主导负TP53突变被HSF1调节的蛋白质稳定网络增强
Rebecca M Sebastian1, Jessica E Patrick1, Tiffani Hui2
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
bioRxiv : the preprint server for biology
|November 18, 2024
概括
在癌细胞中慢性激活热冲击因子1 (HSF1) 可能通过提高像p53这样的蛋白质中破坏稳定的氨基酸替代物的适应性来促进瘤突变. 这表明,抑制HSF1可能会降低耐药性和转移.
科学领域:
- 分子生物学分子生物学
- 生物物理学的生物物理.
- 癌症生物学 癌症生物学
背景情况:
- 蛋白质的稳定性和折叠受突变和细胞蛋白质稳定网络的影响.
- 热冲击因子1 (HSF1) 调节蛋白质稳定,并且在癌细胞中经常长期激活.
- 这种激活可能有助于获得致癌突变.
研究的目的:
- 实验性研究慢性HSF1激活如何影响p53蛋白的突变格局.
- 评估HSF1激活是否影响p53突变在细胞毒性压力下的适应性.
主要方法:
- 量化深度突变扫描 p53.3.
- 在nutlin-3 (MDM2抗剂) 治疗下对p53突变途径的评估.
- 评估HSF1激活对突变适应性的影响.
主要成果:
- HSF1激活大大提高了主导负p53替代物的适应性.
- 这种效应在p53DNA结合域的埋藏区域中表现为非保守的,破坏稳定的替代物.
- HSF1激活优先支持与癌症相关的生物物理不稳定突变.
结论:
- 慢性HSF1激活显著塑造了致癌突变格局.
- 它有利于获得导致癌症的破坏稳定的突变.
- 抑制HSF1可能是限制导致化疗耐药性和转移的突变的策略.
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