一个可化学调节的FOXM1-DHFR传感器揭示了FOXM1对细胞周期的直接影响
Kriengkrai Phongkitkarun1,2, Porncheera Chusorn1,3, Maliwan Kamkaew1
1Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Journal of cell science
|June 30, 2025
概括
叉头盒蛋白M1 (FOXM1) 对于细胞分裂和癌症进展至关重要. 操纵FOXM1水平揭示了其在细胞周期控制中的动态作用,并为癌症治疗提供了新的策略.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 癌症研究 癌症研究
背景情况:
- 叉头盒蛋白M1 (FOXM1) 是一个关键的转录因子,调节细胞周期进展,特别是G2/M过渡.
- 在各种癌症中,FOXM1经常过度表达,导致瘤生长和对治疗的抗性.
- 细胞周期中FOXM1的精确动态调节及其对细胞命运的影响仍然不完全理解.
研究的目的:
- 开发一种用于实时监测和操纵FOXM1水平的新型系统.
- 研究FOXM1在不同细胞周期阶段 (G1,S,G2) 的动态调节.
- 阐明FOXM1动力学在决定细胞周期进展和细胞命运中的作用.
主要方法:
- 在MCF10A细胞中开发可调节的FOXM1-二叶酸减少酶 (DHFR) 传感器 (FOXM1-D).
- 使用trimethoprim稳定FOXM1-D用于生产,降解和核转移的定量分析.
- 在不同的FOXM1-D水平下观察细胞分裂,细胞循环停止和基因表达变化 (例如,p21/CDKN1A).
主要成果:
- 使用FOXM1-D传感器实现了FOXM1水平的实时监测和操纵.
- 过度表达FOXM1加速了G1/S阶段的进展,但在很大一部分细胞中导致细胞周期在第一次分裂后停止.
- 持续的FOXM1过度表达诱导了子细胞中的G1逮捕,通过p21 (CDKN1A) 的上调调节进行调节.
结论:
- FOXM1动力学在决定细胞周期进展和细胞命运方面发挥着至关重要的作用.
- 向FOXM1具有双重的治疗策略:诱导瘤基因诱导的衰老或抑制线粒体的进入.
- 这项研究为开发针对FOXM1动态在癌症治疗中的精密疗法提供了基础.
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