Induction of apoptosis in oral squamous cell carcinoma by activating caspase
| Project/Area Number |
13557172
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Surgical dentistry
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| Research Institution | Hokkaido University |
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Principal Investigator |
TOTSUKA Yasunori Hokkaido Univ. Grad. Sch. Of Dent. Med., Prof., 大学院・歯学研究科, 教授 (00109456)
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| Co-Investigator(Kenkyū-buntansha) |
YASUDA Motoaki Hokkaido Univ. Grad. Sch. Of Dent. Med., Asso. Prof., 大学院・歯学研究科, 助教授 (90239765)
HIGASHINO Fumihiro Hokkaido Univ. Grad. Sch. Of Dent. Med., Inst., 大学院・歯学研究科, 助手 (50301891)
SHINDOH Masanobu Hokkaido Univ. Grad. Sch. Of Dent. Med., Asso. Prof., 大学院・歯学研究科, 助教授 (20162802)
TEI Kanchu Hokkaido Univ. Dental Hospital, Lec., 歯学部付属病院, 講師 (80180066)
KOBAYASHI Masanobu Inst. Genet. Med. Hokkaido Univ., Asso. Prof., 遺伝子病制御研究所, 助教授 (80241321)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2002: ¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 2001: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | Apoptosis / Bnip3 / Transmembrane domain / E4orf6 |
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| Research Abstract |
Bnip3 is a pro-apoptotic pretein, which contains BH3 and transmembrane domains. We constructed several deletion mutants of Bnip3 and investigated their biological functions. The transmembrane domain of Bnip3 was not required fo the association of Bnip3 and ced-3 ; however, transmembrane domain deleted mutant could not initiate the apoptotic cascade. Immunofluorescence study demonstrated that wild type Bnip3 and ced-3 co-localized on mitochondria, and transmembrane domain deleted mutanat could not show the co-localization. These results suggest that recruitment of ced-3/caspase onto the mitochondrial membrane is essential for Bnip3 intiated apoptosis.
The adenovirus E4orf6 is a viral oncoprotein know to cooperate with the E1A gene product in transforming primary murine cells. It has been shown to inhibit the apoptotic activities of p53 and p73 through direct binding to these proteins. Here, we demonstrate that the adenovirus E4orf6 protein inhibits apoptosis mediated by BNIP3 and Bik, which are BH3-only proteins of the Bcl-2 family. This activity was not mediated by p53 and p73 because E4orf6 had the same effect on the apoptosis in Saos-2 cells that do not express p53-related genes. It was also ascertained that E4orf6 could change the mitochondrial localization of BNIP3 and Bik. A mutant lacking the nuclear export signal of E4orf6 failed to inhibit apoptosis and to translocate BNIP3 protein from the mitochondria. Moreover, it was also established that E4orf6 was able to interact with BNIP3 and Bik in vitro. In BNIP3 protein, the region required for the interaction included the transmembrane domain, which is required for the localization of BNIP3 to the mitochondria. These results suggest that E4orf6 is exported from the nucleus to the cytoplasm, enabling it to interact with BH3-only proteins, eventualy leading to the inhibition of apoptotic activity.
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Report
(3 results)
Research Products
(6 results)
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[Publications] Aoyagi M, Higashino F, Yasuda M, Takahashi A, Sawada Y, Totsuka Y, Kohgo T, Sano H, Kobayashi M, Shindoh M: "Nuclear export of the adenovirus E4orf6 protein is necessary for its ability to antagonize the apoptotic activity of the BH3-only proteins"Oncogene. 23, in press. (2003)
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