Radicicol suppresses transformation and restores tropomyosin-2 expression in both ras- and MEK-transformed cells without inhibiting the Raf/MEK/ERK signaling cascade.
Radicicol suppresses transformation and restores tropomyosin-2 expression in both ras- and MEK-transformed cells without inhibiting the Raf/MEK/ERK signaling cascade.
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发表时间：
2001-11
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通讯作者：
P. N. Kim;E. Jonasch;B. Mosterman;J. Mier;R. Janssen
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作者：
P. N. Kim;E. Jonasch;B. Mosterman;J. Mier;R. Janssen
抗生素根赤霉素抑制多种转化细胞的转化。该药物的抑制作用归因于Raf的降解和Ras/Raf/丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶（ERK）信号级联的失活。在这里，我们表明，根赤霉素诱导细胞扩散，抑制锚定独立的细胞生长，并增加高分子量的原肌球蛋白亚型TM-2的表达在细胞中稳定表达的MEK-1的组成型活性形式，以及在Ras转化细胞。此外，在低于从细胞中耗尽Raf或抑制ERK或其底物Elk和pp 90（RSK）磷酸化所需的浓度下实现药物的回复效应。相反，低浓度的根赤霉素显着抑制激活蛋白（AP-1）和血清反应因子（SRF）介导的转录。根赤霉素对细胞表型的影响与Raf/MEK/ERK途径的信号传导活性之间缺乏相关性，表明Raf耗竭或丝裂原活化蛋白激酶途径中近端信号传导事件的破坏不是药物抑制转化表型的主要机制。我们观察到低浓度的根赤霉素阻断AP-1和SRF介导的转录活性，这表明干扰这些转录因子上游的信号传导可能有助于药物的逆转作用。
The antibiotic radicicol suppresses transformation in a variety of transformed cells. The antineoplastic effects of the drug have been attributed to the degradation of Raf and the inactivation of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade. Here we demonstrate that radicicol induces cell spreading, suppresses anchorage-independent cell growth, and increases the expression of the high-molecular weight tropomyosin isoform TM-2 in cells stably expressing a constitutively active form of MEK-1 as well as in ras-transformed cells. Furthermore, the reverting effects of the drug are achieved at concentrations below those required to deplete Raf from the cell or to inhibit the phosphorylation of ERK or its substrates Elk and pp90(RSK). In contrast, low concentrations of radicicol significantly inhibited activator protein (AP-1) and serum response factor (SRF)-mediated transcription. The lack of correlation between the effects of radicicol on cell phenotype and on the signaling activities of the Raf/MEK/ERK pathway indicate that Raf depletion or disruption of proximal signaling events in the mitogen-activated protein kinase pathway are not the predominant mechanisms by which the drug suppresses the transformed phenotype. Our observation that low concentrations of radicicol block transcriptional activities mediated by AP-1 and SRF suggests that interference with signaling upstream of these transcription factors may contribute to the reverting effects of the drug.