细胞核输出的时钟蛋白酰化PRPS，促进新的核苷酸合成和肝肿瘤生长。
Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth.
发表日期：2023 Feb
作者：
Tong Liu, Zheng Wang, Leiguang Ye, Yuran Duan, Hongfei Jiang, Haiyan He, Liwei Xiao, Qingang Wu, Yan Xia, Mengke Yang, Ke Wu, Meisi Yan, Guimei Ji, Yuli Shen, Lei Wang, Lin Li, Peixiang Zheng, Bofei Dong, Fei Shao, Xu Qian, Rilei Yu, Zhiren Zhang, Zhimin Lu, Daqian Xu
来源：
NATURE CELL BIOLOGY
摘要：
昼夜节律失调与癌症发展有关。但是，癌性受体酪氨酸激酶是否调节昼夜节律仍不清楚。我们在这里证明了受体酪氨酸激酶激活可促进CK2介导的CLOCK S106磷酸化和随后的CLOCK-BMAL1二聚体解离，抑制肝细胞癌（HCC）细胞下游基因表达。此外，CLOCK S106磷酸化暴露其核输出信号，以绑定Exportin1进行核输出。细胞质中的CLOCK乙酰化PRPS1/2 K29并阻止HSC70介导的和溶酶体依赖的PRPS1/2降解。稳态的PRPS1/2促进新生核苷酸合成和HCC细胞增殖和肝脏肿瘤生长。此外，CLOCK S106磷酸化和PRPS1/2 K29乙酰化与人类HCC样本中的HCC差生存率呈正相关。这些发现揭示了一个关键的机制，即癌性信号抑制了规范的CLOCK转录活性，并同时赋予CLOCK重要的兼职功能，以促进核苷酸合成和肿瘤生长。©2023年。作者（们）在Springer Nature有限公司专有许可下这样做。
Impairment of the circadian clock is linked to cancer development. However, whether the circadian clock is modulated by oncogenic receptor tyrosine kinases remains unclear. Here we demonstrated that receptor tyrosine kinase activation promotes CK2-mediated CLOCK S106 phosphorylation and subsequent disassembly of the CLOCK-BMAL1 dimer and suppression of the downstream gene expression in hepatocellular carcinoma (HCC) cells. In addition, CLOCK S106 phosphorylation exposes its nuclear export signal to bind Exportin1 for nuclear exportation. Cytosolic CLOCK acetylates PRPS1/2 K29 and blocks HSC70-mediated and lysosome-dependent PRPS1/2 degradation. Stabilized PRPS1/2 promote de novo nucleotide synthesis and HCC cell proliferation and liver tumour growth. Furthermore, CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation are positively correlated in human HCC specimens and with HCC poor prognosis. These findings delineate a critical mechanism by which oncogenic signalling inhibits canonical CLOCK transcriptional activity and simultaneously confers CLOCK with instrumental moonlighting functions to promote nucleotide synthesis and tumour growth.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.