获取功能的p53突变体共用染色体通路来驱动癌症生长
Jiajun Zhu1,2,3, Morgan A Sammons1,2, Greg Donahue1,2
1Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nature
|September 3, 2015
概括
获得功能TP53突变通过调节MLL1等染色体修饰剂来促进癌症. 抑制这些修饰剂可以减少癌细胞的增殖,为TP53突变癌症揭示新的治疗点.
科学领域:
- 癌症学
- 表观遗传学
- 分子生物学
背景情况:
- TP53是人类癌症中最常发生突变的基因.
- 获得功能的 (GOF) p53突变通过改变基因表达促进瘤发生.
- GOF p53驱动癌症进展的确切机制尚未完全理解.
研究的目的:
- 研究p53GOF突变在调节染色体修饰酶中的作用.
- 确定p53GOF突变的癌症的新疗法目标.
主要方法:
- 对癌症基因组图谱 (TCGA) 数据的分析.
- 染色体调节基因的基因表达分析 (MLL1,MLL2,MOZ).
- 涉及MLL1基因淘汰和药物抑制的功能研究.
主要成果:
- p53 GOF突变对染色体调节基因MLL1,MLL2和MOZ进行上调.
- 与野生型或无瘤相比,MLL1,MLL2和MOZ在p53GOF瘤中特别高调.
- 抑制MLL1或抑制其甲基转移酶复合体可显著降低癌细胞的增殖.
结论:
- 通过一种涉及MLL1,MLL2和MOZ的基于染色体的新机制,p53GOF突变驱动癌症的进展.
- 针对这些染色体修饰剂为GOF p53突变的癌症提供了有前途的治疗策略.
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