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Professor: Takeshita, Toshikazu
Assistant Professor: Kojima, Katsuhiko
Assistant Professor: Yamashita, Yuki
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Summary of Activity
One of our research focuses on the molecular mechanism of membrane trafficking of cytokine receptors involved in regulation of intracellular signal transduction. The other interest is the relationship between vector insertional mutagenesis and oncogenesis in viral vector-mediated gene therapy. To clarify these issues we mainly conduct research using molecular biological, biochemical and cell biological approaches. The specific research projects are as follows:
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Research Projects
1. Ubiquitylation-independent endosomal sorting and degradation of cytokine receptors
It has well known that ubiquitylation of receptor tyrosine kinases such as EGF receptor is required for their lysosomal degradation and the consequent attenuation of intracellular signal transduction. We found that a cytokine receptor IL-2Rβ is degraded via a novel pathway in ubiquitylation-independent manner (Yamashita et al., 2008). We are further exploring the consensus signal for ubiquitin-independent endosomal sorting of the cytokine receptor family and trying to identify a novel molecule involved in this degradation pathway.
2. leukemogenesis following gene therapy of X-SCID patients using retroviral vectors
The mutations in the cytokine receptor IL-2Rγ cause X-linked severe combined immunodeficiency (X-SCID). Gene therapy trial for X-SCID patients using retroviral vector achieved successful outcomes, but associated with leukemogenesis in some patients, which is most likely due to activation of oncogenes by vector insertional mutagenesis. In spite of being such a clinical application of human patients, a character of viral vector integration into genomic DNA is not well known. Our investigation of murine leukemia virus (MLV) vector integration sites in human T-cells revealed integration preference near the transcriptional start sites of genes and existence of MLV integration hot spots (Tsukahara et al., 2006). We also found that frequent vector integration into promoter region of the oncogene LMO2, which is thought to be a cause of leukemia in X-SCID gene therapy trials, is a hematopoietic cell-specific event (Yamada et al., 2009).
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- Yamada K., Tsukahara T., Yoshino K., Kojima K., Agawa H., Yamashita Y., Amano Y., Hatta M., Matsuzaki Y., Kurotori N., Wakui K., Fukushima Y., Osada R., Shiozawa T., Sakashita K., Koike K., Kumaki S., Tanaka N. and Takeshita T.: Identification of a high incidence region for retroviral vector integration near exon 1 of the LMO2 locus. Retrovirology, 6, 79, 2009.
- Yamashita Y., Kojima K., Tsukahara T., Agawa H., Yamada K., Amano Y., Kurotori N., Tanaka N., Sugamura K., Takeshita T.: Ubiquitin-independent binding of Hrs mediates endosomal sorting of the interleukin-2 receptor β chain. J Cell Sci., 121, 1727-1738, 2008.
- Kyuuma M., Kikuchi K., Kojima K., Sugawara Y., Sato M., Mano N., Goto J., Takeshita T., Yamamoto A., Sugamura K., Tanaka N,: AMSH, an ESCRT-Ⅲ Associated Enzyme,Deubiquitinates Cargo on MVB/Late Endosomes. Cell Struct Funct., 31(2),159-172, 2006.
- Tsukahara T, Agawa H, Matsumoto S, Matsuda M, Ueno S, Yamashita Y, Yamada K, Tanaka N, Kojima K, and Takeshita T.: Murine leukemia virus vector integration favors promoter regions and regional hot spots in a human T-cell line. Biochem Biophys Res Commun., 345(3), 1099-107, 2006.
- Deborah Brancho, Nobuyuki Tanaka, Anja Jaeschke, Juan-Jose Ventura, Nyaya Kelkar, Yoshinori Tanaka, Masanao Kyuuma, Toshikazu Takeshita, Richard A. Flavell, and Roger J. Davis.: Mechanism of p38 MAP kinase activation in vivo. Genes Dev. ,17,1969-1978, 2003.
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