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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
Relationships between the nodes of the model. The red squares represent the negative relationships of the inputs toward the related nodes. Negative relationship corresponds to mutual binding and inhibition between two members of the Bcl-2 family (see Table 1). The blue squares represent the positive relationships of the inputs toward the related nodes. Positive relation corresponds to activation of the effectors Bax/Bak by certain BH3-only proteins - activators (tBid, Bim) [40,41].
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Figure 1: Relationships between the nodes of the model. The red squares represent the negative relationships of the inputs toward the related nodes. Negative relationship corresponds to mutual binding and inhibition between two members of the Bcl-2 family (see Table 1). The blue squares represent the positive relationships of the inputs toward the related nodes. Positive relation corresponds to activation of the effectors Bax/Bak by certain BH3-only proteins - activators (tBid, Bim) [40,41].

Mentions: Here, rij specifies the relation of the j-th node to i-th node, and it may have three possible values: rij=1 if j-th node activates i-th node, rij=−1 if j-th node inhibits i-th node and rij=0, if nodes j and i are not connected (the relationships between nodes are depicted in the Figure 1). The value of ei defines the expression of the protein represented by the i-th node (see following section).


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

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

Relationships between the nodes of the model. The red squares represent the negative relationships of the inputs toward the related nodes. Negative relationship corresponds to mutual binding and inhibition between two members of the Bcl-2 family (see Table 1). The blue squares represent the positive relationships of the inputs toward the related nodes. Positive relation corresponds to activation of the effectors Bax/Bak by certain BH3-only proteins - activators (tBid, Bim) [40,41].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Relationships between the nodes of the model. The red squares represent the negative relationships of the inputs toward the related nodes. Negative relationship corresponds to mutual binding and inhibition between two members of the Bcl-2 family (see Table 1). The blue squares represent the positive relationships of the inputs toward the related nodes. Positive relation corresponds to activation of the effectors Bax/Bak by certain BH3-only proteins - activators (tBid, Bim) [40,41].
Mentions: Here, rij specifies the relation of the j-th node to i-th node, and it may have three possible values: rij=1 if j-th node activates i-th node, rij=−1 if j-th node inhibits i-th node and rij=0, if nodes j and i are not connected (the relationships between nodes are depicted in the Figure 1). The value of ei defines the expression of the protein represented by the i-th node (see following section).

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