Abstract
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a mechanism whose primary functions are to sense any perturbation in the protein-folding capacity of the cell, and correct the situation to restore homeostasis. This cellular mechanism is called the unfolded protein response (UPR). We propose a biologically plausible computational model for the UPR under ER stress in mammalian cells. The model accounts for the signaling pathways of PERK, ATF6, and IRE1 and has the advantage of simulating the dynamical (timecourse) changes in the relative concentrations of proteins without any a priori steady-state assumption. Several types of ER stress can be assumed as input, including long-term (eventually periodic) stress. Moreover, the model allows for outcomes ranging from cell survival to cell apoptosis.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Chen K, Calzone L, Csikasz-Nagy A, et al (2004) Integrative analysis of cell cycle control in budding yeast. Molecular Biology of the Cell 15:3841–3862
Guido N, Wang X, Adalsteinsson D, McMillen D, et al (2006) A bottom-up approach to gene regulation. Nature 439:856–860
Kim H, Shay T, O’Shea E, Regev A (2009) Transcriptional regulatory circuits: Predicting numbers from alphabets. Science 325:429–432
Marciniak S, Yun C, Oyadomari S, et al (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes and Development 18:3066–3077
Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews. Molecular Cell Biology 8:519–529
Rutkowski T (2009) Personal communication
Rutkowski T, Kaufman R (2004) A trip to the ER: coping with stress. Trends in Cell Biology 14(1):20–28
Rutkowski T, Kaufman R (2007) That which does not kill me makes me stronger: Adapting to chronic ER stress. Trends in Biochemical Sciences 32(10):469–476
Rutkowski T, Arnold S, Miller C, et al (2006) Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLOS Biology 4(11):2024–2041
Shen X, Zhang K, Kaufman R (2004) The unfolded protein response – A stress signaling pathway of the endoplasmic reticulum. Journal of Chemical Neuroanatomy 28:79–92
Trusina A, Papa F, Tang C (2008) Rationalizing translation attenuation in the network architecture of the unfolded protein response. Proceedings of the National Academy of Sciences of the United States of America 105(51):20280–20285
Acknowledgments
We thank Tom Rutkowski for helpful discussions on the problem of unfolded protein response, and for his feedback and critiques during the development of the model.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this paper
Cite this paper
Curtu, R., Diedrichs, D. (2010). Small-Scale Modeling Approach and Circuit Wiring of the Unfolded Protein Response in Mammalian Cells. In: Arabnia, H. (eds) Advances in Computational Biology. Advances in Experimental Medicine and Biology, vol 680. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5913-3_30
Download citation
DOI: https://doi.org/10.1007/978-1-4419-5913-3_30
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-5912-6
Online ISBN: 978-1-4419-5913-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)