| Co-Investigator(Kenkyū-buntansha) |
TANAKA Nobuyuki School of Medicine Department of Oral Surgery, Tokyo Medical & Dental University, assistant professor, 医学部, 助教授 (50163548)
IKEDA Masa-aki Graduate School Section of Molecular Embryology, Tokyo Medical & Dental University, assistant professor, 大学院・医歯学総合研究科, 助教授 (20193211)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
We found that cyclin E1 protein and its kinase activity were hardly detected in HSC-2 oral squamous cacinoma cells (OSCC). Furthermore, antisense inhibition of cyclin E1 had no growth-inhibitory effects on HSC-2. The results suggest that deregulation of its downstream targets may contribute to tumorigenesis. In contrast, pRb-pathway were indispensable in HSC-2, because cyclin D products were abundant and the overexpression of p16 induced G1 arrest. We have not found unusual expressions of Brm and NPAT, which are candidates for Cdk2 substrates, in HSC-2. The abnormally high number of centrosomes, which are Cdk2 substrates, can be found in many tumors. Further analysis is necessary whether the phenomenon is associated with the deficiency of cyclin E1/Cdk2 in HSC-2. In contrast, cyclin E1/Cdk2 correlates with the anchorage dependence and is required for adhesion to the extracellular matrix. It is possible that the disorder of adhesion molecules leads the suppression of cyclin E1/Cdk2 acti
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vity in HSC-2, which were established from metastatic lymph nodes. Future analysis of the relationship between adhesion molecules such as integrin and elevated Cdks is necessary.
The pRb-related protein p130 is also substrate of cyclin E/Cdk2 and may be tumor suppressor. The analysis of 122 cases with OSCC indicated that the expression of p130 was significantly correlated with clinical stage, cervical lymph node metastasis, and tumor differentiation. The high levels of p130 expression indicated a good prognosis, suggesting that p130 may be useful prognostic factor.
We found two points of mutations of p300, which has HAT and transcriptional activity, in HOC313 cells. Although the growth-inhibition of TGF-β was abrogated in HOC313, reintroduction of wild-type p300 restored this effect, showing that p300 acts as a tumor suppressor. In conclusion, we revealed that the expression and phosphorylation of G1 reguratory proteins depended on distinct type of OSCC. These results may be associated with the difference of the degree of OSCC and lead the development of specific molecular target therapy. Less
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