2005 Fiscal Year Final Research Report Summary
Regulatory mechanisms of neuronal apoptosis by necdin/MAGE proteins
| Project/Area Number |
16300118
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Osaka University |
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Principal Investigator |
YOSHIKAWA Kazuaki Osaka University, Institute for Protein Research, Professor, 蛋白質研究所, 教授 (30094452)
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| Co-Investigator(Kenkyū-buntansha) |
OKADA Masato Osaka University, Research Institute of Microbial Diseases, Professor, 微生物病研究所, 教授 (10177058)
NISHIMURA Isao Osaka University, Institute for Protein Research, Instructor, 蛋白質研究所, 助手 (70362621)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Necdin / MAGE family / Neurons / Neurotrophins / Differentiation / Apoptosis / Genomic imprinting / Prader-Willi syndrome |
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| Research Abstract |
We have studied the roles of necdin/MAGE family members in neuronal death (apoptosis), and the following results were obtained.
1. Both necdin and its homologous protein MAGE-G1 (or necdin-like 2) bound to the proapoptotic proteins E2F1 transcription factor and p75 death receptor, and regulated neuronal apoptosis induced by these proteins.
2. Necdin bound to the nerve growth factor (NGF) receptors TrkA and p75, and potentiated the activation of intraneuronal survival signals evoked by NGF.
3. In necdin-deficient mice, apoptosis of NGF-dependent sensory neurons was augmented as a result of the attenuated NGF signaling. These mice displayed a high tolerance to thermal pain.
4. Necdin formed a ternary complex with the homeodomain protein Dlx2 and the proapoptotic MAGE protein MAGE-D1. As Dlx2 promotes differentiation of forebrain GABAergic neurons, the number of these neurons decreased in necdin-deficient mice.
5. In the cerebellar granule neurons of necdin-deficient mice, activation of proapoptotic E2F1 and apoptosis were augmented.
These results suggest that necdin and necdin-related MAGE proteins suppress neuronal apoptosis to promote their survival. The present findings provide valuable insights into the molecular pathogenesis of the genomic imprinting-associated disorder Prader-Willi syndrome.
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