Mathematical modeling of apoptosis
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REVIEW
Open Access
Mathematical modeling of apoptosis Kolja Schleich1 and Inna N Lavrik2*
Abstract Apoptosis is a form of programmed cell death, which is fundamental to all multicellular organisms. Deregulation of apoptosis leads to a number of severe diseases including cancer. Apoptosis is initiated either by extrinsic signals via stimulation of receptors at the cellular surface or intrinsic signals, such as DNA damage or growth factor withdrawal. Apoptosis has been extensively studied using systems biology which substantially contributed to the understanding of this death signaling network. This review gives an overview of mathematical models of apoptosis and the potential of systems biology to contribute to the development of novel therapies for cancer or other apoptosis-related diseases. Keywords: Apoptosis, Death receptors, Systems biology, Modeling, Cancer
Introduction Apoptosis is a certain form of programmed cell death (PCD) playing a key role in the development and homeostasis of multicellular organisms. Defects in the apoptotic pathway can lead to multiple diseases, such as neurodegenerative diseases, autoimmune diseases, AIDS and cancer [1]. In mammalian cells apoptosis can be induced by either extra- or intracellular stimuli, triggering the extrinsic or intrinsic pathway, respectively [2] (Figure 1). The extrinsic pathway is triggered by the stimulation of death receptors (DR) on the plasma membrane. DR stimulation leads to the formation of the death-inducing signaling complex (DISC) and initiator caspase-8 activation [3]. The intrinsic pathway can be triggered by chemotherapeutic drugs, irradiation or growth factor withdrawal and results in mitochondrial outer membrane permeabilization (MOMP), release of cytochrome C into the cytosol and procaspase-9 activation [4]. Both pathways eventually lead to the activation of effector caspases and the apoptotic phenotype including chromatin condensation, nuclear fragmentation, membrane blebbing, cell shrinkage and formation of apoptotic bodies [5-7]. Due to its extreme signaling outcome, i.e. life or death of the cell, apoptosis has to be tightly controlled at multiple levels and by various proteins. In order to better understand those signaling decisions numerous systems biology studies of apoptosis * Correspondence: [email protected] 2 Department of Translational Inflammation, Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany Full list of author information is available at the end of the article
have been conducted. Systems biology is a relatively new field with the ultimate goal to understand biological processes in their entirety. Systems biology is based on the combination of experimental procedures with mathematical modeling that is supported by computer programs [8-10]. In this review we give an overview of systems biology approaches in apoptosis signaling with a focus on DR-induced apoptosis. Especially, we address a number of recent studies that provided new insights into apoptosis regulation since
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