The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Nucleic Acids Res. 2011 Mar;39(6):2234-48. doi: 10.1093/nar/gkq1117. Epub 2010 Nov 21.
Cell growth and proliferation are tightly controlled via the regulation of the p53-MDM2 feedback loop in response to various cellular stresses. In this study, we identified a nucleolar protein called PAK1IP1 as another regulator of this loop. PAK1IP1 was induced when cells were treated with chemicals that disturb ribosome biogenesis. Overexpression of PAK1IP1 inhibited cell proliferation by inducing p53-dependent G1 cell-cycle arrest. PAK1IP1 bound to MDM2 and inhibited its ability to ubiquitinate and to degrade p53, consequently leading to the accumulation of p53 levels. Interestingly, knockdown of PAK1IP1 in cells also inhibited cell proliferation and induced p53-dependent G1 arrest. Deficiency of PAK1IP1 increased free ribosomal protein L5 and L11 which were required for PAK1IP1 depletion-induced p53 activation. Taken together, our results reveal that PAK1IP1 is a new nucleolar protein that is crucial for rRNA processing and plays a regulatory role in cell proliferation via the p53-MDM2 loop.
细胞生长和增殖通过 p53-MDM2 反馈回路的调节来严格控制，以响应各种细胞应激。在这项研究中，我们鉴定了一种核仁蛋白，称为 PAK1IP1，它是该回路的另一个调节剂。当用扰乱核糖体生物发生的化学物质处理细胞时，PAK1IP1 被诱导。PAK1IP1 通过诱导 p53 依赖性 G1 细胞周期停滞来抑制细胞增殖。PAK1IP1 与 MDM2 结合并抑制其泛素化和降解 p53 的能力，从而导致 p53 水平积累。有趣的是，在细胞中敲低 PAK1IP1 也抑制细胞增殖并诱导 p53 依赖性 G1 停滞。PAK1IP1 的缺乏增加了游离核糖体蛋白 L5 和 L11，它们是 PAK1IP1 耗尽诱导的 p53 激活所必需的。总之，我们的结果表明 PAK1IP1 是一种新的核仁蛋白，对 rRNA 加工至关重要，并通过 p53-MDM2 环在细胞增殖中发挥调节作用。
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