PubMed · 11749383
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Z Chen, T B Gibson, F Robinson, L Silvestro, G Pearson, B Xu, A Wright, C Vanderbilt, M H Cobb. 2001. MAP kinases.. https://doi.org/10.1021/cr000241p
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Sensitivity analysis has been widely used in the studies of complicated chemical reaction and biological networks, for example, in combustion studies and metabolic control analysis of pathways. In the latter cases, the responses of system properties at steady states with respect to changes of parameters, such as initial concentrations and rate constants, are often expressed as sensitivities. Besides steady-state sensitivities, time-dependent sensitivities should be useful; however, the explicit use of them in analyzing complicated biological systems has so far been limited. Using the coupled mitogen activated protein kinase (MAPK)-phophatidylinoisitol 3'-kinase (PI3K) system of the Ras pathways, known to be involved in about 30% of human cancers, as an example, we show that time-dependent sensitivities are useful for the studies of complex biological systems. They provide, for example, the following information: (a) multiple time scales existing in a complex system involving cross-talks and feedback loops; (b) the signs and strengths of responses to perturbations (as system complication increases, the signs of global responses are not always easily determined; for example, response may change sign more than once as time evolves); (c) beyond concentration dynamics, sensitivities revealing further details about the intricate dynamics and the effects of the cross-talks; (d) ranking of vulnerability of nodes of a biological network using integrated sensitivity-a first step toward the identification of drug targets; (e) reduced sensitivity serving as a measure of the stability or robustness of pathways. Our results indicate that the role of the PI3K branch in the coupled pathways is to enhance the robustness of the MAPK pathway. More importantly, they demonstrate that time-dependent sensitivity analysis can be a valuable tool in system biology.
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Oxidative stress that generates the reactive oxygen species (ROS) is one of the major causes of DNA damage and mutations. The "DNA damage checkpoint" that arrests cell cycle and repairs damaged DNA has been a focus of recent studies, and the genetically amenable model systems provided by yeasts have been playing a leading role in the eukaryotic checkpoint research. However, means to eliminate ROS are likely to be as important as the DNA repair mechanisms in order to suppress mutations in the chromosomal DNA, and yeasts also serve as excellent models to understand how eukaryotes combat oxidative stress. In this article, we present an overview of the signaling pathways that sense oxidative stress and induce expression of various anti-oxidant genes in the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and the pathogenic yeast Candida albicans. Three conserved signaling modules have been identified in the oxidative stress response of these diverse yeast species: the stress-responsive MAP kinase cascade, the multistep phosphorelay and the AP-1-like transcription factor. The structure and function of these signaling modules are discussed.