Project description:This model is from the article: Systems biology analysis of programmed cell death Shani Bialik, Einat Zalckvar, Yaara Ber, Assaf D. Rubinstein, Adi Kimchi Trends in Biochemical Sciences Volume 35, Issue 10, 556-564, 27 May 2010 20537543 , Abstract: Systems biology, a combined computational and experimental approach to analyzing complex biological systems, has recently been applied to understanding the pathways that regulate programmed cell death. This approach has become especially crucial because recent advances have resulted in an expanded view of the network, to include not just a single death module (apoptosis) but multiple death programs, including programmed necrosis and autophagic cell death. Current research directions in the systems biology field range from quantitative analysis of subprocesses of individual death pathways to the study of interconnectivity among the various death modules of the larger network. These initial studies have provided great advances in our understanding of programmed cell death and have important clinical implications for drug target research. Brief Note about the model: This model is an export of 26 SPIKE Apoptosis Networks to SBML format. This is a pathway model (not quantitative model) of Apoptosis. Apoptosis, or type I cell death, is a form of programmed cell death characterized by fragmentation of the cytoplasm and nucleus, chromatin condensation and fragmentation, cytoskeletal collapse, membrane blebbing, and finally, disintegration of the cell into apoptotic bodies, which are engulfed by adjacent cells, thereby avoiding an inflammatory response. It serves to model tissues during embryonic development, to regulate cell number by eliminating excess cells, and to remove damaged, mutated or infected cells. Defective or excessive apoptosis can lead to cancer or autoimmune and degenerative diseases, respectively. Apoptosis is executed by a family of cysteine proteases, the caspases, which function in a proteolytic cascade that is initiated by either the intrinsic mitochondrial-based pathway leading to apoptosome formation, or the extrinsic pathway, which involves activation of death receptors by their extracellular ligands to form the DISC. The most distal caspases, known as the executioner caspases, cleave numerous cellular substrates, thereby leading to specific dismantling of the cell. Apoptosis is regulated by multiple proteins at several levels, including the Bcl-2 family, which regulate the release of apoptogenic factors from the mitochondria, and the IAP family, which regulate caspase activity, and is countered by survival signals eminating from the NF-kB signaling pathway. Although most of the regulation occurs at the post-translational level, involving protein-protein interactions, proteolysis, changes in subcellular localization and phosphorylation, transcriptional control, such as by p53, can also modulate the expression levels of several key apoptotic proteins. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not. . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Altered metabolism is an important part of malignant transformation of tumor cells. Oncogenic transformation may reprogram tumor metabolism and render tumor cells addicted to extracellular nutrients. Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions. Here, we performed a nutrigenetic screen to determine the phenotypes of isogenic pairs of clear-cell renal cancer cells (ccRCC) with or without VHL upon the deprivation of individual amino acids. We identified that cystine deprivation triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts. Similar cystine addiction was also observed in VHL-deficient primary RCC tumors cells. Blockage of cystine uptake significantly delayed xenograft growth of ccRCC. Importantly, cystine deprivation triggered similar metabolic changes regardless of VHL status. Therefore, metabolic differences due to cystine deprivation are not different enough to readily explain the distinct fate of life vs. death in VHL-deficient and restored cell.. Instead, we found that increased levels of TNFÎ± associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFÎ± in the VHL-deficient ccRCC renders these cells susceptible to the necrosis signaling triggered by cystine deprivation. In addition, we identified that cystine-deprived necrosis in VHL-deficient RCC depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFÎ±-RIP1/3-MLKL necrosis pathways that culminate in MLKL oligomerization and programmed necrosis. Together, our data reveal that the contextual cystine-addictions in VHL-deficient ccRCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis. RNA was extracted by RNAeasy kits (Qiagen) from the RCC4 Vec and VHL-reconstituted cells which were exposed to the control full DMEM or cystine deprived DMEM media for 6 hours (three replicates in each condition).

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Mus musculus

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