Effect of HSP90AB1 and CC domain interaction on Bcr-Abl protein cytoplasm localization and function in chronic myeloid leukemia cells

作者全名："Peng, Yuhang; Huang, Zhenglan; Zhou, Fangzhu; Wang, Teng; Mou, Ke; Feng, Wenli"

作者地址："[Peng, Yuhang; Huang, Zhenglan; Zhou, Fangzhu; Wang, Teng; Mou, Ke; Feng, Wenli] Chongqing Med Univ, Dept Clin Hematol, Sch Lab Med, Key Lab Lab Med Diagnost Designated,Minist Educ, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China"

通信作者："Feng, WL (corresponding author), Chongqing Med Univ, Dept Clin Hematol, Sch Lab Med, Key Lab Lab Med Diagnost Designated,Minist Educ, 1 Yixueyuan Rd, Chongqing 400016, Peoples R China."

来源：CELL COMMUNICATION AND SIGNALING

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000672113400001

JCR分区：Q2

影响因子：8.4

年份：2021

卷号：19

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Chronic myeloid leukemia; Nuclear localization; Bcr-Abl; HSP90AB1; Coiled-coil domain

摘要："Background: The fusion oncoprotein Bcr-Abl is mostly located in the cytoplasm, which causes chronic myeloid leukemia (CML). After moving into the nucleus, the fusion protein can induce apoptosis of CML cells. The coiled-coil domain (CC domain) of Bcr-Abl protein plays a central role in the subcellular localization. However, how CC domain affects subcellular localization of Bcr-Abl remains unclear. Methods: Herein, the key proteins interacting with the Bcr-Abl CC domain were screened by immunoprecipitation binding mass spectrometry. The specific site of Bcr-Abl CC domain binding to target protein was predicted by Deep Viewer. Immunoprecipitation assay was used to confirmed the specific sites of protein binding. IF and western blot were used to observe the subcellular localization of target protein. Western blot was used to examine the protein changes. CCK-8, clonal formation test and FCM cycle detection were used to observe the effect of inhibitor on the proliferation ability of CML cells. FCM apoptosis detection was used to observe the level of cells apoptosis. Results: HSP90AB1 interacts with Bcr-Abl CC domain via N-terminal domain (NTD), preventing the transport of Bcr-Abl protein to the nucleus and maintaining the activation of Bcr-Abl tyrosine kinase. The nucleus-entrapped Bcr-Abl markedly inhibits the proliferation and induces apoptosis of CML cells by activating p73 and repressing the expression of cytoplasmic oncogenic signaling pathways mediated by Bcr-Abl. Moreover, the combination of 17AAG (Tanespimycin) with Leptomycin B (LMB) considerably decreased the proliferation of CML cells. Conclusion: Our study provides evidence that it is feasible to transport Bcr-Abl into the nucleus as an alternative strategy for the treatment of CML, and targeting the NTD of HSP90AB1 to inhibit the interaction with Bcr-Abl is more accurate for the development and application of HSP90 inhibitor in the treatment of CML and other Bcr-Abl-addicted malignancies."

基金机构：National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81572060]

基金资助正文：This work was supported by National Natural Science Foundation of China (No. 81572060 to Wenli Feng).