MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells.
MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells.
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DOI：
10.1002/stem.1358
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发表时间：
2013-06
期刊：
影响因子：
5.2
通讯作者：
Nakano, Ichiro
中科院分区：
文献类型：
--
作者：
Joshi, Kaushal;Banasavadi-Siddegowda, Yeshavanth;Mo, Xiaokui;Kim, Sung-Hak;Mao, Ping;Kig, Cenk;Nardini, Diana;Sobol, Robert W.;Chow, Lionel M. L.;Kornblum, Harley I.;Waclaw, Ronald;Beullens, Monique;Nakano, Ichiro
多形性胶质母细胞瘤（GBM）是一种危及生命的脑肿瘤。越来越多的证据表明，清除GBM中的胶质瘤干细胞样细胞（GSCs）对于实现治愈至关重要。转录因子FOXM1作为多种器官中癌细胞有丝分裂进程的主要调控因子，近年来引起了人们的关注。在这里，我们证明了FOXM1在GSCs中与有丝分裂激酶MELK形成蛋白质复合物，导致FOXM1以MELK激酶依赖的方式磷酸化和激活。这种依赖melk的FOXM1激活导致随后GSCs中有丝分裂调节基因的增加。melk驱动的FOXM1激活受另一种激酶PLK1的结合和随后的FOXM1反式磷酸化调控。在小鼠神经祖细胞（NPC）中，我们发现FOXM1的转基因表达增强，而sirna介导的基因沉默减少了神经球的形成，这表明FOXM1是NPC生长所必需的。在肿瘤发生过程中，FOXM1的表达随着细胞从npc到瘤前祖细胞和gsc的进展而依次增加。与神经干细胞相比，抗生素Siomycin A在GSC中以更高的敏感性破坏melk介导的FOXM1信号。替莫唑胺是治疗GBM的一线化疗药物，它在GBM细胞中同时富集FOXM1（+）和MELK（+）细胞，在替莫唑胺治疗中加入Siomycin A可增强gsc源性颅内肿瘤小鼠的效果。总的来说，我们的数据表明FOXM1信号通过其与MELK的直接相互作用以plk1依赖的方式调节GSCs中的关键有丝分裂基因，因此，该蛋白复合物是GBM的潜在治疗靶点。干细胞2013；31:1051 - 1063
Glioblastoma multiforme (GBM) is a life-threatening brain tumor. Accumulating evidence suggests that eradication of glioma stem-like cells (GSCs) in GBM is essential to achieve cure. The transcription factor FOXM1 has recently gained attention as a master regulator of mitotic progression of cancer cells in various organs. Here, we demonstrate that FOXM1 forms a protein complex with the mitotic kinase MELK in GSCs, leading to phosphorylation and activation of FOXM1 in a MELK kinase-dependent manner. This MELK-dependent activation of FOXM1 results in a subsequent increase in mitotic regulatory genes in GSCs. MELK-driven FOXM1 activation is regulated by the binding and subsequent trans-phosphorylation of FOXM1 by another kinase PLK1. Using mouse neural progenitor cells (NPCs), we found that transgenic expression of FOXM1 enhances, while siRNA-mediated gene silencing diminishes neurosphere formation, suggesting that FOXM1 is required for NPC growth. During tumorigenesis, FOXM1 expression sequentially increases as cells progress from NPCs, to pretumorigenic progenitors and GSCs. The antibiotic Siomycin A disrupts MELK-mediated FOXM1 signaling with a greater sensitivity in GSC compared to neural stem cell. Treatment with the first-line chemotherapy agent for GBM, Temozolomide, paradoxically enriches for both FOXM1 (+) and MELK (+) cells in GBM cells, and addition of Siomycin A to Temozolomide treatment in mice harboring GSC-derived intracranial tumors enhances the effects of the latter. Collectively, our data indicate that FOXM1 signaling through its direct interaction with MELK regulates key mitotic genes in GSCs in a PLK1-dependent manner and thus, this protein complex is a potential therapeutic target for GBM. Stem Cells 2013;31:1051–1063
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影响因子：
37.3
作者：
Beier D;Schulz JB;Beier CP
通讯作者：
Beier CP
影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
影响因子：
4
作者：
Le Page, Yann;Chartrain, Isabelle;Tassan, Jean-Pierre
通讯作者：
Tassan, Jean-Pierre
影响因子：
11.2
作者：
Lathia, Justin D.;Li, Meizhang;Hall, Peter E.;Gallagher, Joseph;Hale, James S.;Wu, Qiulian;Venere, Monica;Levy, Emily;Rani, M. R. Sandhya;Huang, Ping;Bae, Eunnyung;Selfridge, Julia;Cheng, Lin;Guvenc, Hacer;McLendon, Roger E.;Nakano, Ichiro;Sloan, Andrew E.;Phillips, Heidi S.;Lai, Albert;Gladson, Candece L.;Bredel, Markus;Bao, Shideng;Hjelmeland, Anita B.;Rich, Jeremy N.
通讯作者：
Rich, Jeremy N.
DOI：
10.1158/1078-0432.ccr-12-0647
发表时间：
2013-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Guvenc H;Pavlyukov MS;Joshi K;Kurt H;Banasavadi-Siddegowda YK;Mao P;Hong C;Yamada R;Kwon CH;Bhasin D;Chettiar S;Kitange G;Park IH;Sarkaria JN;Li C;Shakhparonov MI;Nakano I
通讯作者：
Nakano I