Organization
Division of Functional Genomics
Staff
Professor
SUZUKI, Takeshi
Assistant Professor
ISHIMURA, Akihiko
Assistant Professor
TERASHIMA, Minoru
A detailed knowledge of the genes and signaling pathways
mutated in cancer will be required to develop the novel targetbased
cancer therapeutics. However, the heterogeneity and
complexity of genomic alterations in most human cancers hamper
straightforward identification of cancer-causing mutations. We use
the retrovirus-infected mice as model systems for identifying new
cancer genes efficiently. Retroviruses induce tumors through
activation of proto-oncogenes or inactivation of tumor suppressor
genes as a consequence of retroviral integrations into host
genome. Thus the viral integration sites provide powerful genetic
tags for cancer gene identification. We are exploring the novel
molecular targets for cancer treatment based on functional
characterization of the cancer genes isolated by high-throughput
screens using retroviral insertional mutagenesis. Once these genes
are identified, we use gene knockout and transgenic mice to
understand how these genes function in tumorigenesis, and to
develop new animal models for human cancer. Our current
projects are as follows.
1) Identification of novel cancer genes using retroviral insertional
mutagenesis in mice
2) Involvement of histone methyltransferases and demethylases
in the initiation and progression of cancer
3) The role of three families of enzymes in DNA demethylation
pathway on cancer development
4) Functional analysis of the novel cancer genes using conditional
knockout mice
Fig.1 ■Efficient isolation of candidate tumor suppressor genes using retrovirus-infected Bloom syndrome model mice
Bloom syndrome is a recessive genetic disorder associated with genomic instability that causes affected people to be prone to cancer. The mutant mice for Bloom (Blm) gene showed increased rate of sister chromatid exchange, somatic recombination and loss of heterozygosity. The Blm mutant mice enhance our ability to identify tumor suppressor genes, because the tumors derived from virus-infected Blm mice are more likely to carry viral integrations in both alleles of tumor suppressor genes through their genomic instability.
Fig.2 ■Most of the genes that encode histone methyltransferases and demethylases are shown to be the targets of retroviral insertional mutagenesis in mice
Histone modifications have important roles in regulating gene expression and genome function by establishing global chromatin environments. The methylation of four lysine (K) residues on the tail of histone H3 (K4, K9, K27 and K36) is regulated by a large number of histone methyltransferases and demethylases. Among them, most of the genes (shown in red) were identified as the targets of retroviral integrations, which indicated their important roles in oncogenesis.
