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

TL;DR

This paper develops a boolean network model of Bcl-2 family interactions to understand MOMP regulation, revealing potential malignant states and key protein roles in apoptosis control.

Contribution

The study introduces a novel boolean network model of Bcl-2 family interactions, highlighting configurations that block MOMP and emphasizing the roles of Mcl-1, Bid, Bim, and Bcl-w.

Findings

Identified configurations blocking MOMP independently of stimuli

Highlighted the importance of Mcl-1 in these configurations

Showed the irreversibility of Bax and Bak activation

Abstract

Mitochondrial outer membrane permeabilization (MOMP) is one of the most important points, in majority of apoptotic signaling cascades. Decision mechanism controlling whether the MOMP occurs or not, is formed by an interplay between members of the Bcl-2 family. To understand the role of individual members of this family within the MOMP regulation, we constructed a boolean network-based mathematical model of interactions between the Bcl-2 proteins. Results of computational simulations reveal the existence of the potentially malign configurations of activities of the Bcl-2 proteins, blocking the occurrence of MOMP, independently of the incoming stimuli. Our results suggest role of the antiapoptotic protein Mcl-1 in relation to these configurations. We demonstrate here, the importance of the Bid and Bim according to activation of effectors Bax and Bak, and the irreversibility of this activation. The model further shows the distinct requirements for effectors activation, where the antiapoptic protein Bcl-w is seemingly a key factor preventing the Bax activation. We believe that this work may help to describe the functioning of the Bcl-2 regulation of MOMP better, and hopefully provide some contribution regarding the anti-cancer drug development research.