Signaling model of cell death shows cell-to-cell stochastic fluctuations are linked to apoptosis related diseases (88.8)

Abstract

Abstract We have developed a detailed computational model of apoptotic cell death signaling that could explain some of the recent experimental observations on apoptosis (Goldkorn et al. Antioxid. Redox Signal, 2005). Specifically, our results show how apoptosis signaling can be slow (~ 10 hours) under weak stimulus due to large cell-to-cell stochastic fluctuations through the type 2 pathway of signaling. We use a novel set of stochastic differential equations to elucidate a robust network design and stochastic effects in apoptosis signaling in a cell-type independent manner. However, apoptosis signaling and diseases that arise from aberrant apoptosis signaling are often cell-type specific. For example, recent experiments have revealed neuroglobin protein as a novel inhibitor of the apoptotic pathway (T. Brittain et al., FEBS Letters, 2006) that has 1000 fold higher concentration level in neural and retinal cells (~ 100 micro-molar) compared to its 10-100 nanomolar concentration in most other cell types. We use our computational model to show that stochastic signaling through the type 2 pathway can explain the presence of such disparate levels of neuroglobin amount depending on the cell type. We also propose a molecular mechanism of apoptosis related diseases, such as degenerative disorders and cancer, due to aberrant signaling through the stochastic type 2 pathway and a faulty type 2 to type 1 switching of apoptotic signaling. A role of aberrant expression of apoptotic inhibitor Bcl2 in such apoptosis related diseases are also discussed.