PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase
PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase
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DOI：
10.1124/mol.53.3.438
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发表时间：
1998-03-01
影响因子：
3.6
通讯作者：
Myrand, SP
中科院分区：
文献类型：
--
作者：
Reiners, JJ;Lee, JY;Myrand, SP
PD 98059 [2-（2 '-amino-3'-methoxyphenyl）-oxanaphthalen-4-one]是一种黄酮类化合物，是丝裂原活化蛋白激酶激酶（MEK）的有效抑制剂。浓度小于或等于20 μ M的PD 98059对永生化人乳腺上皮细胞系MCF 10A的培养物没有细胞毒性。该试剂在大于或等于10 μ M的浓度下是弱细胞抑制性的。在体内暴露于小于或等于20 μ M的PD 98059 2-22小时的培养物不影响总的细胞外信号调节激酶的内容，但是，暴露于PD 98059导致细胞外信号调节激酶的双重磷酸化形式的快速损失（>95%）（IC 50 = 1 μ M）。在加入时或加入2，3，7，8-四氯二苯并-对-二恶英（TCDD）前48小时，用大于或等于1 μ M的PD 98059处理培养物，以浓度依赖性方式抑制诱导稳态CYP 1A 1、CYP 1B 1和NQO 1 mRNA的积累。通过蔗糖梯度离心和电泳迁移率变动测定，在加入TCDD之前，将PD 98059加入大鼠肝胞质溶胶中抑制TCDD结合（IC 50 = 4 μ M）和芳烃受体（AHR）转化（IC 50 = 1 μ M）。黄酮和黄烷酮，两个密切相关的结构类似物的PD 98059，抑制AHR转化TCDD的IC 50值相似的PD 98059。然而，两种类似物在抑制MEK方面都不如PD 98059有效（两者的IC 50均类似于190 μ M）。这些结果表明，PD 98059是AHR的配体，并且在通常用于抑制MEK和需要MEK活化的信号传导过程的浓度下作为AHR拮抗剂起作用。
PD98059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] is a flavonoid and a potent inhibitor of mitogen-activated protein kinase kinase (MEK). Concentrations of PD98059 of less than or equal to 20 mu M were not cytotoxic to cultures of the immortalized human breast epithelial cell line MCF10A. The agent was weakly cytostatic at concentrations of greater than or equal to 10 mu M. In vivo exposure of cultures to less than or equal to 20 mu M PD98059 for 2-22 hr did not affect overall extracellular signal-regulated kinase contents; however, exposure to PD98059 resulted in a rapid loss (>95%) of the dually phosphorylated forms of extracellular signal-regulated kinase (IC50 = 1 mu M). Treatment of cultures with PD98059 of greater than or equal to 1 mu M either at the time of addition or up to 48 hr before the addition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed in a concentration-dependent manner the accumulation of induced steady state CYP1A1, CYP1B1, an NQO1 mRNAs. The addition of PD98059 to rat liver cytosol just before the addition of TCDD suppressed TCDD binding (IC50 = 4 mu M) and aryl hydrocarbon receptor (AHR) transformation (IC50 = 1 mu M), as measured by sucrose gradient centrifugation and electrophoretic mobility shift assays. Flavone and flavanone, two closely related structural analogs of PD98059, inhibited AHR transformation by TCDD with IC50 values similar to that obtained with PD98059. However, neither analog was as potent as PD98059 in inhibiting MEK (IC50 similar to 190 mu M for both). These results suggest that PD98059 is a ligand for the AHR and functions as an AHR antagonist at concentrations commonly used to inhibit MEK and signaling processes that entail MEK activation.