EBP2, a novel NPM-ALK-interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53.
EBP2, a novel NPM-ALK-interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53.
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DOI：
10.1002/1878-0261.12822
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发表时间：
2021-01
影响因子：
6.6
通讯作者：
Funakoshi-Tago M
中科院分区：
文献类型：
--
作者：
Uchihara Y;Tago K;Tamura H;Funakoshi-Tago M
核磷蛋白-间变性淋巴瘤激酶 (NPM-ALK) 通过与间变性大细胞淋巴瘤细胞核仁中的 EBP2 相互作用，负向调节 Akt-mTORC1 通路的激活，从而使肿瘤抑制因子 p53 失活。 间变性大细胞淋巴瘤 (ALCL) 中发现的致癌融合蛋白核磷蛋白-间变性淋巴瘤激酶 (NPM-ALK) 定位于细胞质、核质和核仁。然而，其定位与转化活性之间的关系仍不清楚。我们在此证明，NPM-ALK 通过与核磷蛋白 1 (NPM1) 结合而定位于核仁，核磷蛋白 1 是一种核仁蛋白，在核仁和细胞质之间表现出穿梭活性，其方式依赖于其激酶活性。在核仁中，NPM-ALK 与 Epstein-Barr 病毒核抗原 1 结合蛋白 2 (EBP2) 相互作用，后者参与 rRNA 生物合成。此外，NPM-ALK 的强制表达诱导 EBP2 酪氨酸磷酸化。 EBP2 的敲低促进了肿瘤抑制因子 p53 的激活，导致 NPM-ALK 和 ALCL 患者来源的 Ki-JK 细胞转化的 Ba/F3 细胞出现 G0/G1 期细胞周期停滞，但不包括带有 p53 基因突变的 ALCL 患者来源的 SUDH-L1 细胞。在 NPM-ALK 和 Ki-JK 细胞转化的 Ba/F3 细胞中，敲低 EBP2 诱导的 p53 激活被 Akt 抑制剂 GDC-0068、mTORC1 抑制剂雷帕霉素和敲低 Raptor（mTORC1 的重要组成部分）显着抑制。这些结果表明，EBP2 的敲低通过 Akt-mTORC1 通路在 NPM-ALK 阳性细胞中触发 p53 激活。总的来说，目前的结果揭示了 EBP2 对 p53 活性的关键抑制机制，并为 ALCL 的治疗提供了一种新的治疗策略。
Nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK) inactivates tumor suppressor p53 by negatively regulating the activation of the Akt‐mTORC1 pathway through an interaction with EBP2 in the nucleolus in anaplastic large‐cell lymphoma cells. The oncogenic fusion protein nucleophosmin‐anaplastic lymphoma kinase (NPM‐ALK), found in anaplastic large‐cell lymphoma (ALCL), localizes to the cytosol, nucleoplasm, and nucleolus. However, the relationship between its localization and transforming activity remains unclear. We herein demonstrated that NPM‐ALK localized to the nucleolus by binding to nucleophosmin 1 (NPM1), a nucleolar protein that exhibits shuttling activity between the nucleolus and cytoplasm, in a manner that was dependent on its kinase activity. In the nucleolus, NPM‐ALK interacted with Epstein–Barr virus nuclear antigen 1‐binding protein 2 (EBP2), which is involved in rRNA biosynthesis. Moreover, enforced expression of NPM‐ALK induced tyrosine phosphorylation of EBP2. Knockdown of EBP2 promoted the activation of the tumor suppressor p53, leading to G0/G1‐phase cell cycle arrest in Ba/F3 cells transformed by NPM‐ALK and ALCL patient‐derived Ki‐JK cells, but not ALCL patient‐derived SUDH‐L1 cells harboring p53 gene mutation. In Ba/F3 cells transformed by NPM‐ALK and Ki‐JK cells, p53 activation induced by knockdown of EBP2 was significantly inhibited by Akt inhibitor GDC‐0068, mTORC1 inhibitor rapamycin, and knockdown of Raptor, an essential component of mTORC1. These results suggest that the knockdown of EBP2 triggered p53 activation through the Akt‐mTORC1 pathway in NPM‐ALK‐positive cells. Collectively, the present results revealed the critical repressive mechanism of p53 activity by EBP2 and provide a novel therapeutic strategy for the treatment of ALCL.
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影响因子：
8
作者：
Ceccon M;Merlo MEB;Mologni L;Poggio T;Varesio LM;Menotti M;Bombelli S;Rigolio R;Manazza AD;Di Giacomo F;Ambrogio C;Giudici G;Casati C;Mastini C;Compagno M;Turner SD;Gambacorti-Passerini C;Chiarle R;Voena C
通讯作者：
Voena C
影响因子：
82.9
作者：
Chiarle, R;Simmons, WJ;Inghirami, G
通讯作者：
Inghirami, G
影响因子：
3.4
作者：
Chamousset, Delphine;Mamane, Sarah;Trinkle-Mulcahy, Laura
通讯作者：
Trinkle-Mulcahy, Laura
影响因子：
3.6
作者：
Goudarzi, Kaveh M.;Nister, Monica;Lindstrom, Mikael S.
通讯作者：
Lindstrom, Mikael S.
影响因子：
5.3
作者：
Colombo, E;Bonetti, P;Pelicci, PG
通讯作者：
Pelicci, PG