Two Independent Positive Feedbacks and Bistability in the Bcl-2 Apoptotic Switch

Abstract

BackgroundThe complex interplay between B-cell lymphoma 2 (Bcl-2) family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the ‘Direct Activation Model’ as a better explanation for experimental observations. In this paper, we continue to extend this model by adding interactions according to updating experimental findings.Methodology/Principal FindingsThrough mathematical simulation we found bistability, a kind of switch, can arise from a positive (double negative) feedback in the Bcl-2 interaction network established by anti-apoptotic group of Bcl-2 family proteins. Moreover, Bax/Bak auto-activation as an independent positive feedback can enforce the bistability, and make it more robust to parameter variations. By ensemble stochastic modeling, we also elucidated how intrinsic noise can change ultrasensitive switches into gradual responses. Our modeling result agrees well with recent experimental data where bimodal Bax activation distributions in cell population were found.Conclusions/SignificanceAlong with the growing experimental evidences, our studies successfully elucidate the switch mechanism embedded in the Bcl-2 interaction network and provide insights into pharmacological manipulation of Bcl-2 apoptotic switch as further cancer therapies.

Systems biology and the integration of mechanistic explanation and mathematical explanation

“…Explaining stability under a range of variation in parameter values again requires mathematical modeling. The Eissing et al (2004) study discussed does such an analysis (for more details see Eissing et al, 2005), as do other systems biological studies of bistability in the context of apoptosis (Bagci et al, 2006;Cui et al, 2008;Ho & Harrington, 2010). The bistability modeling by Legewie et al (2006) includes both the extrinsic (death receptor initiated) and intrinsic (mitochondrion initiated) apoptosis pathway.…”

Building biological memory by linking positive feedback loops

“…22). The Bcl2 apoptotic switch provides an additional example, where two independent positive feedback loops participate in producing bistability (23).…”

“…Two additional hypotheses for the presence of multiple positive feedback loops are that different timescales of the loops provide for resistance to noise under certain circumstances (22) or make bistability robust to certain parameter variations (23). Ferrell has noted that coherent linkage of a positive feedback loop and a double-negative feedback loop in a system of opposing enzymes could result in bistability over a wide range of conditions (10).…”

The Steady States and Dynamics of Urokinase-Mediated Plasmin Activation

“…Parameters in a biological system are never known with high confidence, and there are often differences in the same phenomenon between different in vivo models. We did a robustness analysis for the presence of bistable behavior in this system over a broad range of all the parameters (20% on either side of reference) [9] and noted the number of parameter sets which are capable of being bistable using a hysteretic technique similar to [25]. Briefly, each parameter was varied +/-20% of its reference value, keeping the other parameters constant, and each was checked for the presence of hysteretic behavior, i.e.…”

“…A common bifurcation in biology is bistability, or existence of two steady states, which transforms a gradual input change into an "all-or-none" switch. Bistability can explain the switch-like nature of apoptosis [6][7][8][9] and cell-cycle progression [10][11][12][13].…”