We previously described a nucleolar protein RSL1D1 but distributed throughout the nucleus in HCT116 colorectal cancer (CRC) cells to facilitate G1/S transition by inhibiting p53 signaling. Here, we found another nucleolar protein, programmed cell death 11 (PDCD11), also with an “Extra-nucleolar” localization in CRC cells but to regulate G2/M checkpoint. This protein directly interacts with p53 and HDM2 in the nucleoplasm, thereby recruiting p53 to HDM2 for ubiquitination and degradation. The ensuing downregulation of p53 increases the CDK1 level to help the cells pass G2/M checkpoint. Upon DNA damage stress, PDCD11 gains the power to upregulate CDK1 independently of p53. Beyond these, PDCD11 also upregulates CDC25C in a p53-independent manner to dephosphorylate CDK1 to facilitate G2/M transition. Downregulation of PDCD11 greatly reduced cancer cell growth in vitro and in vivo, additionally sensitized cells to DNA damage signals, highlighting that PDCD11 is a crucial driving factor of CRC and a potential target for cancer treatment.

我们之前描述了一种核仁蛋白 RSL1D1，但它分布在 HCT116 结直肠癌 (CRC) 细胞的整个细胞核中，通过抑制 p53 信号传导促进 G1/S 转变。在这里，我们发现了另一种核仁蛋白，程序性细胞死亡 11 (PDCD11)，也在 CRC 细胞中具有“核仁外”定位，但调节 G2/M 检查点。该蛋白直接与核质中的 p53 和 HDM2 相互作用，从而将 p53 募集到 HDM2 进行泛素化和降解。随后 p53 的下调会增加 CDK1 水平，帮助细胞通过 G2/M 检查点。在 DNA 损伤应激下，PDCD11 能够独立于 p53 上调 CDK1。除此之外，PDCD11 还以不依赖于 p53 的方式上调 CDC25C，使 CDK1 去磷酸化，从而促进 G2/M 转变。PDCD11的下调大大减少了体外和体内癌细胞的生长，此外还使细胞对DNA损伤信号敏感，这突显PDCD11是CRC的关键驱动因素和癌症治疗的潜在靶点。