Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea.
Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, South Korea.
Sci Rep. 2017 Jan 4;7:39222. doi: 10.1038/srep39222.
Programmed cell death 5 (PDCD5) is believed to play a crucial role in p53 activation; however, the underlying mechanism of how PDCD5 function is regulated during apoptosis remains obscure. Here, we report that the serine/threonine phosphatase PPEF-1 interacts with and dephosphorylates PDCD5 at Ser-119, which leads to PDCD5 destabilization. Overexpression of wild-type PPEF-1, but not inactive PPEF-1, efficiently suppressed CK2α-mediated stabilization of PDCD5 and p53-mediated apoptosis in response to etoposide (ET). Conversely, PPEF-1 knockdown further enhanced genotoxic stress responses. Notably, PPEF-1 suppressed p53-mediated genotoxic stress response via negative regulation of PDCD5. We also determined that overexpression of wild-type PPEF-1, but not inactive PPEF-1, significantly increased tumorigenic growth and chemoresistance of A549 human lung carcinoma cells. Collectively, these data demonstrate that PPEF-1 plays a pivotal role in tumorigenesis of lung cancer cells by reducing PDCD5-mediated genotoxic stress responses.
程序性细胞死亡蛋白 5（PDCD5）被认为在 p53 激活中发挥关键作用；然而，PDCD5 在细胞凋亡过程中的作用机制仍不清楚。在这里，我们报告丝氨酸/苏氨酸磷酸酶 PPEF-1 与 PDCD5 相互作用，并使其在丝氨酸 119 处去磷酸化，导致 PDCD5 不稳定。野生型 PPEF-1 的过表达，但不是无活性的 PPEF-1，能有效地抑制 CK2α 介导的 PDCD5 稳定和依托泊苷（ET）诱导的 p53 介导的细胞凋亡。相反，PPEF-1 的敲低进一步增强了遗传毒性应激反应。值得注意的是，PPEF-1 通过负调控 PDCD5 抑制 p53 介导的遗传毒性应激反应。我们还确定，野生型 PPEF-1 的过表达，但不是无活性的 PPEF-1，显著增加了 A549 人肺癌细胞的致瘤生长和化疗耐药性。综上所述，这些数据表明，PPEF-1 通过降低 PDCD5 介导的遗传毒性应激反应在肺癌细胞的肿瘤发生中发挥关键作用。
