Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):E771-80. doi: 10.1073/pnas.1106149108. Epub 2011 Sep 6.
Cell death is a complex process that plays a vital role in development, homeostasis, and disease. Our understanding of and ability to control cell death is impeded by an incomplete characterization of the full range of cell death processes that occur in mammalian systems, especially in response to exogenous perturbations. We present here a general approach to address this problem, which we call modulatory profiling. Modulatory profiles are composed of the changes in potency and efficacy of lethal compounds produced by a second cell death-modulating agent in human cell lines. We show that compounds with the same characterized mechanism of action have similar modulatory profiles. Furthermore, clustering of modulatory profiles revealed relationships not evident when clustering lethal compounds based on gene expression profiles alone. Finally, modulatory profiling of compounds correctly predicted three previously uncharacterized compounds to be microtubule-destabilizing agents, classified numerous compounds that act nonspecifically, and identified compounds that cause cell death through a mechanism that is morphologically and biochemically distinct from previously established ones.
细胞死亡是一个复杂的过程，在发育、内稳态和疾病中起着至关重要的作用。由于我们对哺乳动物系统中发生的各种细胞死亡过程的全面特征描述不够完整，尤其是对外源性干扰的反应，因此我们对细胞死亡的理解和控制能力受到了阻碍。我们在这里提出了一种解决这个问题的通用方法，我们称之为调节谱分析。调节谱由第二种细胞死亡调节剂在人细胞系中产生的致死化合物效力和功效的变化组成。我们发现具有相同作用机制的化合物具有相似的调节谱。此外，调节谱聚类揭示了基于基因表达谱单独聚类致死化合物时不明显的关系。最后，对化合物的调节谱分析正确预测了三种以前未被表征的化合物为微管破坏剂，将许多非特异性作用的化合物进行了分类，并确定了通过形态和生化上与先前建立的机制不同的机制导致细胞死亡的化合物。
