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Researchers

Mitsuaki Yoshida

Affiliation

Mitsuaki Yoshida

Cancer Chemotherapy Center  Director's Room  Director

Contact

3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
Tel:81-3-3570-0481
Fax:81-3-3570-0482
Mail:yoshimx@jfcr.or.jp

Education & Professional Career

Education:
1957-1961 Bachelor, Faculty of Pharmaceutical Science, Toyama University
1961-1962 Master, Faculty of Pharmaceutical Science, University of Tokyo
1962-1967 Ph.D., Faculty of Pharmaceutical Science, University of Tokyo


Professional Experience:
1967-1975 Research Associate, Faculty of Pharmaceutical Science, The University of Tokyo
1969-1971 Visiting Research Fellow, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
1975-1989 Department Head of the Viral Oncology, Cancer Institute, Japanese Foundation for Cancer Research
1989-1999 Professor, Department of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo
1996-1998 Director of Institute of Medical Science, The University of Tokyo
1999 Professor Emeritus, The University of Tokyo
1999-2006 Senior Member of the Board & Director, Tsukuba Research Institute, Banyu Pharmaceutical Company, Subsidiary of Merck Corporation
2006-present  Visiting professor, Graduate School of Frontier Science, The University of Tokyo
2009-present Director, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo

Area of Research

・Molecular Biology
・Viral Oncology

Membership

・The Japanese Cancer Association
・Japanese Biochemical Society
・Molecular Biology Society of Japan
・Japanese Society for Virology
・Pharmaceutical Society of Japan
・The Japanese Association for Molecular Target Therapy of Cancer
・The JFCR-International Symposium on Cancer Chemotherapy
・Oncogene Journal, Associate Editor
・Journal AIDS Research and Human Retroviruses, Editorial Board Member

Awards

1984     Science Award of Princess Takamatsu Cancer Research Fund (Princess Takamatsu Cancer Research Fund)
1985     Takeda Medical Science Prize (Medical Science Foundation of Takeda)
1987     Asahi Prize (Asahi News Paper)
2000     Medal with Purple Ribbon (Japanese Government)

Research Projects

Molecular biology of HTLV-1 (Human T-cell Leukemia Virus Type 1)
Discovery of the “Oncogene” in animal tumor viruses has established an unified concept of cancer over species and various cancer-inducing agents. To get more understanding human tumors, great efforts had been devoted to identification of human tumor viruses. In such research stream, we identified a new retrovirus in Adult T-cell Leukemia (ATL) and reported as an ATLV (Adult T-cell Leukemia Virus). Furthermore, we determined structure of the whole viral genome and established the ATLV as a causative agent of ATL with molecular technology. Mechanism of leukemia induction has been molecularly approached through identification of a new viral gene Tax and analysis of its functions. Tax has been turned out to control transcriptional activation/suppression of various genes and also to inhibit tumor suppressive protein functions, which regulate cell growth, apoptosis and cell cycle check point. Later, we demonstrated the identity of the ATLV and HTLV which had been reported by Dr. R. Gallo, NCI, and thus HTLV-1 was proposed as the formal terminology. These research and data are not only contributed to understanding ATL but also to diagnosis of ATL followed by prevention of the viral infection which in turn prevention of ATL through rejection of virus-positive blood from blood bank and also through blocking breast milk to children born to virus-positive mothers. However, it is hard to explain whole story only by an Tax protein, and recently another new viral gene HBZ has been proposed to play additional critical roles in ATL development. We are continuously contributing to the research.


Discovery and functional study of yes concogene
Molecular biology of animal tumor viruses has led to discovery of the oncogene src, and accelerated cancer research revolutionary.  In 1981, we discovered a new oncogene “yes” in avian sarcoma virus Y73, which had been isolated at Yamaguchi University. The protein product, YES, is tyrosine kinase but not receptor type membrane protein. The yes oncogene was found to be highly homologous to oncogene src in amino acid level, but  not so in nucleotide sequence, therefore, it was suggested the yes oncogene has diverged from src preserving the protein function thus forming gene family. Physiological function of yes has been unknown, however, it has been recently proposed to be involved in certain types of human cancers, and thus we are currently involved in innovation of yes inhibitors.


Original articles 


Related to HTLV-1


1.Molecular approach to human leukemia: Isolation and characterization of the first human retrovirus HTLV-1 and its impact on tumorigenesis in Adult T-cell Leukemia. Yoshida M. Proc. Japan Academy, Series B. 86, 117-130 (2010).

2.Discovery of HTLV-1, the first human retrovirus; its unique regulatory mechanisms and insights into pathogenesis. Yoshida M. Oncogene. 24, 5931-5937 (2005). 

3.Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Yoshida M. Ann Rev Immunol. 19, 475-496 (2001).

4.Tax oncoprotein of HTLV-1 binds to the human homologue of Drosophila discs large tumor suppressor protein, hDLG, and perturbs its function in cell growth control. Suzuki, T., Ohsugi, Y., Uchida-Toita, M., Akiyama, M. and Yoshida, M. Oncogene, 18, 5967-5972 (1999).

5.Tax protein of HTLV-1 inhibits CBP/p300-mediated transcription by interfering with recruitment of CBP/p300 onto DNA element of E-box or p53 binding site. Suzuki, T., Kitao,S. Matsushime, H. and Yoshida, M. Oncogene, 18, 4137-4143 (1999).

6.Trans-activator Tax of human T-cell leukemia virus type 1 (HTLV-1) enhances mutation frequency of the cellular genome. Miyake, H., Suzuki, T., Hirai, H. and Yoshida, M. Virology, 253, 155-161 (1998).

7.HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4. Suzuki, T., Kitao, S., Matsushime, H. and Yoshida M. EMBO J., 15, 1607-1614 (1996).

8.HTLV-1 oncoprotein tax and cellular transcription factors. Yoshida, M., Suzuki, T., Fujisawa J. and Hirai, H. Curr. Top. Microbiol. Immunol., 193, 79-89 (1995).

9.Tax protein of HTLV-1 destabilizes the complexes of NF-B and IB- and induces nuclear translocation of NF-B for transcriptional activation. Suzuki, T., Hirai. H., Murakami, T. and Yoshida, M. Oncogene, 10, 1199-1207 (1995).

10.Human T-cell leukemia viruses. Yoshida, M. Encyclopedia of Virology, 2, 682-686 (1994).

11.Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor B and induces nuclear translocation of transcription factor NF-B proteins for transcriptional activation. Hirai, H., Suzuki, T., Fujisawa, J., Inoue, J. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 91, 3584-3588 (1994).

12.The trans-activator Tax of human T-cell leukemia virus type 1 (HTLV-1) interacts with cAMP-responsive element (CRE) binding and CRE modulator proteins that bind to the 21-base-pair enhancer of HTLV-1. Suzuki, T., Fujisawa, J., Toita, M. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 90, 610-614 (1993).

13.Overlap of the p53-responsive element and cAMP-responsive element in the enhancer of human T-cell leukemia virus type I. Aoyama, N., Nagase, T., Sawazaki, T., Mizuguchi, G., Nakagoshi, H., Fujisawa, J., Yoshida, M. and Ishii, S. Proc. Natl. Acad. Sci. USA, 89, 5403-5407, (1992).

14.Transcriptional activator Tax of HTLV-1 binds to the NF-B precursor p105. Hirai, H., Fujisawa, J., Suzuki, T., Ueda, K., Muramatsu, M., Tsuboi A., Arai, N. and Yoshida, M. Oncogene,  7, 1737-1742, (1992).

15.HTLV-1 Rex protein accumulates unspliced RNA in the nucleus as well as in cytoplasm. Inoue, J., Itoh, M., Akizawa, T., Toyoshima, H. and Yoshida, M. Oncogene, 6, 1753-1757 (1991). 

16.Increased replication of HTLV-I in HTLV-I-associated myelopathy. Yoshida, M., Osame, M., Kawai, H., Toita, M., Kuwasaki, N., Nishida, Y., Hiraki, Y., Takahashi, K., Nomura K., Sonoda, S., Eiraku, N., Ijichi, S. and Usuku, K. Ann. Neurol., 26, 331-335 (1989).

17.Two cis-acting elements responsible for post-transcriptional trans-regulation of gene expression of human T cell leukemia virus type I. Seiki, M., Inoue, J., Hidaka, M. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 85, 7124-7128 (1988).

18.Post-transcriptional regulator (rex) of HTLV-1 initiates expression of Viral structural proteins but suppresses expression of regulatory proteins. Hidaka, M., Inoue, J., Yoshida, M. and Seiki, M. EMBO J., 7, 519-523 (1988).

19.Viruses detected in HTLV-1-associated myelopathy and adult T-cell leukemia are identical in DNA blotting. Yoshida, M., Osame, M., Matsumoto, M. and Igata, A. LANCET, May 9, 1987, 1085-1086 (1987).

20.Transcriptional (p40x) and post-transcriptional (p27x-III) regulator are required for the expression and replication of human T-cell leukemia virus type I genes. Inoue, J., Yoshida, M. and Seiki, M. Proc. Natl. Acad. Sci. USA, 84, 3653-3657 (1987).

21.Recent advances in molecular biology of HTLV-1: trans-activation of viral and cellular genes. Yoshida, M. and Seiki, M. Ann. Rev. Immunol., 5, 541-559 (1987).

22.Evidence for aberrant activation of the interleukin-2 autocrine loop by HTLV-1-encoded p40x and T3/Ti complex triggering. Maruyama, M., Shibuya, H., Harada, H., Hatakeyama, M., Seiki, M., Fujita, T., Inoue, J., Yoshida, M. and Taniguchi, T. Cell, 48, 343-350 (1987).

23.Induction of interleukin 2 receptor gene expression by p40x encoded by human T-cell leukemia virus type 1. Inoue, J., Seiki, M., Taniguchi, T., Tsuru, S. and Yoshida, M. EMBO J., 5, 2883-2888 (1986).

24.The second pX product p27x-III of HTLV-1 is required for gag gene expression. Inoue, J., Seiki, M. and Yoshida, M. FEBS., 209, 187-190 (1986).

25.A single species of pX mRNA of human T-cell leukemia virus type 1 encodes trans-activator p40x and two other phosphoproteins. Nagashima, K., Yoshida, M. and Seiki, M. J. Virol., 60, 394-399 (1986).

26.Direct evidence that p40x of human T-cell leukemia virus type I is a trans-acting transcriptional activator. Seiki, M., Inoue, J., Takeda, T. and Yoshida, M. EMBO J., 5, 561-565 (1986).

27.p27x-III and p21x-III, proteins encoded by the pX sequence of human T-cell leukemia virus type I. Kiyokawa, T., Seiki, M., Iwashita, S., Imagawa, K., Shimizu, F. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 82, 8359-8363 (1985).

28.Functional activation of long terminal repeat of human T-cell leukemia virus type I by trans-acting factor. Fujisawa, J., Seiki, M., Kiyokawa, T. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 82, 2277-2281 (1985).

29.Expression of the pX gene of HTLV-1: General splicing mechanism in the HTLV family. Seiki M., Hikikoshi, A., Taniguchi, T. and Yoshida, M. Science, 228, 1532-1534 (1985).

30.Envelope proteins of human T-cell leukemia virus: Expression in Escherichia coli and its application to studies of env genes functions. Kiyokawa, T., Yoshikura, H., Hattori, S., Seiki, M. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 81, 6202-6206 (1984).

31.Identification of a protein (p40x) encoded by a unique sequence pX of human T-cell leukemia virus type I. Kiyokawa, T., Seiki, M., Imagawa, K., Shimizu, F. and Yoshida, M. Gann, 75, 747-751 (1984).

32.Nonspecific integration of the HTLV provirus genome into adult T-cell leukemia cells. Seiki, M., Eddy, R., Shows, T.B. and Yoshida, M. Nature, 309, 640-642 (1984).

33.Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Yoshida, M., Seiki, M., Yamaguchi, K. and Takatsuki, K. Proc. Natl. Acad. Sci. USA, 81, 2543-2537 (1984).

34.HTLV type I (US isolate) and ATLV (Japanese isolate) are the same species of human retrovirus. Watanabe, T., Seiki, M. and Yoshida, M. Virol., 133, 238-241 (1984).

35.Retrovirus terminology. Watanabe, T., Seiki, M. and Yoshida, M. Science, 222, 1178 (1983).

36.Human adult T-cell leukemia virus: Complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Seiki, M., Hattori, S., Hirayama, Y. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 80, 3618-3622 (1983).

37.Human adult T-cell leukemia virus: Molecular cloning of the provirus DNA and the unique terminal structure. Seiki, M., Hattori, S. and Yoshida, M. Proc. Natl. Acad. Sci. USA, 79, 6899-6902 (1982).

38.Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. Yoshida, M., Miyoshi, I. and Hinuma, Y. Proc. Natl. Acad. Sci. USA, 79, 2031-2035 (1982).

39.Isolation and characterization of retrovirus (ATLV) and its association with adult T-cell leukemia. Yoshida, M., Miyoshi, I. and Hinuma, Y. Gann, Monograph on Cancer Research, 28, 229-237 (1982).

Related to yes and other oncogenes

40.Avian sarcoma virus Y73 genome sequence and structural similarity of its transforming gene product to that of Rous sarcoma virus. Kitamura, N., Kitamura, A., Toyoshima, K., Hirayama, Y. and Yoshida, M. Nature, 297, 205-208 (1982).

41.Uninfected avian cells contain structurally unrelated progenitors of viral sarcoma genes. Yoshida, M., Kawai, S. and Toyoshima, K. Nature, 287, 633-654 (1980).

42.Characterization of Y73, an avian sarcoma virus: A unique transforming gene and its product, phosphopolyprotein with protein kinase activity. Kawai, S., Yoshida, M., Segawa, K., Sugiyama, H., Ishizaki, R. and Toyoshima, K. Proc. Natl. Acad. Sci. USA, 77, 6199-6203 (1980).

43.Analysis of spleen focus-forming virus-specific RNA sequences coding for spleen focus-forming virus-specific glycoprotein with a molecular weight of 55,000 (gp55). Yoshida, M. and Yoshikura, H. J. Virol., 33, 587-596 (1980).

44.In vitro translation of avian erythroblastosis virus RNA: Identification of two major polypeptides. Yoshida, M. and Toyoshima, K. Virol., 100, 484-487 (1980).

45.Strain specificity of changes in adenylate cyclase activity in cells transformed by avian sarcoma viruses. Yoshida, M., Owada, M. and Toyoshima, K. Virol., 60, 68-76 (1975).

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