通过β-TrCP-REST-Mad2轴控制染色体稳定性的控制
Daniele Guardavaccaro1, David Frescas, N Valerio Dorrello
1Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, New York 10016, USA.
Nature
|March 21, 2008
概括
压缩器元素-1沉默转录因子 (REST) 被SCF (β-TrCP) 降解,使组装检查点激活. 这种降解对于准确的线粒分裂和预防瘤中的基因组不稳定性至关重要.
科学领域:
- 分子生物学分子生物学
- 细胞循环规则 细胞循环规则
- 癌症生物学 癌症生物学
背景情况:
- 抑制素-1-沉默转录因子 (REST) 通常会在非神经细胞中沉默神经元特异性基因.
- 过度表达的REST及其变体与维持干细胞特征有关,这种特征在瘤中如脑髓母细胞瘤和神经母细胞瘤.
- 尚不完全理解REST在细胞循环调节中的作用及其相互作用伙伴.
研究的目的:
- 通过不偏的选方法识别新的REST交互器.
- 阐明REST影响细胞循环进展和细胞分裂的机制.
- 了解REST调节失调对癌症发展和基因组不稳定性的影响.
主要方法:
- 不偏的选,以确定与REST相互作用的蛋白质.
- 使用REST突变体和F盒蛋白β-TrCP的细胞培养实验.
- 对细胞周期进展,螺旋组装检查点激活和基因组稳定性的分析.
- 对Mad2的表达分析和线粒细胞缺陷的评估.
主要成果:
- REST被确定为F-盒蛋白β-TrCP的交互因子.
- 在G2阶段,REST经历SCF (β-TrCP) 依赖的降解,允许Mad2表达和螺杆检查点激活.
- 无法结合β-TrCP的REST突变,包括致癌的REST-FS变体,导致螺杆检查点激活的缺陷,导致线粒错误和基因组不稳定.
结论:
- 在G2中由SCF (β-TrCP) 介导的REST降解对于正确的螺杆检查点功能和线粒体忠实性至关重要.
- REST 降解的失调,特别是 REST 或其截断形式的积累,有助于基因组不稳定性和癌症中的细胞转化.
- REST与β-TrCP的相互作用代表了细胞周期控制和瘤抑制的关键调节节点.
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