A systematic approach to decipher crosstalk in the p53 signaling pathway using single cell dynamics

摘要

Cells can respond to external and internal inputs by transducing information to the nucleus where transcription factors initiate corresponding cellular responses. Cellular signaling is mediated by several pathways; molecular networks that can interact with each other, which alters signal processing and modulates cellular responses. As deregulated signaling can lead to the development of tumors it is important to understand not only how signaling pathways function but also the contribution of their interaction on the signaling dynamics. Here, we analyzed the interplay of the IKK/ NF- B and p53 pathway, which are both critical for the cellular response to DNA damage and have been implicated in tumor development. To systematically identify interaction points between both pathways, we perturbed IKK/ NF- B signaling and tracked the changes in the response of p53 to DNA damage. Using computational methods, we show that several reactions in the p53 pathway are simultaneously affected by NF- B signaling and that this combined action is necessary to explain altered behaviour of the p53 pathway. Hence, our results provide new insights into the interplay between the NF- B and p53 pathway and help to gain a more comprehensive understanding of the crosstalk.