The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1.
The p90 ribosomal S6 kinase (RSK) inhibitor BI-D1870 prevents gamma irradiation-induced apoptosis and mediates senescence via RSK- and p53-independent accumulation of p21WAF1/CIP1.
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DOI：
10.1038/cddis.2013.386
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发表时间：
2013-10-17
影响因子：
9
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P90核糖体S6激酶(RSK)家族是一组高度保守的丝氨酸/苏氨酸(Ser/Thr)激酶，促进细胞的增殖、生长、运动和存活。由于它们几乎只在细胞外信号调节激酶1和2(ERK1/2)下游被激活，抑制RSK的治疗干预不太可能产生像上游主要调控因子Raf、MEK和ERK1/2被抑制后观察到的严重副作用。在这里，我们报告了有效的RSKs小分子抑制剂BI-D1870诱导细胞凋亡，尽管优先在p21缺乏的背景下。另一方面，BI-D1870还诱导p21蛋白的强烈转录和P53非依赖性积聚，保护细胞免受伽玛射线(γIR)诱导的凋亡，即使在没有γIR的情况下也会导致细胞衰老。虽然我们在体外激酶实验中发现p21是一种新的RSK底物，它可以被Ser116和Ser146处的RSK1-3特异性地磷酸化，但RNA干扰、过度表达和免疫共沉淀研究以及另一种特异的RSK抑制剂SL0101的使用表明，BI-D1870通过一种未知的途径介导p21的积累，除了它的异地靶标Polo-like Kinase-1和AuroraB外，也不涉及RSKs。因此，BI-D1870的这种新的靶外效应应该在未来研究RSKs在细胞信号转导和肿瘤发生中的作用时被认真考虑。
The p90 ribosomal S6 kinase (RSK) family is a group of highly conserved Ser/Thr kinases that promote cell proliferation, growth, motility and survival. As they are almost exclusively activated downstream of extracellular signal-regulated kinases 1 and 2 (ERK1/2), therapeutic intervention by RSK inhibition is less likely to produce such severe side effects as those observed following inhibition of the upstream master regulators Raf, MEK and ERK1/2. Here, we report that BI-D1870, a potent small molecule inhibitor of RSKs, induces apoptosis, although preferentially, in a p21-deficient background. On the other hand, BI-D1870 also induces a strong transcription- and p53-independent accumulation of p21 protein and protects cells from gamma irradiation (γIR)-induced apoptosis, driving them into senescence even in the absence of γIR. Although we identified p21 in in vitro kinase assays as a novel RSK substrate that specifically becomes phosphorylated by RSK1-3 at Ser116 and Ser146, RNA-interference, overexpression and co-immunoprecipitation studies as well as the use of SL0101, another specific RSK inhibitor, revealed that BI-D1870 mediates p21 accumulation via a yet unknown pathway that, besides its off-site targets polo-like kinase-1 and AuroraB, also does also not involve RSKs. Thus, this novel off-target effect of BI-D1870 should be taken into serious consideration in future studies investigating the role of RSKs in cellular signaling and tumorigenesis.