| Project/Area Number |
25460711
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Himeji Dokkyo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
MIYAMOTO Kazuhide 姫路獨協大学, 薬学部, 准教授 (10415317)
SAIGO Katsuyasu 姫路獨協大学, 薬学部, 教授 (20304107)
TANIGUCHI Taizo 姫路獨協大学, 薬学部, 教授 (70346253)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | ユビキチン-プロテアソーム系 / PML/RARA / プロテアソーム阻害剤 / ERストレス / ユビキチンープロテアソーム系 / ユビキチン-プロテアソーム |
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| Outline of Final Research Achievements |
The ubiquitin-proteasome system (UPS) controls normal protein homeostasis in cells. Bortezomib, a proteasome inhibitor, time- and dose-dependently decreased cell viability and induced apoptosis in NB4, an acute promyelocytic leukemia (APL) cell line. We confirmed that UbcH8 is the E2-conjugating enzyme for a fusion protein PML-RARA. Moreover, UbcH8 abundance was dose-dependently increased in the culture supernatant of bortezomib-treated cells. Meanwhile, ER stress was increased by Bortezomib.
We concluded that Bortezomib impairs the UPS that controls normal protein homeostasis by causing excessive accumulation of PML-RARA fusion protein, augmenting ER stress and leading to APL cell death. Furthermore, monitoring of UPS-related enzymes can be used to predict the treatment response to proteasome inhibitors and assess their therapeutic effects.
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