Lyapunov exponents and phase diagrams reveal multi-factorial control over TRAIL-induced apoptosis

被引:46
作者
Aldridge, Bree B. [1 ,2 ]
Gaudet, Suzanne [1 ]
Lauffenburger, Douglas A. [2 ]
Sorger, Peter K. [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Dept Syst Biol, Ctr Cell Decis Proc, Boston, MA 02115 USA
[2] MIT, Dept Biol Engn, Ctr Cell Decis Proc, Cambridge, MA 02139 USA
关键词
apoptosis; caspases; dynamical systems analysis; kinetic modeling; XIAP; X-LINKED INHIBITOR; RECEPTOR-INDUCED APOPTOSIS; CD95; TYPE-I; CASPASE ACTIVATION; XIAP INHIBITION; PROTEIN XIAP; CELL-DEATH; INACTIVATION; DEGRADATION; SMAC/DIABLO;
D O I
10.1038/msb.2011.85
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Receptor-mediated apoptosis proceeds via two pathways: one requiring only a cascade of initiator and effector caspases (type I behavior) and the second requiring an initiator-effector caspase cascade and mitochondrial outer membrane permeabilization (type II behavior). Here, we investigate factors controlling type I versus II phenotypes by performing Lyapunov exponent analysis of an ODE-based model of cell death. The resulting phase diagrams predict that the ratio of XIAP to pro-caspase-3 concentrations plays a key regulatory role: type I behavior predominates when the ratio is low and type II behavior when the ratio is high. Cell-to-cell variability in phenotype is observed when the ratio is close to the type I versus II boundary. By positioning multiple tumor cell lines on the phase diagram we confirm these predictions. We also extend phase space analysis to mutations affecting the rate of caspase-3 ubiquitylation by XIAP, predicting and showing that such mutations abolish all-or-none control over activation of effector caspases. Thus, phase diagrams derived from Lyapunov exponent analysis represent a means to study multi-factorial control over a complex biochemical pathway. Molecular Systems Biology 7: 553; published online 22 November 2011; doi:10.1038/msb.2011.85
引用
收藏
页数:21
相关论文
共 55 条
[21]   Analysis of CD95 threshold signaling - Triggering of CD95 (FAS/APO-1) at low concentrations primarily results in survival signaling [J].
Lavrik, Inna N. ;
Golks, Alexander ;
Riess, Dagmar ;
Bentele, Martin ;
Eils, Roland ;
Krammer, Peter H. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (18) :13664-13671
[22]   Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax [J].
LeBlanc, H ;
Lawrence, D ;
Varfolomeev, E ;
Totpal, K ;
Morlan, J ;
Schow, P ;
Fong, S ;
Schwall, R ;
Sinicropi, D ;
Ashkenazi, A .
NATURE MEDICINE, 2002, 8 (03) :274-281
[23]   The role of receptor internalization in CD95 signaling [J].
Lee, KH ;
Feig, C ;
Tchikov, V ;
Schickel, R ;
Hallas, C ;
Schütze, S ;
Peter, ME ;
Chan, AC .
EMBO JOURNAL, 2006, 25 (05) :1009-1023
[24]   Fundamental limits on the suppression of molecular fluctuations [J].
Lestas, Ioannis ;
Vinnicombe, Glenn ;
Paulsson, Johan .
NATURE, 2010, 467 (7312) :174-178
[25]   Diagnosing and exploiting cancer's addiction to blocks in apoptosis [J].
Letai, Anthony G. .
NATURE REVIEWS CANCER, 2008, 8 (02) :121-132
[26]   TRAIL treatment provokes mutations in surviving cells [J].
Lovric, M. M. ;
Hawkins, C. J. .
ONCOGENE, 2010, 29 (36) :5048-5060
[27]   Smac/DIABLO release from mitochondria and XIAP inhibition are essential to limit clonogenicity of Type I tumor cells after TRAIL receptor stimulation [J].
Maas, C. ;
Verbrugge, I. ;
de Vries, E. ;
Savich, G. ;
de Kooij, L. W. van ;
Tait, S. W. G. ;
Borst, J. .
CELL DEATH AND DIFFERENTIATION, 2010, 17 (10) :1613-1623
[28]   Proteasome-mediated degradation of Smac during apoptosis:: XIAP promotes Smac ubiquitination in vitro [J].
MacFarlane, M ;
Merrison, W ;
Bratton, SB ;
Cohen, GM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (39) :36611-36616
[29]   Is TRAIL the holy grail of cancer therapy? [J].
Newsom-Davis, Thomas ;
Prieske, Silvia ;
Walczak, Henning .
APOPTOSIS, 2009, 14 (04) :607-623
[30]   Inducible Dimerization and Inducible Cleavage Reveal a Requirement for Both Processes in Caspase-8 Activation [J].
Oberst, Andrew ;
Pop, Cristina ;
Tremblay, Alexandre G. ;
Blais, Veronique ;
Denault, Jean-Bernard ;
Salvesen, Guy S. ;
Green, Douglas R. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (22) :16632-16642