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Boolean network-based model of the Bcl-2 family mediated MOMP regulation.

Tokar T, Turcan Z, Ulicny J - Theor Biol Med Model (2013)

Bottom Line: Our results emphasize the role of the antiapoptotic protein Mcl-1 in the majority of these configurations.We demonstrate here the importance of the Bid and Bim for activation of effectors Bax and Bak, and the irreversibility of this activation.In spite of relative simplicity, the Boolean network-based model provides useful insight into main functioning logic of the Bcl-2 switch, consistent with experimental findings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biophysics, University of PJ Safarik, Jesenna 5, 04001 Kosice, Slovakia.

ABSTRACT

Background: Mitochondrial outer membrane permeabilization (MOMP) is one of the most important points in the majority of apoptotic signaling cascades and it is controlled by a network of interactions between the members of the Bcl-2 family.

Methods: To understand the role of individual members of this family within the MOMP regulation, we have constructed a Boolean network-based model of interactions between the Bcl-2 proteins.

Results: Computational simulations have revealed the existence of trapping states which, independently from the incoming stimuli, block the occurrence of MOMP. Our results emphasize the role of the antiapoptotic protein Mcl-1 in the majority of these configurations. We demonstrate here the importance of the Bid and Bim for activation of effectors Bax and Bak, and the irreversibility of this activation. The model further points to the antiapoptotic protein Bcl-w as a key factor preventing Bax activation.

Conclusions: In spite of relative simplicity, the Boolean network-based model provides useful insight into main functioning logic of the Bcl-2 switch, consistent with experimental findings.

Show MeSH
Multiple determination coefficients.R2 of the protein expressions calculated across the sets of unique expressions vectors causing the survival-to-MOMP transitions of given type (for more details see Appendix: A calculation of multiple determination coefficients).
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Figure 5: Multiple determination coefficients.R2 of the protein expressions calculated across the sets of unique expressions vectors causing the survival-to-MOMP transitions of given type (for more details see Appendix: A calculation of multiple determination coefficients).

Mentions: Figure 5 shows that regardless of the transition type, the necessary condition for the transition to MOMP is the expression of at least one of the activators (Bim, tBid). On the other hand it seems that the expression of the Mcl-1 is the most significant factor that prevents the MOMP. The statistical importance of the expression of activators and the absence of Mcl-1 is common for both T1 and T2 transitions. Nevertheless, the transitions of type T2 - the activation of both effectors, additionally requires the absence of Bcl-B expression. This finding is not unexpected as the Bcl-B is the only inhibitor of Bax that is not suppressed by any of the BH3-only proteins [44]. Furthermore, the model predicts that after the T1 transition, the subsequent downregulation of Bcl-B can cause the additional activation of Bax (the arrow pointing from the dark blue square to the red one, Figure 4).


Boolean network-based model of the Bcl-2 family mediated MOMP regulation.

Tokar T, Turcan Z, Ulicny J - Theor Biol Med Model (2013)

Multiple determination coefficients.R2 of the protein expressions calculated across the sets of unique expressions vectors causing the survival-to-MOMP transitions of given type (for more details see Appendix: A calculation of multiple determination coefficients).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716804&req=5

Figure 5: Multiple determination coefficients.R2 of the protein expressions calculated across the sets of unique expressions vectors causing the survival-to-MOMP transitions of given type (for more details see Appendix: A calculation of multiple determination coefficients).
Mentions: Figure 5 shows that regardless of the transition type, the necessary condition for the transition to MOMP is the expression of at least one of the activators (Bim, tBid). On the other hand it seems that the expression of the Mcl-1 is the most significant factor that prevents the MOMP. The statistical importance of the expression of activators and the absence of Mcl-1 is common for both T1 and T2 transitions. Nevertheless, the transitions of type T2 - the activation of both effectors, additionally requires the absence of Bcl-B expression. This finding is not unexpected as the Bcl-B is the only inhibitor of Bax that is not suppressed by any of the BH3-only proteins [44]. Furthermore, the model predicts that after the T1 transition, the subsequent downregulation of Bcl-B can cause the additional activation of Bax (the arrow pointing from the dark blue square to the red one, Figure 4).

Bottom Line: Our results emphasize the role of the antiapoptotic protein Mcl-1 in the majority of these configurations.We demonstrate here the importance of the Bid and Bim for activation of effectors Bax and Bak, and the irreversibility of this activation.In spite of relative simplicity, the Boolean network-based model provides useful insight into main functioning logic of the Bcl-2 switch, consistent with experimental findings.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biophysics, University of PJ Safarik, Jesenna 5, 04001 Kosice, Slovakia.

ABSTRACT

Background: Mitochondrial outer membrane permeabilization (MOMP) is one of the most important points in the majority of apoptotic signaling cascades and it is controlled by a network of interactions between the members of the Bcl-2 family.

Methods: To understand the role of individual members of this family within the MOMP regulation, we have constructed a Boolean network-based model of interactions between the Bcl-2 proteins.

Results: Computational simulations have revealed the existence of trapping states which, independently from the incoming stimuli, block the occurrence of MOMP. Our results emphasize the role of the antiapoptotic protein Mcl-1 in the majority of these configurations. We demonstrate here the importance of the Bid and Bim for activation of effectors Bax and Bak, and the irreversibility of this activation. The model further points to the antiapoptotic protein Bcl-w as a key factor preventing Bax activation.

Conclusions: In spite of relative simplicity, the Boolean network-based model provides useful insight into main functioning logic of the Bcl-2 switch, consistent with experimental findings.

Show MeSH