Increased nuclear expression and transactivation of vitamin D receptor by the cardiotonic steroid bufalin in human myeloid leukemia cells
Increased nuclear expression and transactivation of vitamin D receptor by the cardiotonic steroid bufalin in human myeloid leukemia cells
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DOI：
10.1016/j.jsbmb.2009.01.022
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发表时间：
2009-04-01
影响因子：
4.1
通讯作者：
Makishima, Makoto
中科院分区：
文献类型：
--
作者：
Amano, Yusuke;Cho, Yoshitake;Makishima, Makoto
维生素D3的活性形式1α，25-二羟基维生素D-3[1，25(OH)(2)D-3]是核受体维生素D受体(VDR)的有效配体，可诱导髓系白血病细胞分化。强心类固醇蟾酥能增强维生素D诱导的白血病细胞分化和VDR反式激活活性。在这项研究中，我们研究了1，25(OH)(2)D-3和蟾酥对人白血病细胞分化和VDR靶基因表达的联合作用。蟾酥灵联合1，25(OH)(2)D-3可增强VDR靶基因的表达，如细胞色素P24A1和中草药抗菌肽等，并能有效地诱导分化表型。ERK丝裂原活化蛋白(MAP)激酶通路的抑制剂部分抑制了蟾酥诱导VDR靶基因的表达。1，25(OH)(2)D-3诱导HL60细胞VDR一过性核表达。有趣的是，蟾酥能增强1，25(OH)(2)D-3诱导的VDR的核表达。1，25(OH)(2)D-3诱导的核VDR表达增加，而1，25(OH)(2)D-3加蟾毒灵诱导的核VDR表达无明显变化。蛋白酶体抑制剂也能增强1，25(OH)(2)D-3诱导的细胞色素P24A1的表达和核VDR的表达。东亚钳蝎灵诱导HL60细胞VDR表达与组蛋白乙酰化和VDR募集到细胞色素P24A1启动子有关。因此，Na+，K+-ATPase抑制剂蟾酥通过多种机制调节VDR的功能，包括ERK MAP激活和核VDR表达增加。(C)2009爱思唯尔有限公司。保留所有权利。
The active form of vitamin D3, 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], is a potent ligand for the nuclear receptor vitamin D receptor (VDR) and induces myeloid leukemia cell differentiation. The cardiotonic steroid bufalin enhances vitamin D-induced differentiation of leukemia cells and VDR transactivation activity. In this study, we examined the combined effects of 1,25(OH)(2)D-3 and bufalin on differentiation and VDR target gene expression in human leukemia cells. Bufalin in combination with 1,25(OH)(2)D-3 enhanced the expression of VDR target genes, such as CYP24A1 and cathelicidin antimicrobial peptide, and effectively induced differentiation phenotypes. An inhibitor of the Erk mitogen-activated protein (MAP) kinase pathway partially inhibited bufalin induction of VDR target gene expression. 1,25(OH)(2)D-3 treatment induced transient nuclear expression of VDR in HL60 cells. Interestingly, bufalin enhanced 1,25(OH)(2)D-3-induced nuclear VDR expression. The MAP kinase pathway inhibitor increased nuclear VDR expression induced by 1,25(OH)(2)D-3 and did not change that by 1,25(OH)(2)D-3 plus bufalin. A proteasome inhibitor also enhanced 1,25(OH)(2)D-3-induced CYP24A1 expression and nuclear VDR expression. Bufalin-induced nuclear VDR expression was associated with histone acetylation and VDR recruitment to the CYP24A1 promoter in HL60 cells. Thus, the Na+,K+-ATPase inhibitor bufalin modulates VDR function through several mechanisms, including Erk MAP kinase activation and increased nuclear VDR expression. (C) 2009 Elsevier Ltd. All rights reserved.