Abstract
The molecular mechanism underlying mitochondrial BAK activation during apoptosis remains highly controversial. Two seemingly conflicting models known as the agonism model and the de-repressor model have been proposed. In the agonism model, BAK requires activator BH3 only proteins to initiate a series of events that results in cell apoptosis. In the de-repressor model the antagonism of pro-survival BCL-2 family proteins alone is sufficient for BAK activation kinetics to promote apoptosis. To gain a better understanding of the kinetic implications of these models and reconcile these opposing, but highly evidence-based theories, we have formulated Markov chain models which capture the molecular mechanisms underlying both the agonism and de-repressor models. Our results indicate that both pure agonism and dissociation are mutually exclusive mechanisms capable of initiating mitochondrial apoptosis by BAK activation.
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
Preview
Unable to display preview. Download preview PDF.
References
Adams, J.M., Cory, S.: The bcl-2 protein family: arbiters of cell survival. Science 281, 1322–1326 (1998)
Letai, A., et al.: Pharmacological manipulation of bcl-2 family members to control cell death. J. Clin. Invet. 115, 2648–2655 (2005)
Green, D.R.: Apoptotic pathways: ten minutes to dead. Cell 121, 671–674 (2005)
Scorrano, L., Korsmeyer, S.J.: Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochemical and Biophysical Research Communications 304, 437–444 (2003)
Walensky, L.D., Pitter, K., Morash, J., Oh, K.J., Barbuto, S., et al.: A stapled BID BH3 helix directly binds and activates BAX. Mol. Cell 24(2), 199–210 (2006)
Cheng, E.H., et al.: Bcl-2, Bcl-Xl sequestered BH3 domain only molecules preventing bax and Bak mediated mitochondrial apoptosis. Mol. Cell 8, 705–711 (2001)
Grills, C., Crawford, N., Chacko, A., Johnston, P.G., O’Rourke, S.F.C., Fennell, D.A.: Dynamical systems analysis of mitochondrial BAK activativation kinetics predicts resistance to BH3 domains. PLoS ONE 3(8), 30–38 (2008)
Oltersdorf, T., Elmore, S.W., Shoemaker, A.R., Armstrong, R.C., Augeri, D.J., et al.: An inhibitor of bcl-2 family proteins induces regression of solid tumours. Nature 435(7042), 677–681 (2005)
Walensky, L.D., Kung, A.L., Escher, I., Malia, T.J., Barbuto, S., et al.: Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305(5689), 1466–1470 (2004)
Chen, C., Cui, J., Lu, H., Wang, R., Zhang, S., et al.: Modeling of the role of a bax-activation switch in the mitochondrial apoptosis decision. Biophys. Journal 92(12), 4304–4315 (2007)
Ghosh, S., Ghosh, P., Basu, K., Das, S., et al.: Modeling the stochastic dynamics of gene expression in single cells: A birth and death markov chain analysis. In: IEEE International Conference on Bioinformatics and Biomedicine (BIBM). IEEE, Los Alamitos (2007)
Asavathiratham, C., Roy, S., Lesieutre, B., Verghese, G.: The influence model. Control systems Magazine. IEEE 21(6), 52–64 (2001)
Gillespie, D.T.: Exact stochastic simulation of coupled chemical reactions. J. Phys. Chem. 81, 2340–2361 (1977)
Stirzaker, D.: Stochastic Processes and Models. Oxford University Press, Oxford (2005)
Rudden, R.: Cancer Biology, 3rd edn. Oxford University Press, Oxford (1995)
Centre for Cancer Research and Cell Biology, http://www.qub.ac.uk/research-centres/CentreforCancerResearchCellBiology
Willis, S.N., Fletcher, J.I., Kaufmann, T., van Delft, M.F., Chen, L., et al.: Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science 315(5813), 856–859 (2007)
Ruffolo, S.C., Shore, G.C.: BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization. J. Biol. Chem. 278(27), 25039–25045 (2003)
Falcke, M.: Deterministic and stochastic models of intracellular Ca2+ waves. New Journal of Physics 5, 96.1–96.28 (2003)
Kitano, H.: Computational systems biology. Nature 420, 206–210 (2002)
Gonze, D., Halloy, J., Goldbeter, A.: Deterministic versus stochastic models for circadian rhythms. J. Biol. Phys. 28, 637–653 (2002)
Srivastava, R., You, L., Summers, J., Yin, J.: Stochastic versus deterministic modeling of intracellular viral kinetics. J. Theor. Biol. 218, 309–321 (2002)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Grills, C., Fennell, D.A., Shearer, S.F.C. (2009). Markov Modelling of Mitochondrial BAK Activation Kinetics during Apoptosis. In: Watanabe, O., Zeugmann, T. (eds) Stochastic Algorithms: Foundations and Applications. SAGA 2009. Lecture Notes in Computer Science, vol 5792. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-04944-6_16
Download citation
DOI: https://doi.org/10.1007/978-3-642-04944-6_16
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-04943-9
Online ISBN: 978-3-642-04944-6
eBook Packages: Computer ScienceComputer Science (R0)