Computational Analysis of Dynamical Responses to the Intrinsic Pathway of Programmed Cell Death

Abstract

Multicellular organisms shape development and remove aberrant cells by programmed cell death ("apoptosis"). Because defective cell death (too little or too much) is implicated in various diseases (like cancer and autoimmunity), understanding how apoptosis is regulated is an important goal of molecular cell biologists. To this end, we propose a mathematical model of the intrinsic apoptotic pathway that captures three key dynamical features: a signal threshold to elicit cell death, irreversible commitment to the response, and a time delay that is inversely proportional to signal strength. Subdividing the intrinsic pathway into three modules (initiator, amplifier, executioner), we use computer simulation and bifurcation theory to attribute signal threshold and time delay to positive feedback in the initiator module and irreversible commitment to positive feedback in the executioner module. The model accounts for the behavior of mutants deficient in various genes and is used to design experiments that would test its basic assumptions. Finally, we apply the model to study p53-induced cellular responses to DNA damage. Cells first undergo cell cycle arrest and DNA repair, and then apoptosis if the damage is beyond repair. The model ascribes this cell-fate transition to a transformation of p53 from "helper" to "killer" forms.