Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway
Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway
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DOI：
10.1128/mcb.23.23.8902-8912.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Xiong, Y
中科院分区：
文献类型：
--
作者：
Zhang, YP;Wolf, GW;Xiong, Y
编码p53的基因介导一种主要的肿瘤抑制途径，该途径在人类癌症中经常发生改变。p53功能在正常细胞生长期间保持在低水平，并且响应于各种细胞应激而被激活。MDM 2癌蛋白通过直接抑制细胞核中的p53反式激活活性或促进细胞质中的p53降解在负调节p53活性中起关键作用。DNA损伤和致癌损伤是两种最具特征的p53依赖性检查点途径，它们都通过抑制MDM 2激活p53。在这里，我们报告说，人类同源MDM 2，HDM 2，结合核糖体蛋白L11。Lit结合HDM 2中不同于ARF结合位点的中心区域。我们发现，L11-HDM 2协会的功能后果，如与ARF，结果在预防HDM 2介导的p53泛素化和降解，随后恢复p53介导的反式激活，积累p21蛋白水平，并通过取消HDM 2的抑制功能诱导p53依赖性细胞周期阻滞。低浓度放线菌素D对核糖体生物合成的干扰与L11-HDM 2相互作用的增加和随后的p53稳定化有关。我们认为，L11作为HDM 2的负调节因子发挥作用，并且体内可能存在L11-HDM 2-p53通路来监测核糖体的完整性。
The gene encoding p53 mediates a major tumor suppression pathway that is frequently altered in human cancers. p53 function is kept at a low level during normal cell growth and is activated in response to various cellular stresses. The MDM2 oncoprotein plays a key role in negatively regulating p53 activity by either direct repression of p53 transactivation activity in the nucleus or promotion of p53 degradation in the cytoplasm. DNA damage and oncogenic insults, the two best-characterized p53-dependent checkpoint pathways, both activate p53 through inhibition of MDM2. Here we report that the human homologue of MDM2, HDM2, binds to ribosomal protein L11. Lit binds a central region in HDM2 that is distinct from the ARF binding site. We show that the functional consequence of L11-HDM2 association, like that with ARF, results in the prevention of HDM2-mediated p53 ubiquitination and degradation, subsequently restoring p53-mediated transactivation, accumulating p21 protein levels, and inducing a p53-dependent cell cycle arrest by canceling the inhibitory function of HDM2. Interference with ribosomal biogenesis by a low concentration of actinomycin D is associated with an increased L11-HDM2 interaction and subsequent p53 stabilization. We suggest that L11 functions as a negative regulator of HDM2 and that there might exist in vivo an L11-HDM2-p53 pathway for monitoring ribosomal integrity.