Sphingomyelin Synthase 1 Regulates Neuro-2a Cell Proliferation and Cell Cycle Progression Through Modulation of p27 Expression and Akt Signaling.
Sphingomyelin Synthase 1 Regulates Neuro-2a Cell Proliferation and Cell Cycle Progression Through Modulation of p27 Expression and Akt Signaling.
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DOI：
10.1007/s12035-014-8829-z
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发表时间：
2015
影响因子：
5.1
通讯作者：
Dempsey, Robert J.
中科院分区：
文献类型：
--
作者：
Wesley, Umadevi V.;Hatcher, James F.;Dempsey, Robert J.
鞘磷脂合成酶(SMS)是参与神经鞘蛋白(SM)生成和细胞生长与存活调控的关键酶。然而，丹参对神经细胞增殖和细胞周期进程的影响还没有完全阐明。在这项研究中，我们研究了SMS1在调节表现出神经元特征的Neuro-2a细胞的细胞周期进程和增殖中的直接作用。神经-2a细胞中SMS1的表达水平显著降低。RNA干扰介导的Neuro-2a细胞SMS1缺失导致SM水平显著降低。SMS1水平降低导致细胞增殖率降低，细胞形态发生改变，包括轴突样外生长。此外，SMS1的沉默还导致细胞周期停滞，表现为G0/G1期细胞比例增加，S期细胞比例下降。伴随着这些变化的是细胞周期蛋白依赖性激酶抑制因子p27的上调，以及细胞周期蛋白D1和磷酸化Akt水平的降低。在SMS1缺陷的细胞中，p27的核积聚也很明显。此外，SMS1的缺失抑制了Neuro 2a细胞的迁移能力，这与基质金属蛋白酶水平的降低有关。这些结果表明，SMS1在参与多种细胞活动紧密协调的关键信号通路中发挥重要作用，包括神经元细胞增殖、细胞周期进展和迁移，因此可能在神经退行性疾病中具有重要意义。
Sphingomyelin synthase (SMS) is a key enzyme involved in the generation of sphingomyelin (SM) and regulation of cell growth and survival. However, the effects of SMS on neuronal cell proliferation and cell cycle progression are not completely elucidated. In this study, we examined the direct effects of SMS1 in regulating cell cycle progression and proliferation of Neuro-2a cells that exhibit neuronal characteristics. Neuro-2a cells transfected with SMS specific shRNA expressed significantly lower levels of SMS1. RNA interference-mediated depletion of SMS1 in Neuro-2a cells caused a significant decrease in SM levels. Decreased SMS1 levels resulted in reduced proliferation rate and morphological changes including neurite like out growth. Also, silencing of SMS1 induced cell-cycle arrest as shown by the increased percentage of cells in G0/G1 and decreased proportion of cells in S-phase. These changes were accompanied by up-regulation of cyclin-dependent kinase inhibitor p27, and decreased levels of cyclin D1 and phospho-Akt. Nuclear accumulation of p27 was also evident in SMS1 deficient cells. Furthermore, loss of SMS1 inhibited the migratory potential of Neuro 2a cells in association with decreased levels of matrix metalloproteinases. These results indicate that SMS1 plays an important role in mediating the key signaling pathways that are involved in the tight coordination of multiple cellular activities, including neuronal cell proliferation, cell cycle progression, and migration, and therefore may have significant implications in neurodegenerative diseases.
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影响因子：
16.2
作者：
Frank, Christopher L.;Tsai, Li-Huei
通讯作者：
Tsai, Li-Huei
影响因子：
4.4
作者：
Adibhatla, Rao Muralikrishna;Hatcher, J. F.;Gusain, A.
通讯作者：
Gusain, A.
影响因子：
--
作者：
Assi E;Cazzato D;De Palma C;Perrotta C;Clementi E;Cervia D
通讯作者：
Cervia D
影响因子：
50.3
作者：
Baldassarre, G;Belletti, B;Colombatti, A
通讯作者：
Colombatti, A
影响因子：
5.1
作者：
Adibhatla, Rao Muralikrishna;Hatcher, James F.
通讯作者：
Hatcher, James F.