| Project/Area Number |
14370579
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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 | 一般 |
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| Research Field |
Morphological basic dentistry
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
TSUCHIDA Nobuo Tokyo Medical and Dental University, Graduate School of Medical and Dental Research, Dept of Mol Cell Oncology & Microbiol, Professor, 大学院・医歯学総合研究科, 教授 (60089951)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Takuma Tokyo Medical and Dental University, Graduate School of Medical and Dental Research, Dept of Mol Cell Oncology & Bicrobiology, Asso. Prof., 大学院・医歯学総合研究科, 助教授 (90256678)
OMURA Ken Tokyo Medical and Dental University, Graduate School of Medical and Dental Research, Dept Oral and Maxillofacial Surgery, Professor, 大学院・医歯学総合研究科, 教授 (10334434)
AMAGASA Teruo Tokyo Medical and Dental University, Graduate School of medical and Dental Research, Dept. Mxillofacial Surgery, Professor, 大学院・医歯学総合研究科, 教授 (00014332)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2003: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | oral cancer / ERK / EGFR / Naf1 / mutation / microarra / signal trransduction / SNT2 / EGG / 増殖シグナル / 生存シグナル / AKT / NAF1 / リン酸化 |
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| Research Abstract |
This study was undertook to elucidate detailed mechanisms of aberrant growth signaling in oral squamous cell carcinoma (OSCC). The following results were obtained. (1) We, first in human cancer, found an ERK2 mutation within CD domain of codon 322 from Glu to Lys, which is accompanied with charge alteration and faster migration in PAGE. The similar mutation has been identifed in Drosphila as sevenmaker and the mutant protein reported to have weak binding to MKP, a phosphatase to inactivate ERK. In addition to HSC6, we examined 3 cell lines with EGFR amplification, and found that EGFR was phosphorylated at high levels for 846 and 1068 positions upon EGF treatment and the down regulation was mostly suppressed. Moreover, we found a cell line in which MKP1/2 was not detectably induced. The above changes in growth signaling of OSCC might have contributed at least in part to the constitutive activation of ERK. (2) By yeast 2 hybrid system we isolated two proteins that had not been known to interact with ERK2. Nafi was phosphorylated through EGF/ERK. signaling, while attenuated EGF/ERK signaling. Further experiments showed the protein to be super-phsphoaated (SP) in M phase and the treatment with G2/M inhibitors induced SP species. Besides, we found the C-terminal 1/3 of Nafi enhanced to induce apoptosis. (3) 15 tumor specimen of oral squamous cell carcinoma were examined for levels of phosphorylation of ERK which was related to clinicopathological data. There was good correlation to histopathological differentiation grade but not to TNM classification. (4) RNA expression levels of 35 drug-resitnat genes were not changed in OSCC cell linss irrespective of sensitivity to etoposide, but the expression of etoposide-regulated 2 genes was differentially expressed according to the sensitivity to etoposide. (5) Hypermethylation of 5 tumor-suppressor related genes was found in OSCCs of India but not in normal tissues, which could be used as diagnostic markers.
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