Induction of cell-cycle arrest by all-trans retinoic acid in mouse embryonic palatal mesenchymal (MEPM) cells
Induction of cell-cycle arrest by all-trans retinoic acid in mouse embryonic palatal mesenchymal (MEPM) cells
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全反式视黄酸诱导小鼠胚胎腭间充质 (MEPM) 细胞细胞周期停滞
DOI：
10.1093/toxsci/kfi030
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发表时间：
2005-02-01
影响因子：
3.8
通讯作者：
Li, Y
中科院分区：
文献类型：
--
作者：
Yu, ZL;Lin, JX;Li, Y
全反式维甲酸(AtRA)是维生素A的氧化代谢产物，对胚胎的正常发育至关重要。此外，高水平的atRA在许多物种中都是致畸的，可以有效地诱导小鼠的腭裂。大多数腭裂是由于次级腭架融合失败所致，而维持正常的细胞增殖在这个腭架生长过程中是重要的。目的：阐明全反式维甲酸导致腭裂的机制。观察全反式维甲酸对小鼠胚胎腭间充质(MEPM)细胞增殖活性和细胞周期分布的影响。ATRA以剂量依赖方式诱导MEPM细胞凋亡，从而抑制MEPM细胞的生长。全反式维甲酸还可引起细胞周期G1期阻滞，流式细胞仪检测G0/G1期细胞比例增加，S期细胞比例降低。接下来，我们研究了全反式维甲酸对调节从G1到S相变的分子的影响。这些研究表明atRA在蛋白水平上抑制了细胞周期蛋白D和E的表达。此外，全反式维甲酸处理降低了Rb的磷酸化，降低了CDK2和CDK4的活性。提示全反式维甲酸可能通过调节GIN细胞周期调节因子和抑制MEPM细胞中Rb的磷酸化而发挥抗增殖作用，这可能是维甲酸诱导的腭裂的发病机制之一。
all-trans retinoic acid (atRA), the oxidative metabolite of vitamin A, is essential for normal embryonic development. Also, high levels of atRA are teratogenic in many species and can effectively induce cleft palate in the mouse. Most cleft palate resulted from the failed fusion of secondary palate shelves, and maintenance of the normal cell proliferation is important in this process of shelf growth. To clarify the mechanism by which atRA causes cleft palate. we investigated the effect of atRA on proliferation activity and cell cycle distribution in mouse embryonic palatal mesenchymal (MEPM) cells. atRA inhibited the growth of MEPM cells by inducing apoptosis in a dose-dependent manner. atRA also caused a G1 block in the cell cycle with an increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S phase, as determined by flow cytometry. We next investigated the effects of atRA on molecules that regulate the G1 to S phase transition. These studies demonstrated that atRA inhibited expression of cyclins D and E at the protein level. Further-more, atRA treatment reduced phosphorylated Rb and decreased cdk2 and cdk4 kinase activity. These data suggest that atRA had antiproliferative activity by modulating GIN cell cycle regulators and by inhibition of Rb phosphorylation in MEPM cells, which might account for the pathogenesis of cleft palate induced by retinoic acid.