Analyses of Transcription Co-repressor Complexes Involved in Differentiation Block of Leukemia Cells, and Development of a New Molecular Targeting Therapy.
| Project/Area Number |
17590991
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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 |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
TOMITA Akihiro University Hospital, Research Associate, 医学部附属病院, 助手 (80378215)
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| Co-Investigator(Kenkyū-buntansha) |
KIYOI Hitoshi University Hospital, Assistant Professor, 医学部附属病院, 講師 (90314004)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Transcription factors / Transcription regulators / Acute leukemia / PML-RARα / N-CoR / Histone deacetylases / HDAC3 / APL / 分子標的療法 |
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| Research Abstract |
PML-RAR a is a chimeric transcription factor tightly associated with acute promyelocytic leukemia. PML-RARα plays an important role in the aberrant transcription repression on the target genes of wild-type retinoic acid receptors, recruiting N-CoR/SMRT (nuclear receptor co-repressor / silencing mediator for retinoid and thyroid hormone receptors) co-repressor protein complexes. In this research project, we demonstrated that HDAC3, one component of the N-CoR transcription repressor complex, is a key regulator of the transcription repression by PML-RARα in vivo. Using immunoprecipitation, we demonstrated that PML-RAR a interacts with N-CoR/HDAC3 in vivo without ligand. Next, using chromatin immunoprecipitation (ChIP) assay, this N-CoR/HDAC3 co-repressor complex was recruited to the endogenous target promoters (RARβ and CYP26) through PML-RARα. The neighboring histones were de-acetylated and gene expression was repressed. When HDAC3 protein was knocked down by RNA interference in PML-RARα-expressing cells, the endogenous target genes were significantly activated, which was also confirmed by promoter-luciferase reporter assay. These results provide evidence to show that the N-CoR/HDAC3 co-repressor complex is involved in the aberrant transcription regulation in PML-RARα-expressing cells. We also utilize a dominant-negative protein (DNP) that interfere N-CoR interaction with HDAC3 in vivo. In the presence of DNP, PML-RARα can interact with N-CoR but not with HDAC3. Our data suggest that DNP may be introduced as a new strategy for the molecular targeting therapy focusing on HDAC3 function in leukemia.
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Report
(3 results)
Research Products
(16 results)
