Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells
Rapid effects of retinoic acid on CREB and ERK phosphorylation in neuronal cells
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DOI：
10.1091/mbc.e04-05-0439
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发表时间：
2004-12-01
影响因子：
3.3
通讯作者：
Aranda, A
中科院分区：
文献类型：
--
作者：
Cañón, E;Cosgaya, JM;Aranda, A
视黄酸（RA）是神经细胞分化的有效调节剂。RA通常通过与靶基因调控区域的反应元件（RAREs）相互作用的核受体结合来激活基因表达。我们在这里表明，在类视黄醛引起神经突延伸的PC12细胞亚克隆中，RA诱导了CREB（环AMP反应元件结合蛋白）的快速和持续磷酸化，与非基因组效应兼容。RA还引起大鼠胚胎的脑皮质细胞和背根神经节神经元原代培养中CREB磷酸化的快速增加。ra介导的CREB磷酸化可直接刺激CREB依赖的转录活性，并激活c-fos等基因的表达，这些基因不含RAREs，但在其启动子中含有cAMP反应元件（CREs）。CREB是神经元细胞胞外信号调节激酶ERK1/2信号的主要靶点，我们在这里证明，RA诱导ERK1/2的早期刺激，这是CREB磷酸化和转录活性所必需的。这些结果表明，RA通过非基因组机制刺激信号通路，导致转录因子磷酸化，进而激活参与神经元分化的基因转录。
Retinoic acid (RA) is a potent regulator of neuronal cell differentiation. RA normally activates gene expression by binding to nuclear receptors that interact with response elements (RAREs) in regulatory regions of target genes. We show here that in PC12 cell subclones in which the retinoid causes neurite extension, RA induces a rapid and sustained phosphorylation of CREB (cyclic AMP response element binding protein), compatible with a nongenomic effect. RA also causes a rapid increase of CREB phosphorylation in primary cultures of cerebrocortical cells and of dorsal root ganglia neurons from rat embryos. RA-mediated phosphorylation of CREB leads to a direct stimulation of CREB-dependent transcriptional activity and to activation of the expression of genes such as c-fos, which do not contain RAREs but contain cAMP response elements (CREs) in their promoters. CREB is a major target of extracellular signal regulated kinase ERK1/2 signaling in neuronal cells, and we demonstrate here that RA induces an early stimulation of ERK1/2, which is required both for CREB phosphorylation and transcriptional activity. These results demonstrate that RA, by a nongenomic mechanism, stimulates signaling pathways that lead to phosphorylation of transcription factors, which in turn activate the transcription of genes involved in neuronal differentiation.