Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth
Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth
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谷氨酰胺合成酶许可 APC/C 介导的有丝分裂进程来驱动细胞生长
DOI：
10.1038/s42255-021-00524-2
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发表时间：
2022-02
影响因子：
20.8
通讯作者：
Yu-Xiong F
中科院分区：
文献类型：
--
作者：
Jiang-Sha Zhao;Shuo Shi;Hai-Yan Qu;Zuzana Keckesova;Zi-Jian Cao;Li-Xian Yang;Xiaofu Yu;Limin Feng;Zhong Shi;Joanna Krakowiak;Ruo-Ying Mao;Yi-Tong Shen;Yu-Meng Fan;Tianmin Fu;Cunqi Ye;Daqian Xu;Xiaofei Gao;Jia You;Wenbo Li;Tingbo Liang;Zhimin Lu;Yu-Xiong F
肿瘤可以重新编程代谢酶的功能以促进恶性生长；然而，除了其常规功能之外，尚未发现关键代谢酶可以直接控制细胞有丝分裂。在这里，我们报告谷氨酰胺合成酶（GS）通过独立于其代谢功能许可有丝分裂进展来促进细胞增殖。 GS 消耗，但不损害其酶活性，会导致多种肺癌和肝癌细胞系、患者来源的类器官和异种移植肿瘤的有丝分裂停滞和多核化。从机制上讲，GS 直接与核孔蛋白 NUP88 相互作用，以防止其与 CDC20 结合。这种相互作用允许激活 CDC20 介导的后期促进复合物或环体，以确保适当的中期到后期转变。此外，GS在人类非小细胞肺癌中过度表达，其缺失可减少小鼠肿瘤的生长并提高微管靶向化疗的疗效。我们的研究结果强调了 GS 在控制有丝分裂方面的兼职功能，并说明了一种重要的代谢酶如何在其主要代谢功能之外促进细胞增殖和肿瘤发展。
Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.
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影响因子：
112.7
作者：
J. Pines
通讯作者：
J. Pines
DOI：
10.1073/pnas.1102247108
发表时间：
2011-03
期刊：
Proceedings of the National Academy of Sciences
影响因子：
--
作者：
Slavica Tudzarova;S. Colombo;K. Stoeber;Saul Carcamo;G. Williams;S. Moncada
通讯作者：
Slavica Tudzarova;S. Colombo;K. Stoeber;Saul Carcamo;G. Williams;S. Moncada
影响因子：
21.3
作者：
Cox AG;Hwang KL;Brown KK;Evason K;Beltz S;Tsomides A;O'Connor K;Galli GG;Yimlamai D;Chhangawala S;Yuan M;Lien EC;Wucherpfennig J;Nissim S;Minami A;Cohen DE;Camargo FD;Asara JM;Houvras Y;Stainier DYR;Goessling W
通讯作者：
Goessling W
影响因子：
15.9
作者：
Naylor, Ryan M.;Jeganathan, Karthik B.;van Deursen, Jan M.
通讯作者：
van Deursen, Jan M.
影响因子：
29
作者：
Yang L;Achreja A;Yeung TL;Mangala LS;Jiang D;Han C;Baddour J;Marini JC;Ni J;Nakahara R;Wahlig S;Chiba L;Kim SH;Morse J;Pradeep S;Nagaraja AS;Haemmerle M;Kyunghee N;Derichsweiler M;Plackemeier T;Mercado-Uribe I;Lopez-Berestein G;Moss T;Ram PT;Liu J;Lu X;Mok SC;Sood AK;Nagrath D
通讯作者：
Nagrath D