Yoshiaki Ito
Laboratory of Cell Regulation, Department of Viral Oncology,
Institute for Virus Research, Kyoto University,
Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
(Tel: 81-75-751-4028, Fax: 81-75-752-3232, E-mail: yito@virus.kyoto-u.ac.jp)
There are three mammalian runt-related (RUNX) genes, RUNX1/AML1, RUNX2/CBFAI and RUNX3/PEBP2!!
!C. RUNX1 is essential for generation of hematopoietic stem cells and is most frequently involved in human acute leukemia. RUNX2 is essential for osteogenesis and collaborate with c-myc in T cell lymphoma in mouse. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia (CCD). RUNX genes encode the!!!subunit of the Runt domain transcription factor PEBP2(1). Like RUNX1, the gene encoding PEBP2
!!!, the!!!!subunit of PEBP2, is often involved in chromosome rearrangements associated with acute myeloid leukemia. Chimeric protein, CBF!!!(PEBP2!!!)/SMMHC, is generated as a result of inversion of chromosome 16 in such a way to preserve the heterodimerization domain of PEBP2!!!fused to the C-terminal region of smooth muscle myosine heavy chain. The chimeric gene is shown to be leukemogenic. Hetorodimerisation between RUNX1 and PEBP2!!!to form functionally competent transcription factor is regulated. However, the chimeric protein over-rides the regulatory mechanism of dimerization and this property is considered to be the basis of leukemogenesis(2) We found that there is a second domain in PEBP2!!!/SMHHC which spans the junction between PEBP2!!!and SMMHC and interacts with RUNX1. This second domain shows sequence homology with pl50 subunit of chromatin assembly factor (CAF-1). RUNX1 was found to interact with pl50 and, furthermore, a point mutant of RUNXI found in a leukemia patient(3) and two found in RUNX2 in CCD patients disrupted the interaction with p150. By the studies with the mutants, we were able to identify a new domain in the Runt domain on the three dimensional structure. The results revealed not only the molecular basis of leukemogenesis by PEBP2!!!/SMMHC but also importance of the interaction of RUNX proteins with CAF-1 for the function of RUNX family. How chromatin assembly is related to carcinogenesis is important subject to study. References:
(1) Werner, M.H., Shigesada, K. and Ito, Y. (1999). Runt-domains take the lead in hematopoiesis and osteogenesis. Nature Medicine. 5:1356-1357.
(2) Osato, M., Asou, N., Abdalla, E., Hoshino, K., Yamasaki, H., Okubo, T., Suzushima, H., Takatsuki, K., Kanno, T., Shigesada, K., and Ito, Y. (1999). Biallelic and heterozygous point mutations in the Runt domain of the AML1/PEBP2C!!
!B gene associated with myeloblastic leukemias. Blood. 93: 1817-1824. (3) Huang, G, Shigesada, K., Ito, K., Wee, H.-J. Yokomizo, T., and Ito, Y. (2001) Dimerization with PEBP2b protects RUNX1/AML1 from ubiquitin-proteasome mediated degradation: EMBO J. 20: 723-733. 2001
Yoshiaki Ito 1968-1969 Instructor, Department of Bacteriology School of Medicine, Tohoku University, Sendai, Japan
1969-1972 Research associate, Department of Microbiology and Immunology, Duke University Medical Center, North Carolina, USA (Mentor: Dr. Wolfgang K. Joklik)
1972-1974 Research fellow, Department of Cell Regulation Imperial Cancer Research Fund Laboratories, London, England (Mentor: Dr. Renato Dulbecco)
1974-1979 Scientific staff, Imperial Cancer Research Fund Laboratories, London, England (Mentor: Dr. Renato Dulbecco)
1979-1983 Visiting Scientist, National Institute of Allergy and Infections Diseases, NIH Bethesda, Maryland, USA
1983-1984 Head, Cell Transformation Section, National Cancer Institute, NIH, Frederick, Maryland, USA
1995-present Director, Institute for Virus Research, Kyoto University
Speciality and Special Interest:
Molecular mechanisms of carcinogenesis induced by RUNX (runt-related) gene family which encodes the!!
!subunit of the Runt domain transcription factor, PEBP2/CBF. In particular, RUNX1/AML1 is most frequently involved in human acute leukemia and is being studied most intensely.