細胞がん化

癌の特徴の一つに異常増殖があげられます。当研究室では細胞の増殖、生存に関与する遺伝子に注目し、これらの因子の、ヒトの癌での異常を検出するとともに、モデルマウスや培養細胞を用いた解析システムを構築し利用します。

ヒト癌におけるJab1/CSN5の過剰発現と癌の悪性化

Jab1/CSN5がヒトの様々な癌で高発現していることを見いだしました。

Tomoda, K., Kato, J. Y., Tatsumi, E., Takahashi, T., Matsuo, Y., and Yoneda-Kato, N. The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression. Blood, 105: 775-783, 2005.

Goto, A., Niki, T., Moriyama, S., Funata, N., Moriyama, H., Nishimura, Y., Tsuchida, R., Kato, J. Y., and Fukayama, M. Immunohistochemical study of Skp2 and Jab1, two key molecules in the degradation of P27, in lung adenocarcinoma. Pathol. Int. 54: 675-681, 2004

Fukumoto, A., Ikeda, N., Sho, M., Tomoda, K., Kanehiro, H., Hisanaga, M., Tsurui, Y., Tsutsumi, M., Kato, J. Y., and Nakajima, Y. Prognostic significance of localized p27Kip1 and potential role of Jab1/CSN5 in pancreatic cancer. Oncol. Rep. 11: 277-284, 2004.

Tsuchida R, Miyauchi J, Shen L, Takagi M, Tsunematsu Y, Saeki M, Honna T, Yamada S, Teraoka H, Kato JY, and Mizutani S. Expression of Cyclin-dependent Kinase Inhibitor p27/Kip1 and AP-1 Coactivator p38/Jab1 Correlates with Differentiation of Embryonal Rhabdomyosarcoma. Jpn J Cancer Res., 93: 1000-1006, 2002

Shen L, Tsuchida R, Miyauchi J, Saeki M, Honna T, Tsunematsu Y, Kato J-Y, and Mizutani S. Differentiation-associated expression and intracellular localization of cyclin-dependent kinase inhibitor p27KIP1 and c-Jun co-activator JAB1 in neuroblastoma. Int J Oncol. 17:749-754, 2000

癌細胞におけるJab1/CSN5の機能

種々の癌細胞におけるJab1/CSN5の機能を解析しました。

Mori M, Yoneda-Kato N, Yoshida A, Kato JY. Stable form of Jab1 enhances proliferation and maintenance of hematopoietic progenitors.J. Biol. Chem., 283: 29011-29021, 2008.

Fukumoto, A., Tomoda, K., Yoneda-Kato, N., Nakajima, Y., Kato, J.Y. Depletion of Jab1 inhibits proliferation of pancreatic cancer cell lines. FEBS Lett. 580: 5836-5844, 2006.

Fukumoto, A., Tomoda, K., Kubota, M., Kato, J. Y., and Yoneda-Kato, N. Small Jab1-containing subcomplex is regulated in an anchorage- and cell cycle-dependent manner, which is abrogated by ras transformation. FEBS Lett. 579: 1047-1054, 2005.

Tomoda, K., Kato, J. Y., Tatsumi, E., Takahashi, T., Matsuo, Y., and Yoneda-Kato, N. The Jab1/COP9 signalosome subcomplex is a downstream mediator of Bcr-Abl kinase activity and facilitates cell-cycle progression. Blood, 105: 775-783, 2005.

骨髄性白血病の新規原因因子の単離とその機能解析

白血病発症の一原因に、染色体の異常により生じた異常なタンパク質の発現があります。また、こうした異常なタンパク質は、転写因子やチロシンキナーゼであることが多いですが、まだ、機能未知のものも多く存在します。ここでは、３、５染色体転座で生じた融合タンパク質NPM-MLF1やその正常型MLF1の機能について研究しています。

Yoneda-Kato, N., Kato, J.Y. Shuttling imbalance of MLF1 results in p53 instability and increases susceptibility to oncogenic transformation. Mol Cell Biol. 28: 422-434, 2008.

Yoneda-Kato, N., Tomoda, K., Umehara, M., Arata, Y., and Kato, J. Y.. Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3. EMBO J. 24: 1739-1749, 2005.

Yoneda-Kato N, Fukuhara S, and Kato J-Y. Apoptosis Induced by the Myelodysplastic Syndrome-Associated NPM-MLF1 Chimeric Protein. Oncogene 18: 3716-3724, 1999

Matsumoto N, Yoneda-Kato N, Iguchi T, Kishimoto Y, Kyo T, Sawada H, Tatsumi E, Fukuhara S. Elevated MLF1 expression correlates with malignant progression from myelodysplastic syndrome. Leukemia. 14:1757-65, 2000

Yoneda-Kato N, Fukuhara S, Kato J. Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein. Oncogene. 18:3716-24, 1999

Kuefer MU, Look AT, Williams DC, Valentine V, Naeve CW, Behm FG, Mullersman JE, Yoneda-Kato N, Montgomery K, Kucherlapati R, Morris SW. cDNA cloning, tissue distribution, and chromosomal localization of myelodysplasia/myeloid leukemia factor 2 (MLF2). Genomics 35:392-6, 1996

Yoneda-Kato N, Look AT, Kirstein MN, Valentine MB, Raimondi SC, Cohen KJ, Carroll AJ, Morris SW. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 12:265-75, 1996