JBC：发现核糖体蛋白L11与肿瘤抑制因子ARF有密切联系

p53因编码一种分子质量为53kDa的蛋白质而得名，是一种抗癌基因。其表达产物为基因调节蛋白（P53蛋白），当DNA受到损伤时表达产物急剧增加，可抑制细胞周期进一步运转。一旦p53基因发生突变，P53蛋白失活，细胞分裂失去节制，发生癌变。目前已知人类癌症中约有一半是由于该基因发生突变失活。

在应答于致癌压力时，肿瘤抑制蛋白ARF激活了p53，然而核糖体蛋白L11是在应答核糖体压力时诱导p53。

这两种蛋白都结合在不重叠的MDM2的中心区域，并抑制MDM2对p53的活性。

然而，这两条信号通路是否有功能上的联系还不可知。近日，美国印第安纳大学医学院的Hua Lu等人发现，在体外及细胞内，ARF直接结合到L11，然后与MDM2及p53形成了一个复合体。

L11可以协同的增强ARF诱导的p53的转录活性及细胞周期停滞。后续实验发现：敲除L11会降低ARF介导的p53的积聚，缓和ARF诱导的细胞周期停滞，这些证据支持了这些结论。有趣的是，ARF的过表达提升了无核糖体的L11的水平，增强了L11与MDM2及p53的相互作用。

这些结果表明：ARF至少部分的通过核糖体压力的诱导来激活p53，结果导致L11对MDM2的抑制作用，这表明了ARF-MDM2-p53与L11-MDM2-p53通路是功能上相关的。相关论文发表在3月30日的The Journal of Biological Chemistry。（生物谷Deepblue编译）

doi: 10.1074/jbc.M111.311902
PMC:
PMID:

Physical and functional interaction between ribosomal protein L11 and the tumor suppressor ARF

Mu-Shui Dai, Kishore B. Challagundla, Xiao-Xin Sun, Lakshmi Reddy Palam, Shelya X. Zeng, Ronald C. Wek and Hua Lu.

The ARF tumor suppressor protein activates p53 in response to oncogenic stress, whereas ribosomal protein L11 induces p53 following ribosomal stress.Both proteins bind to central, albeit non-overlapping, regions of MDM2 and suppress MDM2 activity towards p53.However, it is not known whether the two pathways are functionally connected. Here we show that ARF directly binds to L11 in vitro and in cells, which then forms a complex with MDM2 and p53.L11 collaboratively enhances ARF-induced p53 transcriptional activity and cell cycle arrest. Supporting these results, knocking down L11 reduces ARF-mediated p53 accumulation and alleviates ARF-induced cell cycle arrest. Interestingly, overexpression of ARF increases the levels of ribosome-free L11 and enhances the interaction of L11 with MDM2 and p53.
These results demonstrate that ARF activates p53, at least partly by induction of ribosomal stress, which results in L11 suppression of MDM2, and suggest that the ARF-MDM2-p53 and the L11-MDM2-p53 pathways are functionally connected.