在癌症中发现突变导向的新蛋白与蛋白相互作用的系统性
Xiulei Mo1, Qiankun Niu2, Andrey A Ivanov3
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
癌症突变可以产生新的蛋白相互作用, 推动瘤生长. 我们的研究发现了这些新奇的相互作用,
科学领域:
- 癌症学
- 分子生物学
- 基因组学
背景情况:
- 基因组测序揭示了导致癌症的突变.
- 一些突变会导致新型活性,改变蛋白质的功能.
- 新形活性可能导致新型蛋白-蛋白相互作用 (新型PPI).
研究的目的:
- 通过使用高通量选平台,识别流行型新型PPI.
- 了解癌症突变如何产生新的蛋白质相互作用.
- 探索基于这些新PPI的治疗策略.
主要方法:
- 开发了一个定量高通量差分选 (qHT-dS) 平台.
- 在超高通量查 (uHTS) 中配合敏感的BRET生物传感器.
- 在活细胞中监测野生类型和突变蛋白与癌症相关蛋白的相互作用.
主要成果:
- 选了17792个互动,产生了超过200万个数据点.
- 确定了与瘤和瘤抑制突变相关的相互作用效应.
- 发现的BRAF V600E突变调解KEAP1 neoPPI,从而对NQO1基质产生脆弱性.
结论:
- 癌症基因组的改变可以产生新相互作用.
- 这些新PPI提供了对变异导向治疗方法的见解.
- 针对BRAF V600E/KEAP1轴的组合疗法是一个潜在的策略.
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