AurkA nuclear localization is promoted by TPX2 and counteracted by protein degradation.
AurkA nuclear localization is promoted by TPX2 and counteracted by protein degradation.
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DOI：
10.26508/lsa.202201726
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发表时间：
2023-05
影响因子：
4.4
通讯作者：
Guarguaglini, Giulia
中科院分区：
文献类型：
--
作者：
Asteriti, Italia Anna;Polverino, Federica;Stagni, Venturina;Sterbini, Valentina;Ascanelli, Camilla;Naso, Francesco Davide;Mastrangelo, Anna;Rosa, Alessandro;Paiardini, Alessandro;Lindon, Catherine;Guarguaglini, Giulia
这项研究表明，TPX2在未转化的人细胞中过表达，可以诱导AurkA核聚集，并促进其非有丝分裂致癌功能。AurkA激酶是一种众所周知的有丝分裂调节因子，经常在肿瘤中过度表达。微管结合蛋白TPX2控制AurkA的活性、定位和有丝分裂的稳定性。AurkA的非有丝分裂作用正在显现，间期核定位的增加与AurkA的致癌潜能相关。尽管如此，导致AurkA核积聚的机制还没有得到很好的研究。在这里，我们研究了在生理或过度表达条件下的这些机制。我们观察到AurkA的核定位受细胞周期时相和核输出的影响，但不受其激酶活性的影响。重要的是，AURKA的过表达不足以确定其在间期核中的积聚，相反，当AURKA和TPX2共同过表达时，或者在更高程度上，当蛋白酶体活性受损时，才能获得AURKA在间期核中的积聚。表达分析表明，AURKA、TPX2和进口调节因子CSE1L在肿瘤中共同过表达。最后，使用MCF10A大气层，我们证明了TPX2的过度表达驱动了核AurkA下游的促肿瘤过程。我们认为AURKA/TPX2在癌症中的共同过表达是AurkA核致癌功能的关键决定因素。
This study shows that TPX2 co-overexpression in non-transformed human cells induces AurkA nuclear accumulation and promotes its non-mitotic oncogenic functions. The AurkA kinase is a well-known mitotic regulator, frequently overexpressed in tumors. The microtubule-binding protein TPX2 controls AurkA activity, localization, and stability in mitosis. Non-mitotic roles of AurkA are emerging, and increased nuclear localization in interphase has been correlated with AurkA oncogenic potential. Still, the mechanisms leading to AurkA nuclear accumulation are poorly explored. Here, we investigated these mechanisms under physiological or overexpression conditions. We observed that AurkA nuclear localization is influenced by the cell cycle phase and nuclear export, but not by its kinase activity. Importantly, AURKA overexpression is not sufficient to determine its accumulation in interphase nuclei, which is instead obtained when AURKA and TPX2 are co-overexpressed or, to a higher extent, when proteasome activity is impaired. Expression analyses show that AURKA, TPX2, and the import regulator CSE1L are co-overexpressed in tumors. Finally, using MCF10A mammospheres we show that TPX2 co-overexpression drives protumorigenic processes downstream of nuclear AurkA. We propose that AURKA/TPX2 co-overexpression in cancer represents a key determinant of AurkA nuclear oncogenic functions.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
14.8
作者：
Adhikari B;Bozilovic J;Diebold M;Schwarz JD;Hofstetter J;Schröder M;Wanior M;Narain A;Vogt M;Dudvarski Stankovic N;Baluapuri A;Schönemann L;Eing L;Bhandare P;Kuster B;Schlosser A;Heinzlmeir S;Sotriffer C;Knapp S;Wolf E
通讯作者：
Wolf E
影响因子：
5.8
作者：
Grant R;Abdelbaki A;Bertoldi A;Gavilan MP;Mansfeld J;Glover DM;Lindon C
通讯作者：
Lindon C
影响因子：
6.4
作者：
Fujita T;Liu W;Doihara H;Wan Y
通讯作者：
Wan Y