PML-RARα induces all-trans retinoic acid-dependent transcriptional activation through interaction with MED1.
PML-RARα induces all-trans retinoic acid-dependent transcriptional activation through interaction with MED1.
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PML-RARα 通过与 MED1 相互作用诱导全反式视黄酸依赖性转录激活。
DOI：
10.1080/21541264.2019.1624467
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Ito,Mitsuhiro
中科院分区：
文献类型：
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作者：
Fukuoka,Tomoya;Kawai,Asami;Takahara,Taku;Mori,Mahiro;Roeder,RobertG;Hasegawa,Natsumi;Ito,Mitsuhiro
PML-RARα是一种急性早幼粒细胞白血病相关的肿瘤融合蛋白，其转录激活需要药理学浓度的全反式维甲酸（ATRA）。然而，配体PML-RARα复合物导致形成预起始复合物的机制尚未确定。在这里，我们证明了Mediator亚基MED 1在PML-RARα结合启动子的ATRA依赖性激活中起着重要作用。荧光素酶报告基因分析表明，PML-RARα在ATRA的药理剂量（1 μM）下诱导显著转录;然而，这是次最大的，相当于在ATRA的生理剂量（1 nM）下由完整RARα驱动的转录水平。转录依赖于PML-RARα与MED 1的两个LxxLL核受体识别基序的相互作用，LxxLL→LxxAA突变导致最小的转录。在机制上，MED 1通过MED 1的两个LxxLL基序与PML-RARα的RARα部分以ATRA依赖性相互作用。这些结果表明PML-RARα通过与MED 1相互作用启动ATRA诱导的转录。
Transcriptional activation by PML–RARα, an acute promyelocytic leukemia-related oncofusion protein, requires pharmacological concentrations of all-trans retinoic acid (ATRA). However, the mechanism by which the liganded PML–RARα complex leads to the formation of the preinitiation complex has been unidentified. Here we demonstrate that the Mediator subunit MED1 plays an important role in the ATRA-dependent activation of the PML–RARα-bound promoter. Luciferase reporter assays showed that PML–RARα induced significant transcription at pharmacological doses (1 μM) of ATRA; however, this was submaximal and equivalent to the level of transcription driven by intact RARα at physiological doses (1 nM) of ATRA. Transcription depended upon the interaction of PML–RARα with the two LxxLL nuclear receptor recognition motifs of MED1, and LxxLL→LxxAA mutations led to minimal transcription. Mechanistically, MED1 interacted ATRA-dependently with the RARα portion of PML–RARα through the two LxxLL motifs of MED1. These results suggest that PML–RARα initiates ATRA-induced transcription through its interaction with MED1.