| Project/Area Number |
11672316
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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 |
Laboratory medicine
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| Research Institution | Fukuoka University |
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Principal Investigator |
ONO Junko Fukuoka Univ., Sch.Med., Professor, 医学部, 教授 (40108692)
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| Co-Investigator(Kenkyū-buntansha) |
TAMURA Kazuo Fukuoka Univ., Sch.Med., Professor, 医学部, 教授 (60145422)
SUZUMIYA Junji Fukuoka Univ.Hospital, Instructor, 病院・講師 (70206556)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Retinoid / Adult T-Cell Leukemia (ATL) / Apoptosis |
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| Research Abstract |
Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Despite the administration of combined intensive chemotherapy, the reported survival time of patients with acute and lymphoma types of ATL is less 10 months. We therefore examine the effects of all-trans-retinoic acid (ATRA), 9-cis-RA and 13-cis-RA and tried to elucidate the mechanisms of inducing growth inhibition and apoptosis by these RAs using four ATL cell lines. All the investigated RAs inhibited cell growth and the cells were arrested at the G1 phase. Apoptosis was induced in three out of four cell lines. Among the growth regulatory proteins examined, the level of p21^<Waf1/Cip1> protein was found to increase after RA treatment, thus resulting in pRb hypophosphorylation which also induced the arrest of the cells at the G1 phase. The mechanisms of inducing apoptosis by three retinoic acid (RA) isomers, all-trans-RA (ATRA), 9-cis-RA and 13-cis-RA, to the adult T-cell leukemia (ATL) cell line, KK1, were examined to clarify the implications of RA isomers in the Bcl-2 family and caspases. Bcl-2 and Bcl-x_<L/S> are constitutively expressed in KK1 cells. The Bcl-x_L protein decreased, while the Bcl-2 and Bcl-x_S levels were unchanged by RAs. The reduction of the mitochondrial membrane potential and the activation of caspase-3 and -6 without any activation of caspase-1 were observed. Broad range caspase inhibitors prevented DNA fragmentation. These results suggest that the RA-induced apoptotic signals were transduced via the downregulation of Bcl-x_L and the decrease in the mitochondrial membrane function to caspase-3 activation.
Based on these findings, the ability of RAs to induce a remission of ATL is thus strongly suggested.
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