Regulatory mechanisms of neuronal apoptosis by necdin/MAGE proteins

necdin/MAGE蛋白对神经细胞凋亡的调控机制

• 批准号: 16300118
• 负责人: YOSHIKAWA Kazuaki
• 金额: $ 9.54万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300118/
• 关键词: Necdin; MAGE family; Neurons; Neurotrophins; Differentiation; Apoptosis; Genomic imprinting; Prader-Willi syndrome; MAGEファミリー蛋白質; 脳発達

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.

我们研究了necdin/MAGE家族成员在神经元死亡（细胞凋亡）中的作用，得到以下结果： 1． necdin及其同源蛋白MAGE-G1（或necdin-like 2）均与促凋亡蛋白E2F1转录因子和p75死亡受体结合，调节这些蛋白诱导的神经元凋亡。 2． Necdin 与神经生长因子 (NGF) 受体 TrkA 和 p75 结合，并增强 NGF.3 诱发的神经元内生存信号的激活。在necdin缺陷小鼠中，由于NGF信号减弱，NGF依赖性感觉神经元的凋亡增加。这些小鼠表现出对热痛的高度耐受性。4． Necdin 与同源结构域蛋白 Dlx2 和促凋亡 MAGE 蛋白 MAGE-D1 形成三元复合物。由于Dlx2促进前脑GABA能神经元的分化，necdin缺陷小鼠中这些神经元的数量减少。5．在necdin缺陷小鼠的小脑颗粒神经元中，促凋亡E2F1的激活和细胞凋亡增强。这些结果表明necdin和necdin相关的MAGE蛋白抑制神经元凋亡以促进其存活。目前的研究结果为基因组印记相关疾病普瑞德-威利综合征的分子发病机制提供了有价值的见解。

项目成果

Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin

• DOI: 10.1038/ncb1259
• 发表时间: 2005-06-01
• 期刊: NATURE CELL BIOLOGY
• 影响因子: 21.3
• 作者: Tseng, YH;Butte, AJ;Kahn, CR
• 通讯作者: Kahn, CR

Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor

• DOI: 10.1074/jbc.m308454200
• 发表时间: 2004-01-16
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Kuwako, K;Taniura, H;Yoshikawa, K
• 通讯作者: Yoshikawa, K

Role of Src family tyrosine kinases in the down-regulation of epidermal growth factor signaling in PC12 cells

• DOI: 10.1111/j.1365-2443.2005.00909.x
• 发表时间: 2005-12-01
• 期刊: GENES TO CELLS
• 影响因子: 2.1
• 作者: Kasai, A;Shima, T;Okada, M
• 通讯作者: Okada, M