The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells.
The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells.
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DOI：
10.1016/j.fob.2015.04.002
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发表时间：
2015
期刊：
影响因子：
2.6
通讯作者：
Yen, Andrew
中科院分区：
文献类型：
--
作者：
Ibabao, Christopher N.;Bunaciu, Rodica P.;Schaefer, Deanna M. W.;Yen, Andrew
VAF 347增强RA诱导的Vav 1、c-Cbl、林恩和P47 phox的表达。VAF 347增强RA诱导的G 0/G1富集。VAF 347增强RA诱导的CD 11b整合素受体表达VAF 347增强RA诱导的中性粒细胞呼吸爆发活性。在二元细胞命运决定中，驱动一个谱系和抑制另一个是联合的。我们以前曾报道，芳烃受体（AhR）促进维甲酸（RA）诱导的谱系双能HL-60髓性白血病细胞的粒细胞分化。VAF 347是一种AhR激动剂，可损害CD 14 + CD 11b+单核细胞从粒-单核细胞（GM）阶段前体的发育。因此，我们假设VAF 347促进RA诱导的粒细胞分化，并损害D3诱导的HL-60细胞的单核细胞分化。我们的研究结果表明，VAF 347增强RA诱导的细胞周期阻滞，CD 11b整合素表达和中性粒细胞呼吸爆发。已知粒细胞分化由MAPK信号传导事件驱动，所述MAPK信号传导事件由Fgr和林恩Src家族激酶、CD 38细胞膜受体、Vav 1 GEF、c-Cbl衔接子以及AhR调节，所有这些都体现在推定的信号体中。我们发现VAF 347 AhR配体调节信号体。VAF 347增强RA诱导的AhR、林恩、Vav 1和c-Cbl以及p47 phox的表达。信号体中伴侣的几种相互作用似乎增强：Fgr与c-Cbl、CD 38和pS259 c-Raf的相互作用以及AhR与c-Cbl和林恩的相互作用。因此，我们报告说，虽然VAF 347阻碍单核细胞分化诱导的1，25-二羟维生素D3，VAF 347促进RA诱导的分化。这种效应似乎涉及但不限于林恩、Vav 1、c-Cbl、AhR和Fgr。
VAF347 augments RA-induced expression of Vav1, c-Cbl, Lyn, and P47phox. VAF347 augments RA-induced G0/G1 enrichment. VAF347 augments RA-induced expression of CD11b integrin receptor. VAF347 augments RA-induced respiratory burst activity of neutrophils. In binary cell-fate decisions, driving one lineage and suppressing the other are conjoined. We have previously reported that aryl hydrocarbon receptor (AhR) promotes retinoic acid (RA)-induced granulocytic differentiation of lineage bipotent HL-60 myeloblastic leukemia cells. VAF347, an AhR agonist, impairs the development of CD14+CD11b+ monocytes from granulo-monocytic (GM) stage precursors. We thus hypothesized that VAF347 propels RA-induced granulocytic differentiation and impairs D3-induced monocytic differentiation of HL-60 cells. Our results show that VAF347 enhanced RA-induced cell cycle arrest, CD11b integrin expression and neutrophil respiratory burst. Granulocytic differentiation is known to be driven by MAPK signaling events regulated by Fgr and Lyn Src-family kinases, the CD38 cell membrane receptor, the Vav1 GEF, the c-Cbl adaptor, as well as AhR, all of which are embodied in a putative signalsome. We found that the VAF347 AhR ligand regulates the signalsome. VAF347 augments RA-induced expression of AhR, Lyn, Vav1, and c-Cbl as well as p47phox. Several interactions of partners in the signalsome appear to be enhanced: Fgr interaction with c-Cbl, CD38, and with pS259c-Raf and AhR interaction with c-Cbl and Lyn. Thus, we report that, while VAF347 impedes monocytic differentiation induced by 1,25-dihydroxyvitamin D3, VAF347 promotes RA-induced differentiation. This effect seems to involve but not to be limited to Lyn, Vav1, c-Cbl, AhR, and Fgr.
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影响因子：
11.4
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影响因子：
11.2
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通讯作者：
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作者：
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通讯作者：
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