As yet no quantitative, model-based studies of these issues have been reported, but it seems almost certain that sensitivity and resistance will be controlled in a multifactorial manner

As yet no quantitative, model-based studies of these issues have been reported, but it seems almost certain that sensitivity and resistance will be controlled in a multifactorial manner. integrate prosurvival and prodeath signals to control the fates of normal and diseased cells remain poorly comprehended. Successful creation of quantitative and predictive computational models of apoptosis would be significant Vanoxerine from both basic research and clinical perspectives. From the standpoint of basic research, apoptosis is usually a stereotypical systems-level problem in which complex circuits involving graded and competing molecular signals determine binary life-death decisions at a single-cell level. Progress in modeling such decisions has had Vanoxerine a significant impact on the small but growing field of mammalian systems biology. From a clinical perspective, diseases such as malignancy involve disruption of the normal balance between cell proliferation and cell death, and anticancer drugs are thought to achieve their therapeutic effects by inducing apoptosis in cancer cells (Fadeel et al., 1999). However, it is difficult to anticipate whether a tumor cell will or will not be sensitive to a proapoptotic stimulus or drug based on general knowledge of apoptosis biochemistry because the importance of specific processes varies dramatically from one cell type to the next. Predictive, multifactorial, and context-sensitive computational models relevant to disease says will impact drug discovery and clinical care. Apoptosis can be brought on by intrinsic and extrinsic stimuli. In intrinsic apoptosis, the death-inducing stimulus involves cellular damage or malfunction brought about by stress, ultraviolet (UV) or ionizing radiation, oncogene activation, toxin exposure, etc. (Kaufmann and Earnshaw, 2000). Extrinsic apoptosis is usually brought on Vanoxerine by binding of extracellular ligands to specific transmembrane receptors, primarily members of the tumor necrosis factor receptor (TNFR) family (Kaufmann and Earnshaw, 2000). Receptor binding by TNF family ligands activates caspase-dependent pathways that are quite well comprehended in molecular terms. In general, extrinsic apoptosis has received more attention than intrinsic apoptosis from investigators seeking to develop mathematical models, but extrinsic and intrinsic apoptosis share many components and regulatory mechanisms. The best studied inducers of extrinsic apoptosis are TNF-, Fas ligand (FasL, also known as Apo-1/CD95 ligand), and TRAIL (TNF-related apoptosis-inducing ligand, also known as Apo2L; Physique 1A). Binding of these ligands to trimers of cognate receptors causes a conformational change that promotes assembly of death-inducing signaling complexes (DISCs) on receptor cytoplasmic tails (Gonzalvez and Ashkenazi, 2010). DISCs contain multiple adaptor proteins, such as TRADD and FADD, which Rabbit Polyclonal to PDHA1 recruit and promote the activation of initiator procaspases. The composition of the DISC differs from one type of death receptor to the next and also changes upon receptor internalization (Schutze et al., 2008). A remarkable feature of TNF-family receptors is usually that they activate both proapoptotic and prosurvival signaling cascades and the extent of cell death is determined in part by the balance between these competing signals. Prodeath processes are triggered by activation of Vanoxerine initiator procaspases-8 and -10 at the DISC, a process that can be modulated by the catalytically inactive procaspase-8 homolog FLIP (Fuentes-Prior and Salvesen, 2004). Prosurvival processes are generally ascribed to activation of the NF-B transcription factor, but other less well-understood processes are also involved, such as induction of the mitogen-activated protein kinase (MAPK) and Akt (protein kinase B) cascades (Falschlehner et al., 2007). Open in a separate window Physique 1 Modeling Receptor-Mediated Apoptosis(A) Simplified schematic of receptor-mediated apoptosis signaling, with fluorescent reporters for initiator caspases (IC FRET) and effector caspases (EC FRET) indicated. The MOMP reporter steps mitochondrial outer membrane permeablization. (B) Actions involved in converting a biochemical cartoon into a reaction diagram and ordinary differential equations. C8* indicates active caspase-8. Lower panels show a model-based 12 hr simulation of the increase in tBid relative to the time of MOMP and analysis of the sensitivity of MOMP time to Bid levels. The simulation in (B) was adapted from Albeck et al. (2008b). Initiator caspases recruited to the DISC directly cleave effector procaspases-3 and -7 generating active proteases (Fuentes-Prior and Salvesen, 2004). Effector caspases cleave essential structural proteins such as cytokeratins and nuclear lamins and also inhibitor of caspase-activated DNase (iCAD), which liberates the DNase (CAD) to digest chromosomal DNA and cause cell death. So-called type I apoptosis, which comprises a direct.