Two independent positive feedbacks and bistability in the Bcl-2 apoptotic switch.
BACKGROUND
The 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.


RESULTS
Through 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
Along 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.
Cui
Jun
J
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.
Chen
Chun
C
Lu
Haizhu
H
Sun
Tingzhe
T
Shen
Pingping
P
D017209:Apoptosis; D008962:Models, Theoretical; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology*
D019253:Proto-Oncogene Proteins c-bcl-2