Modelling of the mitochondrial apoptosis network

In this paper, we performed an experimental observation-based computer simulation of the regulatory network of mitochondrial apoptosis. By modelling we obtained dynamical understandings of various apoptosis-related proteins, including cytochrome c (cyt c) release and caspase activation. Through parameter analysis, we examined the role of Bcl-2 family proteins and the natural inhibitors of apoptosis in the regulatory network of apoptosis. Furthermore, the effects of several amplified loops in the network were found to enhance caspase activation and make the decision of apoptosis switch like. Consistent with most available experimental evidences, our results yield insights into the complex regulatory mechanism of mitochondrial apoptosis.

[1]  S. Korsmeyer,et al.  Cell Death Critical Control Points , 2004, Cell.

[2]  A. Passaniti,et al.  Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity. , 2001, Carcinogenesis.

[3]  E. Finkel The Mitochondrion: Is It Central to Apoptosis? , 2001, Science.

[4]  P. Vandenabeele,et al.  The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet , 2002, Cell Death and Differentiation.

[5]  D. Green,et al.  The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis , 1997, Science.

[6]  Debaprasad Mandal,et al.  Black tea protects immunocytes from tumor-induced apoptosis by changing Bcl-2/Bax ratio. , 2004, Cancer letters.

[7]  G. Shore,et al.  BCL-2 Selectively Interacts with the BID-induced Open Conformer of BAK, Inhibiting BAK Auto-oligomerization* , 2003, Journal of Biological Chemistry.

[8]  G. Salvesen,et al.  Mechanisms of caspase activation. , 2003, Current opinion in cell biology.

[9]  S. Srinivasula,et al.  Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. , 1998, Molecular cell.

[10]  N. Demaurex,et al.  Apoptosis--the Calcium Connection , 2003, Science.

[11]  A. Letai Pharmacological manipulation of Bcl-2 family members to control cell death. , 2005, The Journal of clinical investigation.

[12]  G. Hajnóczky,et al.  Apoptosis driven by IP3‐linked mitochondrial calcium signals , 1999, The EMBO journal.

[13]  I. McNeish,et al.  Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway. , 2003, Experimental cell research.

[14]  Xiao-Ming Yin,et al.  Inhibition of Bid-induced Apoptosis by Bcl-2 , 2003, The Journal of Biological Chemistry.

[15]  C. Leeuwenburgh,et al.  Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. , 2002, Cancer research.

[16]  R. Huber,et al.  Proteinase-protein inhibitor interaction. , 1991, Biomedica biochimica acta.

[17]  T. Kuwana,et al.  Bcl-2-family proteins and the role of mitochondria in apoptosis. , 2003, Current opinion in cell biology.

[18]  C. Machamer,et al.  Death from within: apoptosis and the secretory pathway. , 2003, Current opinion in cell biology.

[19]  T. Fan,et al.  Mitochondrion and Apoptosis. , 2001, Sheng wu hua xue yu sheng wu wu li xue bao Acta biochimica et biophysica Sinica.

[20]  J. Nielsen,et al.  Mathematical modelling of metabolism. , 2000, Current opinion in biotechnology.

[21]  M. Fussenegger,et al.  A mathematical model of caspase function in apoptosis , 2000, Nature Biotechnology.

[22]  Seamus J. Martin,et al.  Apoptosis‐associated release of Smac/DIABLO from mitochondria requires active caspases and is blocked by Bcl‐2 , 2001, The EMBO journal.

[23]  M. Hengartner The biochemistry of apoptosis , 2000, Nature.

[24]  D. Green,et al.  Pharmacological manipulation of cell death: clinical applications in sight? , 2005, The Journal of clinical investigation.

[25]  V. Notario,et al.  Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity , 2005, Oncogene.

[26]  J. Weinberg,et al.  Apoptosis: definition, mechanisms, and relevance to disease. , 1999, The American journal of medicine.

[27]  D. Green,et al.  Bax-induced Caspase Activation and Apoptosis via Cytochromec Release from Mitochondria Is Inhibitable by Bcl-xL* , 1999, The Journal of Biological Chemistry.

[28]  R. Korneluk,et al.  XIAP: Apoptotic brake and promising therapeutic target , 2001, Apoptosis.

[29]  J. Roth,et al.  Adenovirus-mediated Bax overexpression for the induction of therapeutic apoptosis in prostate cancer. , 2001, Cancer research.

[30]  T. Kuwana,et al.  Apoptosis Induction by Caspase-8 Is Amplified through the Mitochondrial Release of Cytochrome c * , 1998, The Journal of Biological Chemistry.

[31]  L. Owen-Schaub,et al.  Adenoviral Bid Overexpression Induces Caspase-dependent Cleavage of Truncated Bid and p53-independent Apoptosis in Human Non-small Cell Lung Cancers* , 2003, Journal of Biological Chemistry.