Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease.
Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease.
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DOI：
10.1002/jbmr.1884
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发表时间：
2013-06
影响因子：
6.2
通讯作者：
Kurihara, Noriyoshi
中科院分区：
文献类型：
--
作者：
Teramachi, Jumpei;Hiruma, Yuko;Ishizuka, Seiichi;Ishizuka, Hisako;Brown, Jacques P.;Michou, Laetitia;Cao, Huiling;Galson, Deborah L.;Subler, Mark A.;Zhou, Hua;Dempster, David W.;Windle, Jolene J.;Roodman, G. David;Kurihara, Noriyoshi
许多佩吉特病（PD）患者的破骨细胞（OCL）前体表达麻疹病毒核衣壳蛋白（MVNP），并对1,25-(OH)2D3过敏。增加的125 -(OH)2D3敏感性是由TAF12介导的，TAF12是VDR的一种共激活剂，在表达mvnp的OCL前体中，TAF12的水平比正常人高得多。这些结果表明，TAF12在PD患者OCL活性异常中起重要作用。然而，在正常和PD患者中，125 -(OH)2D3对OCL形成的影响以及TAF12对这些影响的作用的分子机制尚不清楚。用特定的TAF12反义构建体抑制TAF12可降低PD患者骨髓样本中OCL的形成和OCL前体对1,25-(OH)2D3的敏感性。此外，来自TAF12表达靶向OCL谱系的转基因小鼠（TRAP-TAF12小鼠）的OCL前体在非常低水平的1,25-(OH)2D3下形成OCL，尽管OCL没有表现出PD OCL的其他特征，包括RANKL超敏感性和超多核。使用抗TAF12抗体对OCL前体进行ChIP分析表明，在125 -(OH)2D3存在的情况下，TAF12结合了24-羟化酶（CYP24A1）启动子，该启动子含有两个功能性维生素D反应元件（VDRE）。由于TAF12直接与ATF7转录因子相互作用，并在其他细胞类型中增强ATF7诱导的ATF7驱动基因的转录激活，我们确定了TAF12是否在OCL前体中是ATF7的功能伙伴。用抗TAF12抗体对WT或mvpnp表达OCL的裂解物进行免疫沉淀，然后用抗ATF7抗体进行印迹，反之亦然，结果表明TAF12和ATF7在OCL中相互作用。在mvnp表达细胞中，敲低ATF7可降低1,25-(OH)2D3对CYP24A1的诱导作用以及TAF12与CYP24A1启动子的结合。这些结果表明，ATF7与TAF12相互作用，并有助于PD患者OCL前体对1,25-(OH)2D3的超敏感性。
Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-(OH)2D3. The increased 1,25-(OH)2D3 sensitivity is mediated by TAF12, a co-activator of VDR, which is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3’s effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 antisense construct decreased OCL formation and OCL precursors sensitivity to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL-precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (TRAP-TAF12 mice), formed OCL at very low levels of 1,25-(OH)2D3, although the OCL failed to exhibit other hallmarks of PD OCL, including RANKL hyper-sensitivity and hyper-multinucleation. ChIP analysis of OCL precursors using an anti-TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDRE), in the presence of 1,25-(OH)2D3. Since TAF12 directly interacts with the ATF7 transcription factor and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined if TAF12 is a functional partner of ATF7 in OCL precursors. Immunoprecipitation of lysates from either WT or MVNP-expressing OCL with an anti-TAF12 antibody followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCL. Knockdown of ATF7 in MVNP-expressing cells decreased CYP24A1 induction by 1,25-(OH)2D3 as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hyper-sensitivity of OCL precursors to 1,25-(OH)2D3 in PD.
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影响因子：
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作者：
Li, XY;Boudjelal, M;Voorhees, JJ
通讯作者：
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影响因子：
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