对抗结核素化疗药物的敏感性由MCL1和FBW7调节
Ingrid E Wertz1, Saritha Kusam, Cynthia Lam
1Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA. ingrid@gene.com
Nature
|March 4, 2011
概括
支持生存的蛋白质MCL1调节由抗结素化疗诱导的亡. 它的降解,由FBW7调解,对于细胞死亡至关重要;FBW7的损失赋予了对这些癌症药物的耐药性.
科学领域:
- 细胞生物学 细胞生物学
- 分子瘤学分子瘤学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 微管对于细胞功能至关重要,并且是Taxol和Vincristine等抗管素化疗药物的目标.
- 这些药物通过不完全理解的机制诱导线索性停止和细胞死亡,瘤抵抗策略尚不清楚.
研究的目的:
- 调查支持生存的蛋白质MCL1在由抗结核素化疗药物触发的亡中的作用.
- 为了阐明瘤细胞逃避这些药物诱导的死亡的机制.
主要方法:
- 在线粒体停止期间研究了MCL1蛋白水平.
- 检查了MCL1的翻译后调节,包括酸化和无处不在.
- 评估了MCL1和FBW7瘤抑制蛋白之间的相互作用.
- 分析了缺乏FBW7功能和原发性瘤样本的患者衍生瘤细胞.
主要成果:
- 在线粒停滞期间,MCL1蛋白水平显著下降,增强细胞死亡.
- 酸化MCL1促进其与FBW7的相互作用,导致多基化和蛋白质体降解.
- 功能丧失的突变或FBW7的缺失阻断了MCL1的降解,赋予了抗结核素剂的耐药性,并促进了多重合体.
- 主要瘤显示为FBW7无活化和MCL1水平升高的丰富.
结论:
- MCL1是抗结素化疗诱导的亡的关键调节者.
- 通过FBW7介导的MCL1降解对这些药物的疗效至关重要.
- 针对FBW7和MCL1状态的瘤概况可以预测患者对抗结核素化疗药物的反应.
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