Masamoto KANNO
Department of Immunology and Parasitology, Faculty of Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan
(Tel: 81-82-257-5 175 Fax: 81-82-257-5 179 E-mail: kanno @ mcai.med.hiroshima-u.ac.jp)
Polycomb group (PcG) genes are known as negative regulators of the transcriptional memory mechanisms via chromatin silencing in Drosophila. They ensure the maintenance of transcription patterns of key regulators such as homeotic genes which were involved in the dictation of body plan, however the other functions and target genes were not well investigated to date.
mel-18 is a mammalian homologue of Drosophila PCG gene posterior sex combs and encodes a transcriptional repressor with tumor suppressive activity. We already demonstrated that mammalian PCG gene (especially mel-18) regulates both cell cycle and cell death mechanisms.
Here we found the spontaneous tumorigenesis in aged mel-18 +/- mice. These tumors are pathologically very similar to an adenocarcinoma/breast cancer. To address the question, we raised two possible explanations; "two-hit theory" and "haplo-insuficiency model". To discriminate these two possibilities, we analyzed the remaining mel-18 gene locus. We found no point mutations nor deletions in entire mel-18 gene locus and mRNA sequence. Therefore we prefer the "haplo-insufficiency model". From the analysis of chromatin silencing protein complex, we found the destabilization of big nuclear Polycomb protein complex (estimated more than 5MDa) leads to a deregulation of downstream target genes. These target genes might be cell cycle regulators (c-myc, cyclins, CDKs) and cell death regulators (bcl-2 family). Therefore we would like to propose that destabilization of Polycomb silencing complex leads to normal cells to be a tumorigenic by changing the higher order of chromatin structure and silencing pattern of gene expression of downstream target genes. Therefore we would like to discuss our results as the regulation mechanisms to control the balance between proliferation and cell death by changing the chromatin structure in tumorigenesis, hence in prospects of applications to prevention, diagnosis and therapy of cancer.
References:
(1) H.Ishihara et al., mel- 18 regulates the susceptibility to cell death in T cell development via controlling the BH3 family expression and their phosphorylation. Immunity in press.
(2) T.Akasaka et al., Mammalian Polycomb group gene products, Mel- 18 and Bmi- 1, show functional redundancy in the maintenance of Hox gene expression. Development in press
(3) O.Tetsu et al., mel- 18, a mammalian Polycomb group gene, negatively regulates cell
cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc.cdc25. Immunity 9: 439-448 (1998).
Masamoto KANNO PhD 1977 B.Pharm. Sci Chiba Univ.,Japan
1979 M.Pharm. Sci Chiba Univ.,Japan
1983 PhD Div. Immunol., Fac. Med., Chiba Univ., Japan
1983-1987 Research Associate, Div. Immunol., Fac. Med., Chiba Univ., Japan
1987-1991 Post-Doc and Res. Sci., INSERM/CNRS, Fac, Med., Unv. Louis Pasteur, Strasbourg, France
1991-1997 Lecture and Assoc.Prof., Div. Immunol., Chiba Univ., Japan
1997-date Professor Dept. Immunology, School of Medicine, Hiroshima Univ.
Speciality and Special Interest:
Transcriptional regulation by chromatin silencing, hematopoietic/lymphid cell development, cell cycle and cell death balance mechanisms, cellular memory mechanisms.