A 5'-distal enhanceosome in the PDGF-A gene is activated in choriocarcinoma cells via ligand-independent binding of vitamin D receptor and constitutive jun kinase signaling.
A 5'-distal enhanceosome in the PDGF-A gene is activated in choriocarcinoma cells via ligand-independent binding of vitamin D receptor and constitutive jun kinase signaling.
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PDGF-A 基因中的 5-远端增强体在绒毛膜癌细胞中通过维生素 D 受体的配体独立结合和组成型 jun 激酶信号传导被激活。
DOI：
10.1038/sj.onc.1208336
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Kaetzel,DavidM
中科院分区：
文献类型：
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作者：
Pedigo,NancyG;Zhang,Hongxing;Bruno,MariaEC;Kaetzel,CharlotteS;Dugan,AmyR;Shanehsaz,Piam;Hennigan,RobertF;Xing,Zhenlan;Koszewski,NicholasJ;Kaetzel,DavidM
Overexpression of platelet-derived growth factor A-chain (PDGF-A) is clearly linked to autocrine and paracrine stimulation of malignant growth in many human cancers. We have shown previously that PDGF-A overexpression in choriocarcinoma, hepatoma and lung carcinoma cell lines is driven by the activity of a 66 bp enhancer element (ACE66) located approximately 7 kb upstream of the PDGF-A transcription start site. In this study, the ACE66 element is shown to be activated in JEG-3 choriocarcinoma cells through synergistic interactions between consensus DNA motifs for binding of vitamin D receptor, AP1 and ELK1. Binding of the vitamin D/retinoid-X receptor (VDR/RXRα) heterodimer to the ACE66 element was reconstituted in vitro with recombinant VDR/RXRα and with JEG-3 nuclear extract, and was verified in living JEG-3 cells by chromatin immunoprecipitation analysis. Transcriptional activity of the ACE66 element, as well as occupancy of the element by VDR/RXRα, was shown to be independent of stimulation with the hormonal VDR ligand, 1, 25-dihydroxyvitamin D 3. The jun kinase pathway of mitogen-activated protein kinase (MAPK) signaling was shown to activate the ACE66 enhancer, most likely through activation of factors binding to the AP1 element. These results identify a novel mechanism of transcriptional enhancement involving ligand-independent activity of the VDR/RXR heterodimer and MAPK signaling pathways that appears to play an important role in the overexpression of PDGF in many different settings of human malignancy.
