Systems biology of the mammalian Unfolded Protein Response

N.A.W. Riel, van, C.A. Tiemann, J.A.L. Jeneson, P.A.J. Hilbers

Research output: Chapter in Book/Report/Conference proceedingConference contributionAcademicpeer-review

Abstract

The Unfolded Protein Response (UPR) is a coordinated endoplasmic reticulum (ER) stress response program. UPR is initiated whenever protein folding in the ER is reduced and accumulation of malfolded proteins takes place. ER stress is associated with diseases, including type 2 diabetes. However, the dynamics and regulation of the underlying signal transduction network are largely unknown.A first mathematical model for the UPR in mammalian cells was proposed including the PERK and ATF6 pathways. The differential equation model was parameterized from Western blot time course data of phosphorylated PERK and cleaved ATF6 after exposing cells to dithiothreitol (DTT), which prevents the formation of disulfide bonds (DuRose et al. Mol. Biol. Cell, 17: 3095-3107, 2006).Sensitivity analysis showed that only a few kinetic parameters were critical for the predicted p-PERK and ATF6 time responses. Interestingly, variations in these parameters could move the UPR system towards different new steady-states. In certain cases the system returned to its original steady-state while the cells were still exposed to DTT (so-called perfect adaptation). In other cases, the stress sensors remained active. However, the difference in endpoints only emerged after 5 hours, when no experimental data was available. This model-based hypothesis is open for experimental testing.
Original languageEnglish
Title of host publicationExperimental biology 2008, San Diego California
PublisherFASEB
Pages1021.1-
Publication statusPublished - 2008
Eventconference; Experimental biology San Diego, United States, April 5-9 2008; 2008-04-05; 2008-04-09 -
Duration: 5 Apr 20089 Apr 2008

Publication series

NameFASEB Journal : The Journal of the Federation of American Societies for Experimental Biology
Volume22
ISSN (Print)0892-6638

Conference

Conferenceconference; Experimental biology San Diego, United States, April 5-9 2008; 2008-04-05; 2008-04-09
Period5/04/089/04/08
OtherExperimental biology San Diego, United States, April 5-9 2008

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