Yamaguchi University School of Medicine

Department of Biochemistry and Molecular Biology

Message from Professor

Research Activities

　 Aims of our researches are to understand molecular mechanisms of protein homeostasis by focusing on heat shock response and heat shock transcription factors (HSFs).

　 We have shown mechanisms of how heat shock transcription factors support cell survival against detrimental effects of various stresses by generating chicken B lymphocyte DT40 cells deficient for HSF1 and HSF3 (9, 11). HSFs regulate heat shock genes, and also other anti-apoptotic genes even in mammalian cells (7). Paradoxically, we also showed that HSF1 promotes mouse male germ cell death when testes are exposed to a thermal stress (10). We revealed that HSF1 activates expression of pro-apoptotic genes in addition to anti-apoptotic heat shock genes (3).

　 Furthermore, we generated HSF1-null (8) and HSF4-null mice (6). Analysis of these mice revealed developmental abnormalities in the lens and olfactory epithelium, indicating that HSFs are essential for development of the sensory organs, and indicate some pathway linking stress response and development (1, 4, 6).

　 Moreover, we would like to understand how HSFs contribute to suppression of protein misfolding deaseses. We found that HSF1 suppresses polyglutamine aggregation through regulation unknown genes as well as heat shock genes, and that overexpression of HSF1 improves lifespan of Huntington's model mice (5).

Selected Publications

1. E. Takaki, M. Fujimoto, T. Nakahari, S. Yonemura, Y. Miyata, N. Hayashida, K. Yamamoto, R. B. Vallee, T. Mikuriya, K. Sugahara, H. Yamashita, S. Inouye, and A. Nakai*. Heat shock transcription factor 1 is required for maintenance of ciliary beating in mice. (2008) J. Biol. Chem. in press

2. S. Inouye, M. Fujimoto, T. Nakamura, E. Takaki, N. Hayashida, T. Hai, and A. Nakai. HSF1 opens chromatin structure of IL-6 promoter to facilitate binding of an activator or a repressor. (2007) J. Biol. Chem. 282, 33210-33217.

3. N. Hayashida, S. Inouye, M. Fujimoto, Y. Tanaka, H. Izu, E. Takaki, H. Ichikawa, J. Rho and A. Nakai. (2006) A novel HSF1-mediated death pathway that is suppressed by heat shock proteins. EMBO J. 25, 4773–4783.

4. E. Takaki, M. Fujimoto, K. Sugahara, T. Nakahari, S. Yonemura, Y. Tanaka, N. Hayashida, S. Inouye, T. Takemoto, H. Yamashita and A. Nakai. (2006) Maintenance of olfactory neurogenesis requires HSF1, a major heat shock transcription factor in mice. J. Biol. Chem. 281, 4931-4937.

5. M. Fujimoto, E. Takaki, T. Hayashi, Y. Kitaura, Y. Tanaka, S. Inouye, and A. Nakai.(2005) Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J. Biol. Chem. 280, 34908-34916.

6. M. Fujimoto, H. Izu, K. Seki, K. Fukuda, T. Nishida, S. Yamada, K. Kato, S. Yonemura, S. Inouye, and A. Nakai. (2004) HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 23, 4297-4306.

7. S. Inouye, H. Izu, E. Takaki, H. Suzuki, M. Shirai, Y. Yokota, H. Ichikawa, M. Fujimoto, A. Nakai. (2004) Impaired IgG production in mice deficient for heat shock transcription factor 1. J. Biol. Chem. 279, 38701-38709.

8. S. Inouye, K. Katsuki, H. Izu, M. Fujimoto, K. Sugahara, S. Yamada, Y. Shinkai, Y. Oka, Y. Katoh, A. Nakai. (2003) Activation of heat shock genes is not necessary for heat shock transcription factor 1 to protect cell death against a single exposure to high temperatures. Mol. Cell. Biol. 23: 5882-5895.

9. A. Nakai, T. Ishikawa. (2001) Cell cycle transition under stress conditions controlled by vertebrate heat shock factors. EMBO J. 20, 2885-2895.

10. A. Nakai, M. Suzuki, M. Tanabe. (2000) Arrest of spermatogenesis in mice expressing an active heat shock transcription factor 1. EMBO J. 19, 1545-1554.

11. M. Tanabe, Y. Kawazoe, S. Takeda, R. I. Morimoto, K. Nagata , A. Nakai. (1998) Disruption of the HSF3 gene results in the severe reduction of heat shock gene expression and loss of thermotolerance. EMBO J. 17, 1750-1758.

Contact Information

Akira Nakai, MD&PhD, Professor, Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube 755-8505, Japan Phone: 0836-22-2214 Fax 0836-22-2315 E-mail: anakai@yamaguchi-u.ac.jp