The recurrent architecture of tumour initiation, progression and drug sensitivity.
The recurrent architecture of tumour initiation, progression and drug sensitivity.
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DOI：
10.1038/nrc.2016.124
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Alvarez MJ
中科院分区：
文献类型：
--
作者：
Califano A;Alvarez MJ
最近对多种肿瘤类型的研究开始揭示一种复发性调控结构，其中基因组改变聚集在功能性主调控（MR）蛋白的上游，其异常活性对于维持肿瘤细胞状态既是必要的，也是充分的。这些蛋白质形成小的、超连接的和自动调节的模块（称为肿瘤检查点），越来越多地成为最佳的生物标志物和治疗靶点。至关重要的是，由于它们的活性大多在翻译后失调，而不是通过相应基因的突变或差异表达，因此用常规方法鉴定MR蛋白具有挑战性。在这篇观点文章中，我们讨论了MR蛋白系统分析的新方法及其实现的模块化调控结构，包括它们作为研究人类疾病遗传异质性和驱动关键翻译应用的有价值的还原框架的使用。
Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state. These proteins form small, hyperconnected and autoregulated modules (termed tumour checkpoints) that are increasingly emerging as optimal biomarkers and therapeutic targets. Crucially, as their activity is mostly dysregulated in a post-translational manner, rather than by mutations in their corresponding genes or by differential expression, the identification of MR proteins by conventional methods is challenging. In this Opinion article, we discuss novel methods for the systematic analysis of MR proteins and of the modular regulatory architecture they implement, including their use as a valuable reductionist framework to study the genetic heterogeneity of human disease and to drive key translational applications.
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