| Co-Investigator(Kenkyū-buntansha) |
ONO Toshio Graduate School of Biomedical Sciences Instructor, 大学院・医歯薬学総合研究科, 教授 (80050607)
BABA Tomomi T. Graduate School of Biomedical Sciences Instructor, 大学院・医歯薬学総合研究科, 助手 (60189727)
TANAKA Ki-ichiro Graduate School of Biomedical Sciences Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (50001954)
KOBAYAKAWA Takeshi School of Dentistry Research Fellow, 歯学部, 教務職員 (10153587)
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| Research Abstract |
Post-translational processing of collagen molecules has been investigated in relation to the function of molecular chaperones. We first investigated the role of Hsp47, a collagen specific molecular chaperone, in scar formation, i.e. excessive and aberrant collagen synthesis triggered by the wounding. We found that Hsp47 as well as type I collagen was not induced in fetal rat wound, in contrast to their enhancement in neonatal rat wound. Hence, we tried to suppress collagen deposition by anti-therapeutic treatment. As a result, scar formation after wounding of neonatal rats was efficiently prevented by an anti-sense oligonucleotide against Hsp47 in vitro (primary-cultured fibroblasts) and in vivo (back wound). These findings strongly suggested that Hsp47 could be a potential target for prevention of scar formation on surgical operations, such as cleft palate.
We also investigated the functional mechanism of Hsp90. E. coli HtpG, a bacterial homologue of mammalian Hsp90, was composed of th
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ree domains at the primary structure level as those of human Hsp90. The N-terminal, middle and C-terminal domains were referred to N, M and C domains, respectively. The client-binding activity of Hsp90 was primarily localized in N domain. There were two interactions between the domains : an intramolecular interaction between N and M domains ; and an intermolecular interaction between M and C domains. The latter interaction mediated dimer formation of HSP90. Liberation of the former interaction accompanied the high temperature-induced activation of the client-binding activity of Hsp90 molecular chaperone. That is, the client-binding site located in N domain was concealed by M domain, but heat shock disrupted the interaction. Importance of the interaction between N and M domains was confirmed by expression of aberrant yeast HSP90 (Hsc82), of which M domain could not interact with N domain. We therefore propose the liberation of the intra-molecular interaction as the mechanism of heat-induced activation of Hsp90 molecular chaperone. Less
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