Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor
Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor
复制标题
DOI：
10.1074/jbc.m308454200
复制
发表时间：
2004-01-16
影响因子：
4.8
通讯作者：
Yoshikawa, K
中科院分区：
文献类型：
--
作者：
Kuwako, K;Taniura, H;Yoshikawa, K
Necdin是一种生长抑制因子，主要在有丝分裂后神经元中表达，并与其终末分化有关。Necdin与MAGE家族蛋白有中等的同源性，其功能作用在很大程度上尚不清楚。人类编码Necdin、MAGEL2(Necdin-like 1)和MAGE-G1(Necdin-like 2)的基因位于15q染色体近端，该区域与Prader-Willi综合征、Angelman综合征和自闭症等神经发育障碍有关。Necdin和MAGEL2基因受到基因组印记，提示它们可能参与了Prader-Willi综合征的病因学。在这项研究中，我们比较了这些Necdin相关MAGE蛋白的小鼠同源基因的生化和功能特征。克隆形成和溴脱氧尿嘧啶核苷掺入分析表明，Necdin和MAGE-G1诱导生长停滞，而MAGEL2没有。Necdin和MAGE-G1通过转录因子E2F1的反式激活结构域与转录因子E2F1相互作用，抑制E2F1依赖的转录，拮抗E2F1诱导的N1E-115神经母细胞瘤细胞的凋亡。此外，Necdin和MAGE-G1通过其独特的细胞内结构域与p75神经营养素受体相互作用。相反，MAGEL2不能与这些Necdin相互作用物结合，这表明MAGEL2在大脑发育过程中没有Necdin样功能。P75易位Necdin和MAGE-G1在细胞膜附近过表达，并减少它们与E2F1的关联，从而促进E2F1诱导的神经母细胞瘤细胞死亡。这些结果表明，Necdin和MAGE-G1都针对E2F1和p75来调节大脑发育过程中的细胞活性。
Necdin is a growth suppressor expressed predominantly in postmitotic neurons and implicated in their terminal differentiation. Necdin shows a moderate homology to the MAGE family proteins, the functional roles of which are largely unknown. Human genes encoding necdin, MAGEL2 (necdin-like 1), and MAGE-G1 (necdin-like 2) are located in proximal chromosome 15q, a region associated with neurodevelopmental disorders such as Prader-Willi syndrome, Angelman syndrome, and autistic disorder. The necdin and MAGEL2 genes are subjected to genomic imprinting and suggested to be involved in the etiology of Prader-Willi syndrome. In this study, we compared biochemical and functional characteristics of murine orthologs of these necdin-related MAGE proteins. The colony formation and bromodeoxyuridine incorporation analyses revealed that necdin and MAGE-G1, but not MAGEL2, induced growth arrest. Necdin and MAGE-G1 interacted with the transcription factor E2F1 via its transactivation domain, repressed E2F1-dependent transcription, and antagonized E2F1-induced apoptosis of N1E-115 neuroblastoma cells. In addition, necdin and MAGE-G1 interacted with the p75 neurotrophin receptor via its distinct intracellular domains. In contrast, MAGEL2 failed to bind to these necdin interactors, suggesting that MAGEL2 has no necdin-like function in developing brain. Overexpression of p75 translocated necdin and MAGE-G1 in the proximity of the plasma membrane and reduced their association with E2F1 to facilitate E2F1-induced death of neuroblastoma cells. These results suggest that necdin and MAGE-G1 target both E2F1 and p75 to regulate cell viability during brain development.