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      纺锤体组装检查点在肺癌中的研究进展 Translated title: Progress in the Study of Spindle Assembly Checkpoint in Lung Cancer

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          Abstract

          纺锤体组装检查点(spindle assembly checkpoint, SAC)是细胞正确进行有丝分裂(mitosis)的一种保护机制,以防止有丝分裂中后期染色体动粒(kinetochore)存在未附着或不正确附着微管的情况下继续有丝分裂,从而避免整条染色体的增加或丢失而产生非整倍体(aneuploidy)细胞。非整倍体以及SAC组成蛋白的表达改变是不同癌症种类,包括肺癌的共同特征之一。因此,SAC是一种潜在的肺癌治疗新靶点。目前,SAC上游组分蛋白单极纺锤体蛋白激酶1(monopolar spindle 1, MPS1)小分子抑制剂已有5种进入临床试验。本文介绍了SAC的生物学功能,总结了SAC组分蛋白在多种癌症中的表达异常和MPS1抑制剂的研究进展,期望对未来开发靶向SAC组分的肺癌治疗策略提供参考。

          Translated abstract

          Spindle assembly checkpoint (SAC) is a protective mechanism for cells to undergo accurate mitosis. SAC prevented chromosome segregation when kinetochores were not, or incorrectly attached to microtubules in the anaphase of mitosis, thus avoiding aneuploid chromosomes in daughter cells. Aneuploidy and altered expression of SAC component proteins are common in different cancers, including lung cancer. Therefore, SAC is a potential new target for lung cancer therapy. Five small molecule inhibitors of monopolar spindle 1 (MPS1), an upstream component protein of SAC, have entered clinical trials. This article introduces the biological functions of SAC, summarizes the abnormal expression of SAC component proteins in various cancers and the research progress of MPS1 inhibitors, and expects to provide a reference for the future development of lung cancer therapeutic strategies targeting SAC components.

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          The spindle-assembly checkpoint in space and time.

          In eukaryotes, the spindle-assembly checkpoint (SAC) is a ubiquitous safety device that ensures the fidelity of chromosome segregation in mitosis. The SAC prevents chromosome mis-segregation and aneuploidy, and its dysfunction is implicated in tumorigenesis. Recent molecular analyses have begun to shed light on the complex interaction of the checkpoint proteins with kinetochores--structures that mediate the binding of spindle microtubules to chromosomes in mitosis. These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression.
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            Cancer treatment and survivorship statistics, 2022

            The number of cancer survivors continues to increase in the United States due to the growth and aging of the population as well as advances in early detection and treatment. To assist the public health community in better serving these individuals, the American Cancer Society and the National Cancer Institute collaborate triennially to estimate cancer prevalence in the United States using incidence and survival data from the Surveillance, Epidemiology, and End Results cancer registries, vital statistics from the Centers for Disease Control and Prevention's National Center for Health Statistics, and population projections from the US Census Bureau. Current treatment patterns based on information in the National Cancer Database are presented for the most prevalent cancer types by race, and cancer-related and treatment-related side-effects are also briefly described. More than 18 million Americans (8.3 million males and 9.7 million females) with a history of cancer were alive on January 1, 2022. The 3 most prevalent cancers are prostate (3,523,230), melanoma of the skin (760,640), and colon and rectum (726,450) among males and breast (4,055,770), uterine corpus (891,560), and thyroid (823,800) among females. More than one-half (53%) of survivors were diagnosed within the past 10 years, and two-thirds (67%) were aged 65 years or older. One of the largest racial disparities in treatment is for rectal cancer, for which 41% of Black patients with stage I disease receive proctectomy or proctocolectomy compared to 66% of White patients. Surgical receipt is also substantially lower among Black patients with non-small cell lung cancer, 49% for stages I-II and 16% for stage III versus 55% and 22% for White patients, respectively. These treatment disparities are exacerbated by the fact that Black patients continue to be less likely to be diagnosed with stage I disease than White patients for most cancers, with some of the largest disparities for female breast (53% vs 68%) and endometrial (59% vs 73%). Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based strategies and equitable access to available resources are needed to mitigate disparities for communities of color and optimize care for people with a history of cancer. CA Cancer J Clin. 2022;72:409-436.
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              Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2

              The mitotic checkpoint prevents cells with unaligned chromosomes from prematurely exiting mitosis by inhibiting the anaphase-promoting complex/cyclosome (APC/C) from targeting key proteins for ubiquitin-mediated proteolysis. We have examined the mechanism by which the checkpoint inhibits the APC/C by purifying an APC/C inhibitory factor from HeLa cells. We call this factor the mitotic checkpoint complex (MCC) as it consists of hBUBR1, hBUB3, CDC20, and MAD2 checkpoint proteins in near equal stoichiometry. MCC inhibitory activity is 3,000-fold greater than that of recombinant MAD2, which has also been shown to inhibit APC/C in vitro. Surprisingly, MCC is not generated from kinetochores, as it is also present and active in interphase cells. However, only APC/C isolated from mitotic cells was sensitive to inhibition by MCC. We found that the majority of the APC/C in mitotic lysates is associated with the MCC, and this likely contributes to the lag in ubiquitin ligase activity. Importantly, chromosomes can suppress the reactivation of APC/C. Chromosomes did not affect the inhibitory activity of MCC or the stimulatory activity of CDC20. We propose that the preformed interphase pool of MCC allows for rapid inhibition of APC/C when cells enter mitosis. Unattached kinetochores then target the APC/C for sustained inhibition by the MCC.
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                Author and article information

                Contributors
                Journal
                Zhongguo Fei Ai Za Zhi
                Zhongguo Fei Ai Za Zhi
                Chinese Journal of Lung Cancer
                Editorial board of Chinese Journal of Lung Cancer (No. 154 Anshan Road, Heping District, Tianjin, PRC, 300052 )
                1009-3419
                1999-6187
                20 April 2023
                : 26
                : 4
                : 310-318
                Affiliations
                [1] 999078 澳门,澳门科技大学中药质量研究国家重点实验室,埃尔文内尔博士生物物理与创新药物实验室 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
                Author notes
                马丽娟,E-mail: ljma@ 123456must.edu.mo
                Lijuan MA, E-mail: ljma@ 123456must.edu.mo

                秦馨晨与张瑶为共同第一作者

                Xinchen QIN and Yao ZHANG contributed equally to this paper.

                Article
                10.3779/j.issn.1009-3419.2023.101.13
                10186262
                37183646
                80fcb5e7-cc3f-435f-aaf4-577a459fef7e
                Copyright @ 2023

                This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) License. See: https://creativecommons.org/licenses/by/3.0/.

                History
                : 20 March 2023
                Funding
                Funded by: 澳门科学技术发展基金
                Funded by: Macau Science and Technology Development Fund, Macau, China
                Award ID: 0062/2021/A2
                Funded by: 澳门科学技术发展基金
                Funded by: Macau Science and Technology Development Fund, Macau, China
                Award ID: 002/2023/ALC
                Categories
                Review

                纺锤体组装检查点,非整倍体,有丝分裂,有丝分裂检查点复合体,spindle assembly checkpoint,aneuploidy,mitosis,mitotic checkpoint complex

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