| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
The ubiquitin-proteasome system is involved in the regulation of cell cycle and signal transduction, and it has been reported that the breakdown of this system participates in the development of many kind diseases including malignancy. A proteasome inhibitor, Bortezomib, has now become an indispensable agent for the treatment of multiple myeloma, and it is expected that other new therapeutic agents targeting this system should also be explored hereafter. Despite of such circumstances, there is little clinical laboratory system to analyze ubiquitin-proteasome pathway inpatients' samples.
I the present study, we thus tried to establish a laboratory system for ubiquitin-proteasome pathway in adult T-cell leukemia(ATL)as a model disease of malignancy that we have been studying for long time. Since it has already been shown that the expression of SCF^<Fbl1/Skp2>, one of the ubiquitin ligase(E3), correlates with the grade of malignancy, we first examined SCF^<Fbl1/Skp2>. Unexpectedly, SCF^<Fb
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l1/Skp2>mRNA was not elevated in ATL cells compare to normal, lymphocytes. In the analysis of other E3s, however, we found that the expression of Mdm2, which ubiquitinates the tumor suppressor protein p53, was significantly elevated in ATL cells. More importantly, the expression was not correlated with the grade of malignancy suggesting that the increase of Mdm2 is an early event in the process of ATL development, and that Mdm2 becomes a marker for an early diagnosis in ATL.
A new chemotherapeutic agent Nutlin-3a that specifically inhibits the activity of Mdm2 is now drawing attention as a p53-tarteted therapy. Since ATL cells express abundant Mdm2, it is expected that ATL cells are sensitive to Nutlin-3a. Indeed, Nutlin-3a was highly toxic to ATL cells with wild-type p53 gene and induced apoptosis and cell senescence. On the other hand, ATL cells with mutated p53 gene were resistant to Nutlin-3a. As we have reported previously, since more than 80% of ATL cells carry wild-time p53, these results support the idea that Nutlin-3a is effective to more than 80% of ATL cases.
In our farther study of ubiquitin-proteasome pathway by microarray, we found that CYLD gene, a deubiquitination enzyme, was deleted in ATL patients. Combining these results, we are now trying to establish a new approach for the analysis of ubiquitin-proteasome system in clinical samples. Less
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