Small-Scale Modeling Approach and Circuit Wiring of the Unfolded Protein Response in Mammalian Cells

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 680)


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.


Endoplasmic reticulum stress Unfolding protein response Signaling pathways PERK ATF6 IRE1 


  1. 1.
    Chen K, Calzone L, Csikasz-Nagy A, et al (2004) Integrative analysis of cell cycle control in budding yeast. Molecular Biology of the Cell 15:3841–3862PubMedCrossRefGoogle Scholar
  2. 2.
    Guido N, Wang X, Adalsteinsson D, McMillen D, et al (2006) A bottom-up approach to gene regulation. Nature 439:856–860PubMedCrossRefGoogle Scholar
  3. 3.
    Kim H, Shay T, O’Shea E, Regev A (2009) Transcriptional regulatory circuits: Predicting numbers from alphabets. Science 325:429–432PubMedCrossRefGoogle Scholar
  4. 4.
    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 18:3066–3077PubMedCrossRefGoogle Scholar
  5. 5.
    Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews. Molecular Cell Biology 8:519–529PubMedCrossRefGoogle Scholar
  6. 6.
    Rutkowski T (2009) Personal communicationGoogle Scholar
  7. 7.
    Rutkowski T, Kaufman R (2004) A trip to the ER: coping with stress. Trends in Cell Biology 14(1):20–28PubMedCrossRefGoogle Scholar
  8. 8.
    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):469–476PubMedCrossRefGoogle Scholar
  9. 9.
    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):2024–2041CrossRefGoogle Scholar
  10. 10.
    Shen X, Zhang K, Kaufman R (2004) The unfolded protein response – A stress signaling pathway of the endoplasmic reticulum. Journal of Chemical Neuroanatomy 28:79–92PubMedCrossRefGoogle Scholar
  11. 11.
    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):20280–20285PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of MathematicsUniversity of IowaIowa CityUSA

Personalised recommendations