The Development of novel therapeutic strategy for anaplastic thyroid carcinoma by manipulating the ubiquitin-proteasome activity
| Project/Area Number |
12671088
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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 |
Endocrinology
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| Research Institution | Tottori University |
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Principal Investigator |
TANIGUCHI Shin-ichi Tottori University, 1st Dept. of Internal Med., Clinical assistant, 医学部, 助手 (30304207)
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| Co-Investigator(Kenkyū-buntansha) |
NARASAKI Koji Tottori University, 1st Dept. of Internal Med., Clinical and research fellow, 医学部・附属病院, 医員
UETA Yoshihiko Tottori University, 1st Dept. of Internal Med., Assistant professor, 医学部・附属病院, 講師 (80283993)
HISATOME Ichiro Tottori University, 1st Dept. of Internal Med., Associate professor, 医学部, 助教授 (60211504)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | UBIQUITIN / PROTEASOME / ANAPLASTIC CARCINOMA / THYROID / プロテアソーム活性化因子 / Tet onシステム |
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| Research Abstract |
Anaplastic thyroid carcinoma is a poorly differentiated carcinoma found in elderly people. The patients with anaplastic carcinoma always suffer from poor prognosis. It is an urgent business to develop the effective strategy to suppress the growth of anaplastic carcinoma and prolong the prognosis of patients. We focused on the ubiqitin-proteasome system. Proteasome is a major intracellular proteinase found as a large protein complex composed of at least 14 distinct but homologous subunits with molecular masses of 21-32 kD and they are assembled into an approximately 700 kDa cylindcal structure. It is involved in the destruction of regulatory proteins responsible for biological processes such as cell cycle progression. We analyzed the expression of proteasome subunits in anaplastic thyroid carcinoma and found that proteasome subunit C2 and proteasome activator g (PA28g) are highly expressed in its rapid-growing cancer cells. This result is repeatedly confirmed by western blotting and imm
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unocytochemistry, when other types of thyroid carcinoma were also estimated. Interestingly, PA 28g is localized in nuclei of cancer cells, suggesting PA28g could be one of the good candidate for manipulating the growth of cancer cells. We then analyzed the detailed turn-over of PA28g using rat functional thyroid cell line, FRTL5 cells. The growth-stimuli, TSH and insulin, induced PA28-γ expression in FRTL5 cell. Intere stingly, both treatment not only upregulate PA28-γ expression but also recruite PA28-γ from cytosol to nucleus. The combination of TSH and insulin showed highest inducibility of PA28-γ as well as dual DNA synthesis of FRTL5. Proteasome inhibitors such as lactacystin significantly blocked the DNA synthesis induced by TSH and insulin, indicating the intrinsic 20S proteasome is involved in thyroid cell growth. Thus, our results indicate PA28-γ is induced by goitrogenic factors, TSH and insulin, in thyroid cell and potentially contribute to thyroid cell growth by potentiating 20S proteasome activity.
Taken together, overexpressed proteasome component such as C2 or PA28-γ will be good candidates for manipulating proteasome activity, thereby interfering with anaplastic cancer cell growth. Less
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Report
(3 results)
Research Products
(2 results)
