Cohen A A, Geva-Zatorsky N, Eden E, Frenkel-Morgenstern M, Issaeva I, Sigal A, Milo R, Cohen-Saidon C, Liron Y, Kam Z, Cohen L, Danon T, Perzov N, Alon U
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Science. 2008 Dec 5;322(5907):1511-6. doi: 10.1126/science.1160165. Epub 2008 Nov 20.
Why do seemingly identical cells respond differently to a drug? To address this, we studied the dynamics and variability of the protein response of human cancer cells to a chemotherapy drug, camptothecin. We present a dynamic-proteomics approach that measures the levels and locations of nearly 1000 different endogenously tagged proteins in individual living cells at high temporal resolution. All cells show rapid translocation of proteins specific to the drug mechanism, including the drug target (topoisomerase-1), and slower, wide-ranging temporal waves of protein degradation and accumulation. However, the cells differ in the behavior of a subset of proteins. We identify proteins whose dynamics differ widely between cells, in a way that corresponds to the outcomes-cell death or survival. This opens the way to understanding molecular responses to drugs in individual cells.
为什么看似相同的细胞对药物的反应却不同？为了解决这个问题，我们研究了人类癌细胞对化疗药物喜树碱的蛋白质反应的动力学和变异性。我们提出了一种动态蛋白质组学方法，该方法能够在高时间分辨率下测量单个活细胞中近1000种不同的内源性标记蛋白质的水平和位置。所有细胞都显示出特定于药物作用机制的蛋白质的快速易位，包括药物靶点（拓扑异构酶-1），以及较慢的、广泛的蛋白质降解和积累的时间波动。然而，细胞在一部分蛋白质的行为上存在差异。我们鉴定出了那些在细胞间动力学差异很大的蛋白质，其差异方式与细胞死亡或存活的结果相对应。这为理解单个细胞对药物的分子反应开辟了道路。
