Programmed cell death (or apoptosis) has an essential biological function, enabling successful embryonic development, as well as maintenance of a healthy living organism [6]. Apoptosis is a physiological process which enables an organism to remove unwanted or damaged cells. Malfunctioning apoptotic pathways can lead to many diseases, including cancer and inflammatory or immune system related problems. A family of proteins called caspases are primarily responsible for execution of the apoptotic process: basically, in response to appropriate stimuli, initiator caspases (for instance, caspases 8, 9) activate effector caspases (for instance, caspases 3, 7), which will then cleave various cellular substrates to accomplish the cell death process [22].
Nuclear factor κB (NFκB) is a transcription factor for a large group of genes which are involved in several different pathways. For instance, NFκB activates its own inhibitor (IκB) [14] as well as groups of pro-apoptotic and anti-apoptotic genes [21]. Among the latter, NFκB activates transcription of a gene encoding for inhibitor of apoptosis protein (IAP). This protein in turn contributes to downregulate the activity of the caspase cascade which forms the core of the apoptotic pathway [6, 8].
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
R. Albert and H.G. Othmer. The topology of the regulatory interactions predicts the expression pattern of the drosophila segment polarity genes. J. Theor. Biol., 223:1–18, 2003.
G. Bernot, J.-P. Comet, A. Richard, and J. Guespin. Application of formal methods to biological regulatory networks: extending Thomas' asynchronous logical approach with temporal logic. J. Theor. Biol., 229:339–347, 2004.
R. Casey, H. de Jong, and J.L. Gouzé. Piecewise-linear models of genetic regulatory networks: equilibria and their stability. J. Math. Biol., 52:27–56, 2006.
M. Chaves, T. Eissing, and F. Allgöwer. Bistable biological systems: a characterization through local compact input-to-state stability. IEEE Trans. Automat. Control, 53:87–100, 2008.
M. Chaves, E.D. Sontag, and R. Albert. Methods of robustness analysis for boolean models of gene control networks. IEE Proc. Syst. Biol., 153:154–167, 2006.
N.N. Danial and S.J. Korsmeyer. Cell death: critical control points. Cell, 116:205–216, 2004.
H. de Jong, J.L. Gouzé, C. Hernandez, M. Page, T. Sari, and J. Geiselmann. Qualitative simulation of genetic regulatory networks using piecewise linear models. Bull. Math. Biol., 66:301–340, 2004.
T. Eissing, H. Conzelmann, E.D. Gilles, F. Allgöwer, E. Bullinger, and P. Scheurich. Bistability analysis of a caspase activation model for receptor-induced apoptosis. J. Biol. Chem., 279:36892–36897, 2004.
A. Fauré, A. Naldi, C. Chaouiya, and D. Thieffry. Dynamical analysis of a generic boolean model for the control of the mammalian cell cycle. Bioinformatics, 22(14):e124–e131, 2006.
C. Frelin, V. Imbert, V. Bottero, N. Gonthier, A.K. Samraj, K. Schulze-Osthoff, P. Auberger, G. Courtois, and J.F. Peyron. Inhibition of the NF-κB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-κB essential modulator NEMO. Cell Death Differ., 15:152–160, 2008.
T. Gedeon. Attractors in continuous-time switching networks. Communications on Pure and Applied Analysis, 2:187–209, 2003.
L. Glass. Classification of biological networks by their qualitative dynamics. J. Theor. Biol., 54:85–107, 1975.
L. Glass and S.A. Kauffman. The logical analysis of continuous, nonlinear biochemical control networks. J. Theor. Biol., 39:103–129, 1973.
A. Hoffmann, A. Levchenko, M.L. Scott, and D. Baltimore. The IκB-NFκB signaling module: temporal control and selective gene activation. Science, 298:1241–1245, 2002.
A.E.C. Ihekwaba, D. Broomhead, R. Grimley, N. Benson, and D.B. Kell. Sensitivity analysis of parameters controlling oscillatory signalling in the NF-κB pathway: the roles of IKK and IκBα. IEE Syst. Biol., 1:93–103, 2004.
G. Lahav, N. Rosenfeld, A. Sigal, N. Geva-Zatorsky, A.J. Levine, M. Elowitz, and U. Alon. Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat. Genetics, 36:147–150, 2004.
T. Lipniacki, P. Paszek, A.R. Brasier, B. Luxon, and M. Kimmel. Mathematical model of NFκB regulatory module. J. Theor. Biol., 228:195–215, 2004.
E.R. McDonald and W.S. El-Deiry. Suppression of caspase-8 and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth. Proc. Natl. Acad. Sci. USA, 101:6170–6175, 2004.
D.E. Nelson, A.E.C. Ihekwaba, M. Elliott, J.R. Johnson, C.A. Gibney, B.E. Foreman, G. Nelson, V. See, C.A. Horton, D.G. Spiller, S.W. Edwards, H.P. McDowell, J.F. Unitt, E. Sullivan, R. Grimley, N. Benson, D. Broomhead, D.B. Kell, and M.R.H. White. Oscillations in NF-κB signaling control the dynamics of gene expression. Science, 306:704–708, 2004.
E.L. O'Dea, D. Barken, R.Q. Peralta, K.T. Tran, S.L. Werner, J.D. Kearns, A. Levchenko, and A. Hoffmann. A homeostatic model of IκB metabolism to control constitutive NFκB activity. Mol. Syst. Biol., 3:111, 2007.
N.D. Perkins. Integrating cell-signalling pathways with NF-κB and IKK function. Nat. Rev. Mol. Cell Biol., 8:49–62, 2007.
M. Rehm, H. Düßmann, R.U. Jänicke, J.M. Tavaré, D. Kögel, and J.H.M. Prehn. Single-cell fluorescence resonance energy transfer analysis demonstrates that cas-pase activation during apoptosis is a rapid process. J. Biol. Chem., 277:24506–24514, 2002.
M. Schliemann. Modelling and experimental validation of TNFα induced pro- and antiapoptotic signalling. Master's thesis, University of Stuttgart, Germany, 2006.
M. Schliemann, T. Eissing, P. Scheurich, and E. Bullinger. Mathematical modelling of TNF-α induced apoptotic and anti-apoptotic signalling pathways in mammalian cells based on dynamic and quantitative experiments. In Proc. 2nd Int. Conf. Foundations Systems Biology in Engineering (FOSBE), Stuttgart, Germany, pages 213–218, 2007.
R. Thomas. Boolean formalization of genetic control circuits. J. Theor. Biol., 42:563–585, 1973.
R. Thomas, D. Thieffry, and M. Kaufman. Dynamical behaviour of biological regulatory networks - i. biological rule of feedback loops and practical use of the concept of the loop-characteristic state. Bull. Math. Biol., 57:247–276, 1995.
Acknowledgments
The authors thank Peter Scheurich and Monica Schliemann for their many interesting and fruitful discussions.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Birkhäuser Boston, a part of Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Chaves, M., Eissing, T., Allgöwer, F. (2009). Regulation of Apoptosis via the NFκB Pathway: Modeling and Analysis. In: Ganguly, N., Deutsch, A., Mukherjee, A. (eds) Dynamics On and Of Complex Networks. Modeling and Simulation in Science, Engineering and Technology. Birkhäuser Boston. https://doi.org/10.1007/978-0-8176-4751-3_2
Download citation
DOI: https://doi.org/10.1007/978-0-8176-4751-3_2
Published:
Publisher Name: Birkhäuser Boston
Print ISBN: 978-0-8176-4750-6
Online ISBN: 978-0-8176-4751-3
eBook Packages: Computer ScienceComputer Science (R0)