Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA171577 | ENA |
REPOSITORIES: ENA
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Project description:For years, the term apoptosis was used synonymously for programmed cell death. However, it was recently discovered that programmed necrosis M-bM-^@M-^S dependent on the kinases Receptor-Interacting-Protein-Kinase (RIP)1 and RIP3 (also called necroptosis) M-bM-^@M-^S represents a major programmed cell-death pathway in development and immunity. At present, the functions of necroptosis in hepatitis, liver cancer development and biliary disease are unclear. Here we show that in mice with chronic hepatitis due to conditional ablation of TGF-beta-activated kinase1 (TAK1) in liver parenchymal cells (LPC), both apoptotic and necroptotic signaling pathways are activated. Strikingly, only Caspase-8-dependent apoptosis promotes spontaneous liver cancer development, while in contrast LPC necroptosis inhibits hepatic tumourigenesis. The tumour-promoting effect of apoptosis results from an induction of strong compensatory proliferation of LPC, linked with the paracrine action of growth factors like Insulin-like growth factor-2 (IGF-2) not induced by necroptosis. In addition to prevention of HCC development, induction of necroptosis leads to massive cholestasis and hyperbilirubinemia, resulting from an insufficient ductular reaction and biliary regeneration from the hepatic stem cell niche as a response to chronic hepatitis. These results indicate previously undefined distinctive functions of apoptosis and programmed necrosis in controlling cancer development and cholestasis in the liver with important implications for future therapeutic strategies in chronic liver disease. 8 samples were analysed. We compared groups of 4 Tak1/Caspase8 LPC double knockout mice and 4 Tak1 LPC-KO/Rip3-/- mice to detect genes differentially regulated by apoptotic and necrotic signalling pathways.
2013-04-01 | E-GEOD-39750 | biostudies-arrayexpress
Project description:For years, the term apoptosis was used synonymously for programmed cell death. However, it was recently discovered that programmed necrosis – dependent on the kinases Receptor-Interacting-Protein-Kinase (RIP)1 and RIP3 (also called necroptosis) – represents a major programmed cell-death pathway in development and immunity. At present, the functions of necroptosis in hepatitis, liver cancer development and biliary disease are unclear. Here we show that in mice with chronic hepatitis due to conditional ablation of TGF-beta-activated kinase1 (TAK1) in liver parenchymal cells (LPC), both apoptotic and necroptotic signaling pathways are activated. Strikingly, only Caspase-8-dependent apoptosis promotes spontaneous liver cancer development, while in contrast LPC necroptosis inhibits hepatic tumourigenesis. The tumour-promoting effect of apoptosis results from an induction of strong compensatory proliferation of LPC, linked with the paracrine action of growth factors like Insulin-like growth factor-2 (IGF-2) not induced by necroptosis. In addition to prevention of HCC development, induction of necroptosis leads to massive cholestasis and hyperbilirubinemia, resulting from an insufficient ductular reaction and biliary regeneration from the hepatic stem cell niche as a response to chronic hepatitis. These results indicate previously undefined distinctive functions of apoptosis and programmed necrosis in controlling cancer development and cholestasis in the liver with important implications for future therapeutic strategies in chronic liver disease.
2013-04-01 | GSE39750 | GEO
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.
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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.
2005-01-01 | MODEL1107050000 | BioModels
Project description:The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 (Mig-6) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of Mig-6 in the liver, we conditionally ablated Mig-6 in the liver using the Albumin-Cre mouse model (Albcre/+Mig-6f/f; Mig-6d/d). Mig-6d/d mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the Mig-6d/d mice. The daily excretion of fecal bile acids was significantly decreased in the Mig-6d/d mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the Mig-6d/d mice compared to Mig-6f/f controls. These results indicate that Mig-6 plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of Mig-6 develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which Mig-6 regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease. Eight week old Mig-6f/f vs Mig-6d/d male mice after undergoing a 24 hour fast
2011-08-30 | E-GEOD-31752 | biostudies-arrayexpress
Project description:Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.
2023-08-23 | GSE237138 | GEO
Project description:Oxygen-glucose deprivation (OGD) is a cellular phenomenon consistently observed upon occurrence of ischemic stroke which eventually results in neuronal death. Neuronal cell death after ischemia takes place via two distinct processes, necrosis and apoptosis. Apoptosis, programmed cell death, is denoted by chromatin condensation, nuclear blebbing, cellular shrinkage, and DNA fragmentation. Unlike apoptosis, cellular swelling and lysis is suggestive of necrosis. However, these two processes are related not only to the severity but also to the duration of ischemia.
2013-12-31 | GSE23158 | GEO
Project description:Enforced Snail expression in hepatocytes is sufficient for induction of steatohepatitis and liver tumorigenesis through disruption of the biliary canaliculus and bile acid homeostasis in the liver.
2020-02-21 | GSE141110 | GEO
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 TNFα associated with VHL loss in the VHL-deficient RCC force them to rely on intact RIPK1 to inhibit apoptosis. However, this pre-existing elevated TNFα 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 TNFα-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).
2016-07-01 | E-GEOD-60422 | biostudies-arrayexpress
Project description:Oxygen-glucose deprivation (OGD) is a cellular phenomenon consistently observed upon occurrence of ischemic stroke which eventually results in neuronal death. Neuronal cell death after ischemia takes place via two distinct processes, necrosis and apoptosis. Apoptosis, programmed cell death, is denoted by chromatin condensation, nuclear blebbing, cellular shrinkage, and DNA fragmentation. Unlike apoptosis, cellular swelling and lysis is suggestive of necrosis. However, these two processes are related not only to the severity but also to the duration of ischemia. Microarray analysis was carried out using 20 Illumina mouse Ref8V1.1 genechip arrays. The assignment of the arrays was as follows: Controls (n=5); exposure to OGD for 10min, 5h, 8h, 15h and 24 h (n=3 respectively).
2013-12-31 | E-GEOD-23158 | biostudies-arrayexpress
Project description:Caspase-8 is a critical regulator of apoptosis, programmed necrosis, and inflammatory gene expression. Caspase-8 is necessary for optimal transcription of inflammatory and antimicrobial host defense genes, including Il12 and Il1b. While the mechanisms of caspase-8-mediated control of apoptosis and programmed necrosis are well-described, how caspase-8 controls inflammatory gene expression is less clear. We show that caspase-8 is necessary for optimal nuclear translocation of the NF-κB family member c-Rel, and consequently, for recruitment of c-Rel to caspase-8-dependent gene promoters. Furthermore, caspase-8 deficiency led to an inability to control acute Toxoplasma gondii infection. These findings provide new insight into how caspase-8 contributes to inflammatory gene expression and host defense.
2019-05-15 | GSE131171 | GEO