Computational analysis of the roles of ER-Golgi network in the cell cycle

Abstract

Background: ER-Golgi network plays an important role in the processing, sorting and transport of proteins, and it's also a site for many signaling pathways that regulate the cell cycle. Accumulating evidence suggests that, the stressed ER and malfunction of Golgi apparatus are associated with the pathogenesis of cancer and Alzheimer's disease (AD). Our previous work discovered and verified that altering the expression levels of target SNARE and GEF could modulate the size of Golgi apparatus. Moreover, Golgi's structure and size undergo dramatic changes during the development of several diseases. It is of importance to investigate the roles of ER-Golgi network in the cell cycle progression and some diseases. Results: In this work, we first develop a computational model to study the ER stress-induced and Golgi-related apoptosis-survival signaling pathways. Then, we propose and apply both asynchronous and synchronous model checking methods, which extend our previous verification technique, to automatically and formally analyze the ER-Golgi-regulated signaling pathways in the cell cycle progression through verifying some computation tree temporal logic formulas. Conclusions: The proposed asynchronous and synchronous verification technique has advantages for large network analysis and verification over traditional simulation methods. Using the model checking method, we verified several Alzheimer's disease and cancer-related properties, and also identified important proteins (NFΚB, ATF4, ASK1 and TRAF2) in the ER-Golgi network, which might be responsible for the pathogenesis of cancer and AD. Our studies indicate that targeting the ER stress-induced and Golgi-related pathways might serve as potent therapeutic targets for the treatment of cancer and Alzheimer's disease.