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ETV6/FLT3 融合是 Hsp90 的一种新型客户蛋白。

ETV6/FLT3 Fusion Is a Novel Client Protein of Hsp90.

机构信息

Department of Food Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City, Vietnam.

Department for Management of Science and Technology Development, Ton Duc Thang University, Ho Chi Minh City, Vietnam.

出版信息

Oncol Res. 2018 Sep 14;26(8):1201-1205. doi: 10.3727/096504018X15154104709325. Epub 2018 Feb 22.

DOI:10.3727/096504018X15154104709325
PMID:29471895
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7844643/
Abstract

FMS-like tyrosine kinase-3 fragments from exon 14 to the end without any mutations or deletions have been reported to fuse to ETV6 (TEL) in a few cases of myeloid/lymphoid neoplasms with eosinophilia carrying a translocation t(12;13)(p13;q12). This fusion protein confers constitutive activation on the FLT3 fragment and induces factor-independent growth in transfected Ba/F3 cells, indicating that it is an oncoprotein. However, the mechanism controlling the stability of this oncoprotein is unknown. In this study, we focus on finding factors controlling the stability of ETV6/FLT3. We have shown that the stability of ETV6/FLT3 is regulated by the Hsp90 chaperone. ETV6/FLT3 fusion protein forms a complex with Hsp90 by coimmunoprecipitation analyses using an Hsp90 antibody. The association between ETV6/FLT3 fusion protein and Hsp90 was impaired after treating ETV6/FLT3 transient transfection cos7 cells with 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG induced a time- and dose-dependent downregulation of ectopically expressed ETV6/FLT3 protein in cos7 and HeLa-transfected cells. By using cycloheximide to block new protein translation, we found that 17-AAG accelerated the decay of ETV6/FLT3. Our findings could contribute to more understanding of the ETV6/FLT3 regulation through Hsp90 chaperone and open the way to finding effective treatment strategies for this rare disease.

摘要

已经有报道称，在少数伴有嗜酸性粒细胞增多的髓系/淋系肿瘤中，无突变或缺失的 FMS 样酪氨酸激酶-3 片段 14 号外显子到末端与 ETV6（TEL）融合。该融合蛋白赋予 FLT3 片段组成性激活，并在转染的 Ba/F3 细胞中诱导因子非依赖性生长，表明其是一种癌蛋白。然而，控制这种癌蛋白稳定性的机制尚不清楚。在这项研究中，我们专注于寻找控制 ETV6/FLT3 稳定性的因素。我们已经表明，ETV6/FLT3 的稳定性受 Hsp90 伴侣的调控。通过使用 Hsp90 抗体进行 coimmunoprecipitation 分析，显示 ETV6/FLT3 融合蛋白与 Hsp90 形成复合物。在用 17-allylamino-17-demethoxygeldanamycin（17-AAG）处理 ETV6/FLT3 瞬时转染 cos7 细胞后，ETV6/FLT3 融合蛋白与 Hsp90 之间的关联受到损害。17-AAG 在 cos7 和 HeLa 转染细胞中诱导异位表达的 ETV6/FLT3 蛋白的时间和剂量依赖性下调。通过使用环己酰亚胺阻断新蛋白翻译，我们发现 17-AAG 加速了 ETV6/FLT3 的降解。我们的发现有助于更深入地了解通过 Hsp90 伴侣对 ETV6/FLT3 的调控，并为寻找针对这种罕见疾病的有效治疗策略开辟了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/b09eacd1a31f/OR-26-1201-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/4efc20012059/OR-26-1201-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/059dd6278a54/OR-26-1201-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/b09eacd1a31f/OR-26-1201-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/4efc20012059/OR-26-1201-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/059dd6278a54/OR-26-1201-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/58a9/7844643/b09eacd1a31f/OR-26-1201-g003.jpg

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2
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3
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4
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