很多信号通道的基本构成部分在一个生物体中对大多数细胞来说都是相同的。那么为什么不同细胞类型以不同方式对同样的原始刺激进行反应？现在，研究人员用一种新颖的系统模拟方法来研究这一问题，重点是两个截然不同的细胞系。结果显示，细胞特性的主要决定因子是上游信号事件的类型、强度和组合。这些细胞类型特异性信号被相同的促动因子所整合，产生细胞类型特异性结果。揭开细胞特性之谜对于了解胚胎发育、生物恒定性及定向疗法的副作用等都很重要。 原始出处: Nature448, 604-608 (2 August 2007) |doi:10.1038/nature06001; Received 10 April 2007; Accepted 7 June 2007; Published online 18 July 2007 Common effector processing mediates cell-specific responses to stimuli Kathryn Miller-Jensen1,2,5, Kevin A. Janes1,3,5, Joan S. Brugge3 & Douglas A. Lauffenburger1,2,4 1. Center for Cell Decision Processes, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA 2. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA 3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA 4. Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA 5. These authors contributed equally to this work. Correspondence to: Douglas A. Lauffenburger1,2,4 Correspondence and requests for materials should be addressed to D.A.L. (Email: lauffen@mit.edu). Abstract The fundamental components of many signalling pathways are common to all cells1, 2, 3. However, stimulating or perturbing the intracellular network often causes distinct phenotypes that are specific to a given cell type4, 5. This 'cell specificity' presents a challenge in understanding how intracellular networks regulate cell behaviour and an obstacle to developing drugs that treat signalling dysfunctions6, 7. Here we apply a systems-modelling approach8 to investigate how cell-specific signalling events are integrated through effector proteins to cause cell-specific outcomes. We focus on the synergy between tumour necrosis factor and an adenoviral vector as a therapeutically relevant stimulus that induces cell-specific responses9, 10, 11. By constructing models that estimate how kinase-signalling events are processed into phenotypes through effector substrates, we find that accurate predictions of cell specificity are possible when different cell types share a common 'effector-processing' mechanism. Partial-least-squares regression models based on common effector processing accurately predict cell-specific apoptosis, chemokine release, gene induction, and drug sensitivity across divergent epithelial cell lines. We conclude that cell specificity originates from the differential activation of kinases and other upstream transducers, which together enable different cell types to use common effectors to generate diverse outcomes. The common processing of network signals by downstream effectors points towards an important cell biological principle, which can be applied to the understanding of cell-specific responses to targeted drug therapies6. 摘自《生物谷》 |
