All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation.
All-trans retinoic acid modulates ORMDL3 expression via transcriptional regulation.
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全反式视黄酸通过转录调节调节 ORMDL3 表达
DOI：
10.1371/journal.pone.0077304
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhou GP
中科院分区：
文献类型：
--
作者：
Zhuang LL;Huang BX;Feng J;Zhu LH;Jin R;Qiu LZ;Zhou GP
全反式维甲酸（All-trans retinoic acid， ATRA）是维生素A的活性代谢物，对哮喘具有保护作用，包括维持气道上皮完整性、抑制哮喘效应细胞分化、调节免疫反应等。然而，ATRA对Th2反应的促进作用限制了ATRA在哮喘治疗中的临床应用。ORMDL3是儿童发病哮喘的候选基因，ORMDL3的高转录与哮喘的发生有关。本研究表明，ATRA在体外通过诱导pka依赖性CREB磷酸化增加ORMDL3的产生，而CREB磷酸化反过来与ORMDL3启动子区域的CRE元件结合并启动ORMDL3转录。这一发现与之前的报道一致，即ATRA可以在启动子区域不存在视黄酸反应元件（RARE），而通过PKA/CREB等其他信号调节靶基因。然而，在本研究中，传统的ATRA信号通路视黄酸受体（retinoic acid receptor， RAR）信号转导通路间接调节ORMDL3的表达。RAR-α激动剂（Am-80）增加ORMDL3的产生，尽管ORMDL3启动子、内含子或3 '下游区域没有RARE。此外，由于Am-80无法诱导CREB激活，RAR信号可能与ATRA不同。综上所述，我们的数据表明ATRA可能通过PKA/CREB促进ORMDL3的产生，这可能是ATRA与哮喘更详细机制研究的起点。
All-trans retinoic acid (ATRA) is an active metabolite of Vitamin A, it shows protective effects on asthma, including maintains airway epithelial integrity, inhibits asthma effector cells differentiation, modulates immune response, et al. However, the promoting effect of ATRA on Th2 response has restricted the clinical application of ATRA in asthma treatment. ORMDL3 is a candidate gene of childhood onset asthma, and high-transcript of ORMDL3 is associated with the development of asthma. Here we show that ATRA increases ORMDL3 production in vitro via inducing PKA-dependent CREB phosphorylation which in turn binds to the CRE element in promoter region of ORMDL3 and initiates ORMDL3 transcription. This finding is in consistent with the previous reports that ATRA could regulate target genes without the presence of retinoic acid response element (RARE) in promoter region but through other signals such as PKA/CREB. Nevertheless, in the present study, the traditional signal pathway of ATRA, retinoic acid receptor (RAR) signal transduction pathway, indirectly modulated ORMDL3 expression. RAR-α agonist (Am-80) increased ORMDL3 production even though there was no RARE in ORMDL3 promoter, introns or 3′-downstream region. Besides, the signal of RAR might differ from that of ATRA since Am-80 failed to induce CREB activation. In conclusion, our data indicate that ATRA facilitates ORMDL3 production probable through PKA/CREB, and this may be a starting point for more detailed mechanism researches on ATRA and asthma.
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