Glucose deprivation is associated with Chk1 degradation through the ubiquitin-proteasome pathway and effective checkpoint response to replication blocks.
Glucose deprivation is associated with Chk1 degradation through the ubiquitin-proteasome pathway and effective checkpoint response to replication blocks.
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DOI：
10.1016/j.bbamcr.2011.03.012
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Yun J
中科院分区：
文献类型：
--
作者：
Kim AJ;Kim HJ;Jee HJ;Song N;Kim M;Bae YS;Chung JH;Yun J
Chk1 在 DNA 复制检查点和保持基因组完整性方面发挥着关键作用。此前的研究表明，Chk1功能降低会导致检查点反应缺陷，并与肿瘤发生密切相关。在这里，我们报告葡萄糖剥夺导致 Chk1 蛋白降解，但不会干扰细胞周期进程。在各种癌细胞系和正常人成纤维细胞中观察到葡萄糖剥夺诱导 Chk1 降解。因此，这似乎是哺乳动物细胞中的普遍现象。一种特定的蛋白酶体抑制剂可阻止葡萄糖剥夺引起的 Chk1 降解。检测到 Chk1 泛素化，表明蛋白酶体-泛素通路在葡萄糖剥夺时介导 Chk1 降解。机制研究表明 Chk1 在 Ser317 和 Ser345 位点的 ATR 依赖性磷酸化不是必需的，这表明葡萄糖剥夺时 Chk1 降解的分子机制与基因毒性应激诱导的降解不同。在葡萄糖剥夺的条件下，细胞对复制应激、喜树碱或羟基脲表现出有缺陷的检查点反应。 Myc-Chk1 的强制表达部分挽救了葡萄糖剥夺时对复制阻断的缺陷反应。综上所述，我们的结果表明葡萄糖剥夺会诱导泛素介导的 Chk1 降解和检查点反应缺陷，这意味着它在基因组不稳定和肿瘤发展中的潜在作用。
Chk1 plays a key role in the DNA replication checkpoint and in preserving genomic integrity. Previous studies have shown that reduced Chk1 function leads to defects in the checkpoint response and is closely associated with tumorigenesis. Here, we report that glucose deprivation caused the degradation of Chk1 protein without perturbing cell cycle progression. The induction of Chk1 degradation in response to glucose deprivation was observed in various cancer cell lines and in normal human fibroblasts. Therefore, it appears to be a universal phenomenon in mammalian cells. A specific proteasome inhibitor blocked glucose deprivation-induced Chk1 degradation. Ubiquitination of Chk1 was detected, indicating that the proteasome-ubiquitin pathway mediates Chk1 degradation upon glucose deprivation. Mechanistic studies have demonstrated that ATR-dependent phosphorylation of Chk1 at the Ser317 and Ser345 sites is not required, suggesting that the molecular mechanism for Chk1 degradation upon glucose deprivation is distinct from genotoxic stress-induced degradation. Under conditions of glucose deprivation, the cells manifested a defective checkpoint response to replication stress, camptothecin or hydroxyurea. The forced expression of Myc-Chk1 partially rescued the defective response to the replication block upon glucose deprivation. Taken together, our results indicate that glucose deprivation induces ubiquitin-mediated Chk1 degradation and defective checkpoint responses, implying its potential role in genomic instability and tumor development.
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