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Published on: August 4, 2019

ARF改变PAF1复合体的完整性,在p53损失时选择性地抑制瘤转录程序

Jinli Wang¹, Nikole L Fendler², Ashutosh Shukla¹

¹Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.

|November 12, 2024

概括

替代阅读框架 (ARF) 瘤抑制剂通过分解PAF1复合体 (PAF1c) 和调节RUNX1.1,抑制瘤转录. 失去ARF通过GDF/BMP信号传递促进细胞生长,提供治疗点.

科学领域:

分子生物学分子生物学
癌症生物学癌症生物学
转录条例转录条例转录条例

背景情况:

聚合酶相关因子1 (PAF1) 复合体 (PAF1c) 对于RNA聚合酶II (RNA Pol II) 转录延长至关重要.
在细胞命运过渡过程中PAF1c活动的调节尚未得到充分理解.
替代阅读框架 (ARF) 瘤抑制剂在防止不受控制的细胞生长方面发挥着作用.

研究的目的:

研究ARF在细胞命运过渡期间对PAF1c活动的调节机制.
阐明ARF如何抑制瘤性转录程序.
确定针对ARF介导瘤抑制的潜在治疗策略.

主要方法:

研究了ARF与PAF1子单元的相互作用及其对PAF1c分解的影响.
分析了ARF针对RUNX1进行选择性基因转录调整的向.
利用p53损失的小鼠细胞模型来研究ARF的功能.
评估了GDF/BMP信号传递和RUNX1扰动对细胞增殖的影响.

主要成果:

ARF通过与PAF1亚单元结合来促进PAF1c的分解,从而减少RNA Pol II相互作用和转录.
通过准RUNX1.1,ARF可以选择性地调节基因转录.
失去ARF会导致RUNX1-和PAF1c-依赖的GDF/BMP配体的激活,促进异常细胞生长.
药物抑制GDF/BMP信号传递和RUNX1的遗传干扰减弱了p53和ARF缺乏细胞中的细胞增殖.

结论:

通过双重机制,ARF通过抑制PAF1c依赖的瘤转录来起到关键的瘤抑制作用.
ARF对PAF1c和RUNX1的调节控制了细胞生长途径,特别是GDF/BMP-Smad1/5轴.
准GDF/BMP信号传输或RUNX1为具有双重p53和ARF损失的癌症提供了潜在的治疗途径.

关键词:

在ARF中,ARF是ARF.这就是CDKN2A.一个PAF1的PAF1.的RNA聚合酶II.在RUNX中使用RUNX.细胞的增殖细胞的增殖.在 p53 里,p53 是一个 p53 的类型.转录转录是一种转录.这是一种瘤抑制剂.瘤发生的起源

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