蛋白SET通过调节SHMT2酶活性来促进血清衍生的单碳代谢
Zishan Jiao1, Mi Zhang2, Jingyuan Ning1
1State Key Laboratory of Common Mechanism Research for Major Diseases and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
概括
蛋白SET通过与SHMT2相互作用来调节癌细胞代谢,影响瘤生长至关重要的单碳通路. 向SHMT1和SHMT2可以抑制SET驱动的瘤进展.
科学领域:
- 生物化学 生化学
- 癌症生物学 癌症生物学
- 代谢途径 代谢途径
背景情况:
- 癌细胞为生物合成和抗氧化剂防御重新编程一碳代谢.
- 瘤基因和瘤抑制基因功能障碍导致代谢变化,但机制尚不清楚.
研究的目的:
- 确定癌症中单碳代谢的关键调节者.
- 阐明上蛋白SET在代谢重编程中的作用.
- 研究瘤发生中的SET-SHMT2轴.
主要方法:
- 不定位的代谢分析,以确定代谢调节者.
- 生物化学测试用于评估蛋白质相互作用和酶活性.
- 在体内研究使用Kras/Lkb1肺瘤小鼠模型.
- 在人类肺瘤中对SET和SHMT2表达的临床分析.
主要成果:
- 蛋白SET被确定为单碳新陈代谢的关键调节者.
- 在物理上与线粒体SHMT2活动相互作用并增强SET.
- 失去SET抑制了氨酸衍生的单碳流量; SET再表达增加了它.
- 药理上抑制SHMT1/SHMT2可显著抑制SET诱导的瘤生长.
- 在小鼠模型中,SET损失会影响瘤形成和SHMT2活性.
- 过度表达SET和SHMT2与肺癌的预后不佳相关.
结论:
- 一个新的SET-SHMT2轴调节了来自血清的单碳代谢.
- 由SET驱动的代谢重编程是瘤发生的一个机制.
- 针对细胞SHMT提供了针对SET驱动癌症的治疗策略.
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