Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells
Activation of the phosphatidylinositol 3-kinase/Akt signaling pathway by retinoic acid is required for neural differentiation of SH-SY5Y human neuroblastoma cells
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DOI：
10.1074/jbc.m201869200
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发表时间：
2002-07-12
影响因子：
4.8
通讯作者：
Barettino, D
中科院分区：
文献类型：
--
作者：
López-Carballo, G;Moreno, L;Barettino, D
维甲酸(RA)诱导SH-SY5Y神经母细胞瘤细胞分化我们发现在RA诱导SHSY5Y细胞分化的过程中，抑制分化的基本螺旋-环-螺旋转录因子ID1、ID2和ID3的mRNA水平下调。ID蛋白水平的下降与观察到的转录抑制平行。其他基础螺旋-环-螺旋基因的表达在RA诱导分化过程中发生变化：RA诱导分化过程中，神经母细胞特异性ASCL1(HASH-1)基因表达迅速降低，而促进分化基因NEUROD6(NEX-1、HATH-2)和NEUROD1表达增加。另一种神经母细胞瘤细胞分化诱导剂12-O-十四酰佛波醇-13-乙酸酯的处理也导致ID基因表达的协同下调，强调了ID基因在分化中的作用。RA对ID基因表达的下调涉及一个复杂的机制，因为完整的转录抑制需要新合成的蛋白质和磷脂酰肌醇3-激酶(PI3K)的信号。RA处理激活了PI3K/Akt信号通路，导致RA处理的细胞提取物中PI3K活性增加，并使Ser-473中Akt的磷酸化水平迅速增加。根据形态和生化指标，LY294002抑制PI3K可抑制RA诱导的分化。我们认为RA通过激活PI3K/Akt信号通路，在神经细胞存活的调节中发挥重要作用。
Retinoic acid (RA) induces neural differentiation of SH-SY5Y neuroblastoma cells. We show that the mRNA levels of the differentiation-inhibiting basic helix-loop-helix transcription factors ID1, ID2, and ID3 are down-regulated during RA-induced differentiation of SHSY5Y cells. The levels of ID proteins decreased in parallel to the observed transcriptional repression. The expression of other basic helix-loop-helix genes changed during RA-induced differentiation: expression of neuroblast-specific ASCL1 (HASH-1) gene was promptly reduced after RA treatment, whereas expression of differentiation-promoting genes NEUROD6 (NEX-1, HATH-2) and NEUROD1 was increased. Treatments with 12-O-tetradecanoylphorbol-13-acetate, another inducer of neuroblastoma cell differentiation, also resulted in coordinated down-regulation of ID gene expression, underscoring the role of ID genes in differentiation. Downregulation of ID gene expression by RA involves a complex mechanism because full transcriptional repression required newly synthesized proteins and signaling by phosphatidylinositol 3-kinase (PI3K). RA treatment activates the PI3K/Akt signaling pathway, resulting in increased PI3K activity in extracts from RA-treated cells and a rapid increase in phosphorylation of Akt in Ser-473. Inhibition of PI3K by LY294002 impaired RA-induced differentiation, as assessed by morphological and biochemical criteria. We propose that RA, by activating the PI3K/Akt signaling pathway, plays an important role in the regulation of neuronal cell survival.