p53 is activated in response to disruption of the pre-mRNA splicing machinery
p53 is activated in response to disruption of the pre-mRNA splicing machinery
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DOI：
10.1038/onc.2012.38
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发表时间：
2013-01-01
期刊：
影响因子：
8
通讯作者：
Saville, M. K.
中科院分区：
文献类型：
--
作者：
Allende-Vega, N.;Dayal, S.;Saville, M. K.
在这项研究中，我们证明了干扰剪接机制会导致肿瘤抑制因子P53的激活。剪接体通过小干扰RNA介导的不同小核核糖核蛋白复合体相关蛋白的敲除和小分子剪接调节剂TG003的作用而成为靶点。这些干预导致：P53积聚，P53转录活性增加，并可导致P53依赖的G(1)细胞周期停滞。MDM2和MDMX是p53的两个关键抑制因子。我们发现MDMX蛋白水平的降低有助于靶向剪接体的P53的激活。干扰剪接体也会增加MDM2的降解速度。剪接的改变与肿瘤的发展有关。在癌症中，剪接经常发生全球性的变化。我们的研究表明，P53的激活可能参与了对剪接体中潜在的促肿瘤缺陷的保护。许多已知的P53激活剂影响剪接机制，这可能有助于它们上调P53的能力。临床前研究表明，肿瘤细胞可能比正常细胞对小分子剪接体抑制剂更敏感。P53的激活可能会影响这种治疗方法的选择性抗肿瘤活性。Oncogene(2013年)32，1-14；doi：10.1038/onc.2012.38；2012年2月20日在线发布
In this study, we show that interfering with the splicing machinery results in activation of the tumour-suppressor p53. The spliceosome was targeted by small interfering RNA-mediated knockdown of proteins associated with different small nuclear ribonucleoprotein complexes and by using the small-molecule splicing modulator TG003. These interventions cause: the accumulation of p53, an increase in p53 transcriptional activity and can result in p53-dependent G(1) cell cycle arrest. Mdm2 and MdmX are two key repressors of p53. We show that a decrease in MdmX protein level contributes to p53 activation in response to targeting the spliceosome. Interfering with the spliceosome also causes an increase in the rate of degradation of Mdm2. Alterations in splicing are linked with tumour development. There are frequently global changes in splicing in cancer. Our study suggests that p53 activation could participate in protection against potential tumour-promoting defects in the spliceosome. A number of known p53-activating agents affect the splicing machinery and this could contribute to their ability to upregulate p53. Preclinical studies indicate that tumours can be more sensitive than normal cells to small-molecule spliceosome inhibitors. Activation of p53 could influence the selective anti-tumour activity of this therapeutic approach. Oncogene (2013) 32, 1-14; doi:10.1038/onc.2012.38; published online 20 February 2012