Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, Sichuan, China.
Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Cell Cycle. 2022 Jan;21(2):140-151. doi: 10.1080/15384101.2021.2014249. Epub 2021 Dec 8.
The main biological function of the tumor suppressor p53 is to control cell cycle arrest and apoptosis. Among the p53 target genes, p21 has been identified as a key player in p53-mediated G1 arrest, while Killin, via its high DNA binding affinity, has been implicated in S and G2/M arrest. However, whether Killin is involved in G1 arrest remains unclear. This research aimed to explore the role of Killin in p53-mediated G1 arrest. Knockout of in human colorectal cells led to a dramatic decrease in p53-mediated G1 arrest upon DNA damage. Moreover, double knockout of and completely abolished G1 arrest, similar to that of knockout cells. We further showed that Killin could upregulate p21 protein expression independent of p53 via ubiquitination pathways. Immunoprecipitation studies indicated that Killin may directly bind to proteasome subunits, thereby disrupting proteasomal degradation of p21. Together, these results demonstrate that Killin is involved in multiple cell cycle checkpoint controls, including p53-mediated G1 arrest.
肿瘤抑制因子 p53 的主要生物学功能是控制细胞周期停滞和细胞凋亡。在 p53 的靶基因中，p21 已被确定为 p53 介导的 G1 期阻滞的关键因子，而 Killin 通过其高 DNA 结合亲和力，被认为参与 S 和 G2/M 期阻滞。然而，Killin 是否参与 G1 期阻滞仍不清楚。本研究旨在探讨 Killin 在 p53 介导的 G1 期阻滞中的作用。在人结直肠细胞中敲除 后，导致 DNA 损伤时 p53 介导的 G1 期阻滞显著减少。此外， 和 的双重敲除完全消除了 G1 期阻滞，类似于 敲除细胞。我们进一步表明，Killin 可以通过泛素化途径独立于 p53 上调 p21 蛋白表达。免疫沉淀研究表明，Killin 可能直接与蛋白酶体亚基结合，从而破坏 p21 的蛋白酶体降解。总之，这些结果表明 Killin 参与多种细胞周期检查点控制，包括 p53 介导的 G1 期阻滞。
