Watanabe T. (2013). Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promotes T-cell growth. Cancer Sci. 104: 1097-1106.

10. Nakano K. and Watanabe T. (2012). HTLV-1 Rex: the courier of viral messages, making use of the host vehicle. Front. Microbiol. 3:330. (Epub doi: 10.3389/fmicb.2012.00330)

11. Yamagishi M., Nakano K., Miyake A., Yamochi T., Kagami Y., Tsutsumi A., Matsuda Y., Sato-Otsubo A., Muto S., Utsunomiya A., Yamaguchi K., Uchimaru K., Ogawa S., and Watanabe T. (2012). Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kB pathway in adult t cell leukemia and other cancers. Cancer Cell 21: 121?135.

Other Activities
(1) Board member of Japanese HTLV-1 Association
(2) Management board member of The 18th International Conference on Human Retrovirology: HTLV and Related Viruses (Tokyo, 2017)
(3) Memberships of academic societies: Japanese HTLV-1 Association, Japanese Cancer Association, Japanese Society of Hematology, Japanese Society for Virology, The Molecular Biology Society of Japan
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Future Plan
My goal is to clarify the genetic and molecular disorders accumulated in HTLV-1 infected T cells, which trigger the onset of ATL, by means of virological and oncological approaches. Also, by taking advantage of our research base at the Institute of Medical Science University of Tokyo, cooperation between basic research and practical medicine will be further promoted for the development of a new therapeutic approach to ATL.
Messages to Students
In graduate school, you will be the first researcher of your research. Therefore, there are no paved roads to your goal. You may have to struggle to find your way to reach the goal. Such experiences can sometimes be very tough. However, they will strengthen you and will certainly be invaluable in your future. I hope that you will learn something that is going to be the foundation of your life through your research in the graduate program.
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