LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin
LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin
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LKB1 失活通过 p53 依赖性生存素上调导致着丝粒缺陷和基因组不稳定
DOI：
10.18632/aging.103473
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Zhi
中科院分区：
文献类型：
--
作者：
Liyan Jin;Kui;Longjiang Xu;Rui;K. Werle;Yong Wang;Xiao;Qiu Chen;Zhuo;Ke Zhang;Ying Zhao;G. Jiang;F. Cui;Zhi
肝激酶B1（LKB 1）肿瘤抑制基因的失活突变是Peutz-Jeghers综合征（PJS）的基础，经常发生在各种人类癌症中。我们以前表明，LKB 1通过PLK 1调节中心体复制。在这里，我们报告说，LKB 1进一步有助于维持基因组的稳定性，通过负调控生存素，一个成员的染色体乘客复合体（CPC）介导的CPC针对着丝粒。我们发现，LKB 1的丢失导致在中期和后期积累的不对齐和落后的染色体，并增加多核和微核细胞的出现。异位LKB 1表达减少了这些功能，并提高了LKB 1缺陷细胞的有丝分裂保真度。通过药理学和遗传学操作，我们发现LKB 1介导的生存素抑制不依赖于AMPK，但需要p53。与LKB 1对生存素表达的关键影响一致，免疫组化分析表明生存素在PJS患者的肠息肉中高度表达。最后，我们通过证明LKB 1缺陷细胞对生存素抑制剂的敏感性增加，重申了治疗LKB 1突变肿瘤的潜在治疗途径。
Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.
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影响因子：
16
作者：
Banko, Max R.;Allen, Jasmina J.;Schaffer, Bethany E.;Wilker, Erik W.;Tsou, Peiling;White, Jamie L.;Villen, Judit;Wang, Beatrice;Kim, Sara R.;Sakamoto, Kei;Gygi, Steven P.;Cantley, Lewis C.;Yaffe, Michael B.;Shokat, Kevan M.;Brunet, Anne
通讯作者：
Brunet, Anne
影响因子：
6
作者：
O'Connor, DS;Schechner, JS;Altieri, DC
通讯作者：
Altieri, DC
影响因子：
11.2
作者：
Zeng, Ping-Yao;Berger, Shelley L.
通讯作者：
Berger, Shelley L.
影响因子：
2.7
作者：
Zhang XH;Feng R;Lv M;Jiang Q;Zhu HH;Qing YZ;Bao JL;Huang XJ;Zheng XL
通讯作者：
Zheng XL