2 research outputs found
Computational study of the mechanism of Bcl-2 apoptotic switch
Programmed cell death - apoptosis is one of the most studied biological
phenomenon of recent years. Apoptotic regulatory network contains several
significant control points, including probably the most important one - Bcl--2
apoptotic switch. There are two proposed hypotheses regarding its internal
working - the indirect activation and direct activation models. Since these
hypotheses form extreme poles of full continuum of intermediate models, we have
constructed more general model with these two models as extreme cases.
By studying relationship between model parameters and steady-state response
ultrasensitivity we have found optimal interaction pattern which reproduces
behavior of Bcl-2 apoptotic switch. Our results show, that stimulus-response
ultrasensitivity is negatively related to spontaneous activation of Bcl-2
effectors - subgroup of Bcl-2 proteins. We found that ultrasensitivity requires
effector's activation, mediated by another subgroup of Bcl-2 proteins -
activators. We have shown that the auto-activation of effectors forms
ultrasensitivity enhancing feedback loop, only if mediated by monomers, but not
by oligomers. Robustness analysis revealed that interaction pattern proposed by
direct activation hypothesis is able to conserve stimulus-response dependence
and preserve ultrasensitivity despite large changes of its internal parameters.
This ability is strongly reduced as for the intermediate to indirect side of
the models.
Computer simulation of the more general model presented here suggest, that
stimulus-response ultrasensitivity is an emergent property of the direct
activation model, that cannot originate within model of indirect activation.
Introduction of indirect-model-specific interactions does not provide better
explanation of Bcl-2 functioning compared to direct model