Computational Analysis of the Roles of ER-Golgi Network in the Cell Cycle — ASN Events
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Computational Analysis of the Roles of ER-Golgi Network in the Cell Cycle (#55)

Haijun Gong 1 , Lu Feng 1
  1. Saint Louis University, St. Louis, MO, United States

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 [1,2] suggests that, the stressed ER and malfunction of Golgi apparatus are associated with the pathogenesis of cancer and Alzheimer’s disease (AD). Moreover, our previous work [3,4]  discovered and verified that altering the expression levels of target SNARE and GEF could modulate the size of Golgi apparatus. While Golgi’s size changes dramatically 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 develop a computational model to systematically investigate the ER stress-induced and Golgi-related apoptosis-survival signaling pathways. Then, we propose and apply both Synchronous and Asynchronous Model Checking methods, which extend our previous verification technique [5,6], to automatically and formally analyze different signaling pathways regulated by ER-Golgi network and identify important regulatory components in the cell cycle progression through verifying some computation tree temporal logic (CTL) formulas. Our technique has advantages for large network verification (it can check up to 10100 possible states in minutes) over traditional methods.

Conclusion: The proposed Asynchronous and Synchronous Symbolic Model Checkers verified several temporal and dynamic properties related to cancer and Alzheimer's disease. We also identified some signaling components in the ER-Golgi network, including the NFκB, IKK, ATF4, ASK1 and TRAF2, which might be key players in 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 of cancer and Alzheimer's disease, and the crosstalk among different signaling pathways may be responsible for the pathogenesis of AD and cancer even if some pathways are blocked by certain single-gene targeted therapies.

  1. Kadowaki H, Nishitoh H: Signaling pathways from the Endoplasmic Reticulum and their roles in disease. Genes 2013
  2. Wlodkowic D, Skommer J, et al.: ER-Golgi network - a future target for anti-cancer therapy. Leuk Res 2009.
  3. Gong H, Sengupta H, Linstedt A, Schwartz R: Simulated De Novo Assembly of Golgi Compartments by Selective Cargo Capture during Vesicle Budding and Targeted Vesicle Fusion. Biophysical Journal 2008
  4. Gong H, Guo Y, Linstedt A, Schwartz R: Discrete, continuous, and stochastic models of protein sorting in the Golgi apparatus. Physical Review E 2010
  5. Gong H, Zuliani P, Komuravelli A, Faeder JR, Clarke EM: Analysis and Verification of the HMGB1 Signaling Pathway. BMC Bioinformatics 2010
  6. Gong H: Analysis of intercellular signal transduction in the tumor microenvironment. BMC Systems Biology 2013