2003 Fiscal Year Final Research Report Summary
Involvement molecular chaperone in apoptosis signaling in human salivary gland cell line
| Project/Area Number |
14571772
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Iwate Medical University |
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Principal Investigator |
SATO Nobuko Iwate Med. Uni. Sch. Dent., Dept. Biochem, Professor, 歯学部, 教授 (00048399)
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| Co-Investigator(Kenkyū-buntansha) |
CHOSA Naoyuki Iwate Med. Uni. Sch. Dent., Dept. Biochem, Research Associate, 歯学部, 助手 (80326694)
KYAKUMOTO Seiko Iwate Med. Uni. Sch. Dent., Dept. Biochem, Assistant Professor, 歯学部, 講師 (90118274)
KAMO Masaharu Iwate Med. Uni. Sch. Dent., Dept. Biochem, Associate Professor, 歯学部, 助教授 (40214564)
TAKAOKA Yutaka Iwata Med. Uni. Sch. Dent., Dept. Biochem, Research Associate, 歯学部, 助手 (20332281)
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| Project Period (FY) |
2002 – 2003
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| Keywords | apoptosis / molecular chaperone / HSP9O / geldanamycin / Fas / caspase / signaling / human salivary gland |
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| Research Abstract |
Fas-mediated cell death in a human salivary gland adenocarcinoma cell line (HSG) was induced by treatment of the cells with anti-Fas antibody (CH-11), and this cell death was enhanced by pre-treatment with TNF-α. The. enhancement of the apoptosis caused byTNF-α resulted from increased sensitivity to CH-11-mediated apoptosis due to the induction of Fas, caspase 8 and 3 proteins by TNF-α via the activation of NFid3. Fas-mediated apoptosis was mainly inhibited by the caspase-8 inhibitor. CH-11-induced apoptosis was mainly mediated by the death signaling pathway that is caused by a caspase cascade initiated by the activation of caspase-8 at the death-inducing signaling complex (DISC).
Heat shock protein (HSP9O) is involved in the regulation of signaling cascades including apoptosis. Using a specific inhibitor for HSP90, geldanamycin (GDM), we investigated the involvement of HSP90 in CH-11-induced apoptosis. When HSG A Is were treated with GDM alone, apoptotic cell death was observed. The pretreatment with GDM prior to that with CH-11 significantly increased the cell death as compared with that obtained with GDM or CH-11 alone. The transfect ion of HSG cells with recombinant HSP90a significantly inhibited the CH-11 and GDM-induced apoptosis. These results showed that HSP90 had an anti-apoptotic activity toward HSG cells. We, next, tried to determine the target protein on the Fas signaling pathway. Immunoprecipitation with anti-human・HSP9O antibody and subsequent Western blotting analysis of these precipitates detected bands for caspase-8 and FADD-like ICE inhibitory protein (FLIP) that is known to regulate Fas cascade. Therefore, caspase-8 and FLIP were shown to be target proteins of HSP90.
These results suggest that HSP90 inhibits apoptosis by associat ing with caspase-8 and FLIP and negatively regulating their functions.
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[Publications] Taira, M., Chosa, N., Sasaki K., Saitoh, S., Sato, N., Takahashi, J.and Araki, Y.: "Effects of the medium type, serum amount and dexamethasone induction on the cell proliferation and alkaline phosphatase activity of twice-passaged SD rats' bone marrow stromal cells."J.Oral Tissue Eng.. 1(1)(in press). (2004)
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