Gene expression associations with the growth inhibitory effects of small molecules on live cells: specificity of effects and uniformity of mechanisms.
Gene expression associations with the growth inhibitory effects of small molecules on live cells: specificity of effects and uniformity of mechanisms.
复制标题
基因表达与小分子对活细胞的生长抑制作用的关联：作用的特异性和机制的一致性。
DOI：
10.1002/sam.10049
复制
发表时间：
2009
影响因子：
1.3
通讯作者：
Rosania,Gus
中科院分区：
文献类型：
--
作者：
Shedden,Kerby;Yang,Yang;Rosania,Gus
NCI60人肿瘤细胞系筛选是研究小分子选择性和非选择性抑制肿瘤细胞生长的公共资源。通过将生长抑制筛选数据与不同细胞系的生物学特性相结合，可以推断一些可观察到的选择性活性模式的作用机制。利用这些数据，已经确定了机制关系，包括单个基因和密切相关化合物的小家族之间的特定关联，以及涉及几个合作基因的生物过程和更广泛的化合物家族之间的不太特定的关系。在这里，我们的目标是表征这些数据中存在的这种具体和一般关系的程度。一个相关的问题是，对于所有相关的化合物，基因是否倾向于以统一的机制发挥作用，或者是否通常涉及多种机制。我们在一个统计框架中解决这两个问题，特别强调基因表达和化学筛选数据中测量误差的影响。我们发现，随着测量精度的提高，表观关联的模式从以孤立的基因/化合物对为主的模式转变为由平均25个化合物组成的家庭与同一基因关联的模式。与此同时，似乎在影响化合物活动方面发挥作用的基因数量减少。对于不到一半的基因，正相关和负相关的存在表明了通过不同的作用机制与分子的多效性关联。版权所有(C)2009威利期刊公司，统计分析和数据挖掘2：175-185,2009
The NCI60 human tumor cell line screen is a public resource for studying selective and nonselective growth inhibition of small molecules against cancer cells. By coupling growth inhibition screening data with biological characterizations of the different cell lines, it becomes possible to infer mechanisms of action underlying some of the observable patterns of selective activity. Using these data, mechanistic relationships have been identified including specific associations between single genes and small families of closely related compounds, and less specific relationships between biological processes involving several cooperating genes and broader families of compounds. Here, we aim to characterize the degree to which such specific and general relationships are present in these data. A related question is whether genes tend to act with a uniform mechanism for all associated compounds, or whether multiple mechanisms are commonly involved. We address these two issues in a statistical framework placing special emphasis on the effects of measurement error in the gene expression and chemical screening data. We find that as measurement accuracy increases, the pattern of apparent associations shifts from one dominated by isolated gene/compound pairs, to one in which families consisting of an average of 25 compounds are associated to the same gene. At the same time, the number of genes that appear to play a role in influencing compound activities decreases. For less than half of the genes, the presence of both positive and negative correlations indicates pleiotropic associations with molecules via different mechanisms of action. Copyright © 2009 Wiley Periodicals, Inc. Statistical Analysis and Data Mining 2: 175–185, 2009