Polo-like kinase 1 (PLK1) O-GlcNAcylation is essential for dividing mammalian cells and inhibits uterine carcinoma.
Polo-like kinase 1 (PLK1) O-GlcNAcylation is essential for dividing mammalian cells and inhibits uterine carcinoma.
复制标题
Polo 样激酶 1 (PLK1) O-GlcNAc 酰化对于哺乳动物细胞分裂和抑制子宫癌至关重要
DOI：
10.1016/j.jbc.2023.102887
复制
发表时间：
2023-02
影响因子：
4.8
通讯作者：
Li, Jing
中科院分区：
文献类型：
--
作者：
Yan, Sheng;Peng, Bin;Kan, Shifeng;Shao, Guangcan;Xiahou, Zhikai;Tang, Xiangyan;Chen, Yong-Xiang;Dong, Meng-Qiu;Liu, Xiao;Xu, Xingzhi;Li, Jing
O-linked β- n -乙酰氨基葡萄糖（O-GlcNAc）转移酶（OGT）介导细胞内O-GlcNAc酰化修饰。o - glcn酰化发生在丝氨酸/苏氨酸残基上，对许多生理过程都很重要。OGT对哺乳动物细胞分裂至关重要，并与许多人类疾病有关；然而，它在细胞分裂过程中的许多基本底物仍然未知。在这里，我们重点关注OGT对polo样激酶1 （PLK1）的影响，PLK1是一种控制DNA复制、有丝分裂进入、染色体分离和有丝分裂退出的主激酶。我们发现PLK1与OGT相互作用并被o - glcn酰化。利用阶梯碰撞能/高能碰撞解离质谱法，我们发现了一个被O-GlcNAc修饰的PLK1肽片段。PLK1的进一步突变分析表明，T291A突变体降低了o - glcnac酰化。有趣的是，T291N是癌症基因组图谱中的子宫癌突变体。生化实验表明，T291A和T291N均能提高PLK1的稳定性。利用稳定的H2B-GFP细胞，我们发现PLK1-T291A和PLK1-T291N突变体表现出染色体分离缺陷，导致染色体错位和滞后。在小鼠异种移植模型中，我们证明了o - glcnac缺陷的PLK1-T291A和PLK1-T291N突变体可促进动物子宫癌的发生。因此，我们提出OGT通过PLK1的o - glcn酰化部分发挥其有丝分裂功能，这可能是o - glcnnac水平升高促进肿瘤发生的机制之一。
The O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) mediates intracellular O-GlcNAcylation modification. O-GlcNAcylation occurs on Ser/Thr residues and is important for numerous physiological processes. OGT is essential for dividing mammalian cells and is involved in many human diseases; however, many of its fundamental substrates during cell division remain unknown. Here, we focus on the effect of OGT on polo-like kinase 1 (PLK1), a mitotic master kinase that governs DNA replication, mitotic entry, chromosome segregation, and mitotic exit. We show that PLK1 interacts with OGT and is O-GlcNAcylated. By utilizing stepped collisional energy/higher-energy collisional dissociation mass spectrometry, we found a peptide fragment of PLK1 that is modified by O-GlcNAc. Further mutation analysis of PLK1 shows that the T291A mutant decreases O-GlcNAcylation. Interestingly, T291N is a uterine carcinoma mutant in The Cancer Genome Atlas. Our biochemical assays demonstrate that T291A and T291N both increase PLK1 stability. Using stable H2B-GFP cells, we found that PLK1-T291A and PLK1-T291N mutants display chromosome segregation defects and result in misaligned and lagging chromosomes. In mouse xenograft models, we demonstrate that the O-GlcNAc–deficient PLK1-T291A and PLK1-T291N mutants enhance uterine carcinoma in animals. Hence, we propose that OGT partially exerts its mitotic function through O-GlcNAcylation of PLK1, which might be one mechanism by which elevated levels of O-GlcNAc promote tumorigenesis.
登录
查看更多内容
影响因子：
5.2
作者：
Liu C;Li J
通讯作者：
Li J
影响因子：
5.7
作者：
Gutteridge RE;Ndiaye MA;Liu X;Ahmad N
通讯作者：
Ahmad N
影响因子：
4.3
作者：
Ma, Junfeng;Li, Yaoxiang;Wu, Ci
通讯作者：
Wu, Ci
DOI：
10.1083/jcb.200309035
发表时间：
2004-01-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lindon C;Pines J
通讯作者：
Pines J
影响因子：
14.9
作者：
Ma J;Chen T;Wu S;Yang C;Bai M;Shu K;Li K;Zhang G;Jin Z;He F;Hermjakob H;Zhu Y
通讯作者：
Zhu Y