Department of Information and Computer Science, School of Science, Aalto University, Aalto, Finland.
IEEE/ACM Trans Comput Biol Bioinform. 2012 Sep-Oct;9(5):1326-37. doi: 10.1109/TCBB.2012.66.
The heat shock response is a well-conserved defence mechanism against the accumulation of misfolded proteins due to prolonged elevated heat. The cell responds to heat shock by raising the levels of heat shock proteins (hsp), which are responsible for chaperoning protein refolding. The synthesis of hsp is highly regulated at the transcription level by specific heat shock (transcription) factors (hsf). One of the regulation mechanisms is the phosphorylation of hsf's. Experimental evidence shows a connection between the hyper-phosphorylation of hsfs and the transactivation of the hsp-encoding genes. In this paper, we incorporate several (de)phosphorylation pathways into an existing well-validated computational model of the heat shock response. We analyze the quantitative control of each of these pathways over the entire process. For each of these pathways we create detailed computational models which we subject to parameter estimation in order to fit them to existing experimental data. In particular, we find conclusive evidence supporting only one of the analyzed pathways. Also, we corroborate our results with a set of computational models of a more reduced size.
热休克反应是一种经过良好保守的防御机制，可防止由于长时间高温导致的错误折叠蛋白的积累。细胞通过提高热休克蛋白（hsp）的水平来应对热休克，热休克蛋白负责协助蛋白质重折叠。hsp 的合成在转录水平受到特定热休克（转录）因子（hsf）的高度调控。一种调节机制是 hsf 的磷酸化。实验证据表明，hsfs 的过度磷酸化与 hsp 编码基因的转录激活之间存在联系。在本文中，我们将几种（去）磷酸化途径纳入到现有的热休克反应的经过良好验证的计算模型中。我们分析了这些途径中的每一种对整个过程的定量控制。对于每一种途径，我们都创建了详细的计算模型，并对其进行参数估计，以使其与现有的实验数据相匹配。特别是，我们找到了支持仅有一种分析途径的确凿证据。此外，我们还使用一组规模较小的计算模型来证实我们的结果。
