瘤性KRAS突变调节BAX介导的细胞死亡
Anabela Ferreira1, Stéphen Manon2, Akandé Rouchidane Eyitayo2
1Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal.
Biochimica et biophysica acta. Molecular cell research
|November 8, 2024
概括
在结肠直肠癌 (CRC) 中,突变的基尔斯顿大鼠肉瘤病毒瘤基因同源 (KRAS) 通过直接与亲亡蛋白 BAX.相互作用,赋予细胞死亡的抵抗力. 这种相互作用会影响BAX诱导的细胞死亡和细胞染色体c的释放.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 在瘤学瘤学.
背景情况:
- 基尔斯大鼠肉瘤病毒瘤基因同源 (KRAS) 是一种参与细胞信号传递和细胞亡的GTPase.
- 瘤性KRAS突变在30-50%的结直肠癌 (CRC) 患者中普遍存在.
- 克拉斯突变在细胞亡调节中的作用,特别是关于BAX的作用,尚不清楚.
研究的目的:
- 调查人类突变KRAS在调节BAX中的作用,BAX是一种关键的亲亡蛋白.
- 为了阐明KRAS异型和BAX之间的相互作用.
- 在KRAS突变和BAX的背景下,探索酸对细胞死亡的影响.
主要方法:
- 使用了酵母模型Saccharomyces cerevisiae.
- 同表达的野生类型KRAS (KRASWT) 或常见的CRC KRAS突变 (KRASG12D,KRASG12V,KRASG13D) 与缺乏ras2异型的酵母细胞中的人类BAX.
- 评估细胞死亡,细胞染色体c的释放,以及蛋白质在线粒体的同定位.
主要成果:
- 与KRASWT不同的是,KRAS突变对BAX诱导的细胞死亡和细胞染色体c释放产生了抵抗力.
- 证据表明,KRAS异型和BAX.之间的直接相互作用和线粒体同定位.
- 乙酸显著增加了表达BAX和瘤性KRAS突变细胞的细胞死亡,但不是KRASWT.
结论:
- 突变的KRAS直接调节BAX功能,导致对亡的抵抗.
- 这些发现表明KRAS和BAX在线粒体之间存在直接的物理相互作用.
- 瘤性KRAS突变可能使癌细胞对酸盐敏感,提供潜在的治疗见解.
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