p53-mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells
p53-mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells
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p53 介导的 G1 期停滞需要在人结肠癌细胞中诱导 p21 和 Killin
DOI：
10.1080/15384101.2021.2014249
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发表时间：
2021-12-10
期刊：
影响因子：
4.3
通讯作者：
Liang, Peng
中科院分区：
文献类型：
--
作者：
Luo, Dan;Yu, Chune;Liang, Peng
摘要抑癌基因p53的主要生物学功能是控制细胞周期阻滞和凋亡。在p53靶基因中，p21已被鉴定为p53介导的G1期阻滞中的关键参与者，而Killin通过其高DNA结合亲和力参与S期和G2/M期阻滞。然而，Killin是否参与G1逮捕仍不清楚。本研究旨在探讨Killin在p53介导的G1期阻滞中的作用。敲除人结直肠细胞中的杀伤蛋白导致DNA损伤后p53介导的G1期阻滞显著减少。此外，双敲除killin和p21完全取消G1期阻滞，类似于p53敲除细胞。我们进一步表明，Killin可以通过泛素化途径上调p21蛋白表达，而不依赖于p53。免疫沉淀研究表明，Killin可以直接结合蛋白酶体亚基，从而破坏p21的蛋白酶体降解。总之，这些结果表明，Killin参与多个细胞周期检查点控制，包括p53介导的G1期阻滞。
ABSTRACT 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 killin in human colorectal cells led to a dramatic decrease in p53-mediated G1 arrest upon DNA damage. Moreover, double knockout of killin and p21 completely abolished G1 arrest, similar to that of p53 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.