Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, PR China.
Cell Signal. 2013 Jan;25(1):144-9. doi: 10.1016/j.cellsig.2012.09.023. Epub 2012 Sep 23.
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a stress signaling pathway. The UPR coordinates the induction of ER chaperones with decreased protein synthesis and growth arrest in G1 phase of the cell cycle. However, the molecular mechanism underlying UPR-induced G1 cell cycle arrest remains largely unknown. Here we report that activation of the UPR response by tunicamycin (TM), an ER stress inducer, leads to accumulation of p27 and G1 cell cycle arrest in melanoma cells. This accumulation of p27 is due to the inhibition on its polyubiquitination and subsequent degradation upon TM treatment. Correlated with p27 stabilization, the levels of Skp2, an E3 ligase for p27, are decreased in response to TM treatment. More importantly, knockdown of p27 greatly reduces TM-induced G1 cell cycle arrest. Taken together, these data implicate p27 as a critical mediator of ER stress-induced growth arrest.
内质网（ER）中未折叠蛋白的积累会触发未折叠蛋白反应（UPR），这是一种应激信号通路。UPR 协调 ER 伴侣的诱导，同时减少蛋白质合成，并使细胞周期 G1 期停滞。然而，UPR 诱导的 G1 细胞周期停滞的分子机制在很大程度上仍不清楚。在这里，我们报告称，衣霉素（TM）作为 ER 应激诱导剂激活 UPR 反应会导致黑色素瘤细胞中 p27 的积累和 G1 细胞周期停滞。这种 p27 的积累是由于其多泛素化的抑制及其在 TM 处理后的后续降解。与 p27 稳定相关的是，E3 连接酶 Skp2 的水平在 TM 处理后下降。更重要的是，p27 的敲低大大减少了 TM 诱导的 G1 细胞周期停滞。总之，这些数据表明 p27 是 ER 应激诱导的生长停滞的关键介质。
