Abstract
Programmed cell death (PCD) is an essential cellular mechanism that is evolutionary conserved, mediated through various pathways and acts by integrating different stimuli. Many diseases such as neurodegenerative diseases and cancers are found to be caused by, or associated with, regulations in the cell death pathways. Yeast Saccharomyces cerevisiae, is a unicellular eukaryotic organism that shares with human cells components and pathways of the PCD and is therefore used as a model organism. Boolean modeling is becoming promising approach to capture qualitative behavior and describe essential properties of such complex networks. Here we present large literature-based and to our knowledge first Boolean model that combines pathways leading to apoptosis (a type of PCD) in yeast. Analysis of the yeast model confirmed experimental findings of anti-apoptotic role of Bir1p and pro-apoptotic role of Stm1p and revealed activation of the stress protein kinase Hog proposing the maximal level of activation upon heat stress. In addition we extended the yeast model and created an in silico humanized yeast in which human pro- and anti-apoptotic regulators Bcl-2 family and Valosin-contain protein (VCP) are included in the model. We showed that accumulation of Bax in silico humanized yeast shows apoptotic markers and that VCP is essential target of Akt Signaling. The presented Boolean model provides comprehensive description of yeast apoptosis network behavior. Extended model of humanized yeast gives new insights of how complex human disease like neurodegeneration can initially be tested.
Highlights
Apoptosis is a complex process which is strictly under control of several regulatory networks
Many proteins residing in the cytoplasm, nucleus, mitochondria, ER, peroxisomes, and lysosomes have been identified as the regulators of apoptosis
Seventeen elements are active in nucleus and are shown in gray, 12 mitochondria species are shown in yellow, and 34 orange boxes represent species residing in cytoplasm
Summary
Apoptosis is a complex process which is strictly under control of several regulatory networks. Any kind of malfunctioning in these controlling systems due to insufficient or excessive apoptosis signal can potentially lead to threatening diseases such as various types of cancer and neurodegenerative disorders. Keeping this process tightly regulated is important for the cell. Ammonium, NO, ROS (that can be generated within the cell by mitochondria and the ER, and induced by H2O2 addition (Madeo et al, 1999) and other factors), damage (proteins, lipids, nucleic acids) as a consequence of aging and mutations (Mazzoni et al, 2005; Weinberger et al, 2005; Hauptmann et al, 2006), as well as expression of heterologous proteins, such as human pro-apoptotic proteins (Eisenberg et al, 2007).
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