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https://www.readbyqxmd.com/read/28106882/combination-of-iap-antagonist-and-ifn%C3%AE-activates-novel-caspase-10-and-ripk1-dependent-cell-death-pathways
#1
Maria C Tanzer, Nufail Khan, James A Rickard, Nima Etemadi, Najoua Lalaoui, Sukhdeep Kaur Spall, Joanne M Hildebrand, David Segal, Maria Miasari, Diep Chau, WendyWei-Lynn Wong, Mark McKinlay, Srinivas K Chunduru, Christopher A Benetatos, Stephen M Condon, James E Vince, Marco J Herold, John Silke
Peptido-mimetic inhibitor of apoptosis protein (IAP) antagonists (Smac mimetics (SMs)) can kill tumour cells by depleting endogenous IAPs and thereby inducing tumour necrosis factor (TNF) production. We found that interferon-γ (IFNγ) synergises with SMs to kill cancer cells independently of TNF- and other cell death receptor signalling pathways. Surprisingly, CRISPR/Cas9 HT29 cells doubly deficient for caspase-8 and the necroptotic pathway mediators RIPK3 or MLKL were still sensitive to IFNγ/SM-induced killing...
January 20, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28096356/active-mlkl-triggers-the-nlrp3-inflammasome-in-a-cell-intrinsic-manner
#2
Stephanie A Conos, Kaiwen W Chen, Dominic De Nardo, Hideki Hara, Lachlan Whitehead, Gabriel Núñez, Seth L Masters, James M Murphy, Kate Schroder, David L Vaux, Kate E Lawlor, Lisa M Lindqvist, James E Vince
Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28088644/tert-butyl-hydroperoxide-t-bhp-induced-apoptosis-and-necroptosis-in-endothelial-cells-roles-of-nox4-and-mitochondrion
#3
Wenwen Zhao, Haitao Feng, Wen Sun, Kang Liu, Jin-Jian Lu, Xiuping Chen
Oxidative stress causes endothelial death while underlying mechanisms remain elusive. Herein, the pro-death effect of tert-butyl hydroperoxide (t-BHP) was investigated with low concentration (50μM) of t-BHP (t-BHPL) and high concentration (500μM) of t-BHP (t-BHPH). Both t-BHPL and t-BHPH induced endothelial cell death was determined. T-BHPL induced caspase-dependent apoptosis and reactive oxygen species (ROS) generation, which was inhibited by N-acetyl-L-cysteine (NAC). Furthermore, NADPH oxidase inhibitor diphenyleneiodonium (DPI), NOX4 siRNA, and NOX4 inhibitor GKT137831 reduced t-BHPL-induced ROS generation while mitochondrial respiratory chain inhibitors rotenone (Rot), 2-thenoyltrifluoroacetone (TTFA), and antimycin A (AA) failed to do so...
January 5, 2017: Redox Biology
https://www.readbyqxmd.com/read/28069136/the-inflammatory-signal-adaptor-ripk3-functions-beyond-necroptosis
#4
K Moriwaki, F K-M Chan
Receptor interacting protein kinase 3 (RIPK3) is an essential serine/threonine kinase for necroptosis, a type of regulated necrosis. A variety of stimuli can cause RIPK3 activation through phosphorylation. Activated RIPK3 in turn phosphorylates and activates the downstream necroptosis executioner mixed lineage kinase domain-like (MLKL). Necroptosis is a highly inflammatory type of cell death because of the release of intracellular immunogenic contents from disrupted plasma membrane. Indeed, RIPK3-deficient mice exhibited reduced inflammation in many inflammatory disease models...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28065786/cisplatin-induced-necroptosis-in-tnf%C3%AE-dependent-and-independent-pathways
#5
Yanfang Xu, Hua-Bin Ma, Yu-Lu Fang, Zhi-Rong Zhang, Jing Shao, Mao Hong, Chao-Jun Huang, Jing Liu, Rui-Qing Chen
Cisplatin is a chemotherapeutic drug for treatment of many solid tumors. It has been shown to induce apoptosis and/or necrosis in different types of cancer cells. However, the underlying mechanisms remain elusive. In this study, we provide evidences that cisplatin induces necroptosis in receptor-interacting protein 3 (RIP3)-expressing cell lines, but not in cell lines lacking RIP3 protein expression. Deficiency of core components of necroptotic pathway, RIP1, RIP3, or mixed lineage kinase domain-like protein (MLKL) blocked cisplatin-induced cell death in L929 cells...
January 6, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28004006/the-different-effects-of-atorvastatin-and-pravastatin-on-cell-death-and-parp-activity-in-pancreatic-nit-1-cells
#6
Ya-Hui Chen, Yi-Chun Chen, Chin-San Liu, Ming-Chia Hsieh
Statins have been widely used drugs for lowering low-density lipoprotein and for preventing heart attack and stroke. However, the increased risk for developing diabetes during extended stain use and the molecular mechanisms remain unclear. The objective of this study was to elucidate the signaling pathway and biological function between necrosis and autophagy induced by atorvastatin (AS) and pravastatin (PS). Here we observed that atorvastatin (AS) can increase intracellular reactive oxygen species (ROS) and induce necrotic cell death and autophagy in NIT-1 cells, whereas pravastatin (PS) does not cause ROS and cell death but also induces autophagy...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27999438/necroptosis-in-development-inflammation-and-disease
#7
Ricardo Weinlich, Andrew Oberst, Helen M Beere, Douglas R Green
In the early 2000s, receptor-interacting serine/threonine protein kinase 1 (RIPK1), a molecule already recognized as an important regulator of cell survival, inflammation and disease, was attributed an additional function: the regulation of a novel cell death pathway that came to be known as necroptosis. Subsequently, the related kinase RIPK3 and its substrate mixed-lineage kinase domain-like protein (MLKL) were also implicated in the necroptotic pathway, and links between this pathway and apoptosis were established...
December 21, 2016: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/27999433/insane-in-the-membrane-a-structural-perspective-of-mlkl-function-in-necroptosis
#8
REVIEW
Emma J Petrie, Joanne M Hildebrand, James M Murphy
Necroptosis (or 'programmed necrosis') is a caspase-independent cell death pathway that operates downstream of death receptors, including Tumour Necrosis Factor Receptor-1 (TNFR1), and the Toll-like receptors, TLR3 and TLR4. Owing to its immunogenicity, necroptosis has been attributed roles in the pathogenesis of several diseases, including inflammatory bowel disease and the tissue damage arising from ischemic-reperfusion injuries. Only over the past 7 years has the core machinery of this pathway, the receptor-interacting protein kinase-3 (RIPK3) and the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), been defined...
December 21, 2016: Immunology and Cell Biology
https://www.readbyqxmd.com/read/27978789/heat-shock-proteins-therapeutic-perspectives-in-inflammatory-disorders
#9
Rekha Khandia, Ashok K Munjal, Hafiz M N Iqbal, Kuldeep Dhama
Heat shock proteins (HSPs) are highly conserved proteins present in all kingdoms of organisms. These are expressed under stress conditions in order to protect the cells from injuries. The stress induced protein denaturation is rectified by refolding and remodelling. These are intracellular proteins but can be present in extracellular fluid like serum of the patients suffering from trauma, autoimmune and inflammatory disorders. Virtually in most inflammatory diseases, immune response towards HSPs is developed...
December 13, 2016: Recent Patents on Inflammation & Allergy Drug Discovery
https://www.readbyqxmd.com/read/27959630/necroptosis-mechanisms-and-relevance-to-disease
#10
Lorenzo Galluzzi, Oliver Kepp, Francis Ka-Ming Chan, Guido Kroemer
Necroptosis is a form of regulated cell death that critically depends on receptor-interacting serine-threonine kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) and generally manifests with morphological features of necrosis. The molecular mechanisms that underlie distinct instances of necroptosis have just begun to emerge. Nonetheless, it has already been shown that necroptosis contributes to cellular demise in various pathophysiological conditions, including viral infection, acute kidney injury, and cardiac ischemia/reperfusion...
December 5, 2016: Annual Review of Pathology
https://www.readbyqxmd.com/read/27932417/molecular-pathways-the-necrosome-a-target-for-cancer-therapy
#11
Lena Seifert, George Miller
Necroptosis is a caspase 8-independent cell death that requires co-activation of receptor-interacting protein (RIP) 1 and RIP 3 kinases. The necrosome is a complex consisting of RIP1, RIP3 and Fas-associated protein with death domain (FADD) leading to activation of the pseudokinase mixed lineage kinase like (MLKL) followed by a rapid plasma membrane rupture and inflammatory response through the release of damage-associated molecular patterns (DAMPs) and cytokines. The necrosome has been shown to be relevant in multiple tumor types, including pancreatic adenocarcinoma, melanoma and several hematological malignancies...
December 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27924226/questions-and-controversies-the-role-of-necroptosis-in-liver-disease
#12
REVIEW
Lily Dara, Zhang-Xu Liu, Neil Kaplowitz
Acute and chronic liver injury results in hepatocyte death and turnover. If injury becomes chronic, the continuous cell death and turnover leads to chronic inflammation, fibrosis and ultimately cirrhosis and hepatocellular carcinoma. Controlling liver cell death both in acute injury, to rescue the liver from acute liver failure, and in chronic injury, to curb secondary inflammation and fibrosis, is of paramount importance as a therapeutic strategy. Both apoptosis and necrosis occur in the liver, but the occurrence of necroptosis in the liver and its contribution to liver disease is controversial...
2016: Cell Death Discovery
https://www.readbyqxmd.com/read/27920255/mlkl-channel-in-necroptosis-is-octamer-formed-by-tetramers-in-a-dyadic-process
#13
Deli Huang, Xinru Zheng, Zi-An Wang, Xin Chen, Wan-Ting He, Yingying Zhang, Jin-Gen Xu, Hang Zhao, Wenke Shi, Xin Wang, Yongqun Zhu, Jiahuai Han
Oligomerization of the mixed lineage kinase domain-like protein (MLKL) is essential for its cation channel function in necroptosis. Here we show that the MLKL channel is an octamer comprising of two previously identified tetramers most likely in their side-by-side position. Inter-molecule disulfide bonds are present in the tetramer but are not required for the octamer assembly and necroptosis. MLKL forms oligomers in the necrosome, and is then released from the necrosome before or during its membrane translocation...
December 5, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27900566/autophagy-regulates-death-of-retinal-pigment-epithelium-cells-in-age-related-macular-degeneration
#14
REVIEW
Kai Kaarniranta, Paulina Tokarz, Ali Koskela, Jussi Paterno, Janusz Blasiak
Age-related macular degeneration (AMD) is an eye disease underlined by the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillares, but the exact mechanism of cell death in AMD is not completely clear. This mechanism is important for prevention of and therapeutic intervention in AMD, which is a hardly curable disease. Present reports suggest that both apoptosis and pyroptosis (cell death dependent on caspase-1) as well as necroptosis (regulated necrosis dependent on the proteins RIPK3 and MLKL, caspase-independent) can be involved in the AMD-related death of RPE cells...
November 29, 2016: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/27886851/the-role-of-necroptosis-in-pulmonary-diseases
#15
REVIEW
Kenji Mizumura, Shuichiro Maruoka, Yasuhiro Gon, Augustine M K Choi, Shu Hashimoto
By regulating the cell number and eliminating harmful cells, programmed cell death plays a critical role in development, homeostasis, and disease. While apoptosis is a recognized form of programmed cell death, necrosis was considered a type of uncontrolled cell death induced by extreme physical or chemical stress. However, recent studies have revealed the existence of a genetically programmed and regulated form of necrosis, termed necroptosis. Necroptosis is defined as necrotic cell death that is dependent on receptor-interacting protein kinase 3 (RIPK3)...
November 2016: Respiratory Investigation
https://www.readbyqxmd.com/read/27869161/therapeutic-targeting-of-necroptosis-by-smac-mimetic-bypasses-apoptosis-resistance-in-acute-myeloid-leukemia-cells
#16
C Safferthal, K Rohde, S Fulda
Resistance to apoptosis, for example due to overexpression of Inhibitor of Apoptosis (IAP) proteins, is associated with poor prognosis in acute myeloid leukemia (AML). Here, we identify that Smac mimetics such as BV6, which antagonizes IAP proteins, elicit necroptosis in AML cells, in which apoptosis is inhibited pharmacologically by caspase inhibitors or genetically by caspase-8 knockdown. Importantly, BV6 triggers necroptosis also in apoptosis-resistant patient-derived AML blasts, underlining the clinical relevance of our findings...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27856241/palmitate-induces-rip1-rip3-dependent-necrosis-via-mlkl-mediated-pore-formation-in-the-plasma-membrane-of-raw-264-7%C3%A2-cells
#17
Seong Keun Kim, Mihee Yun, Gimoon Seo, Ji-Young Lee, Seong-Beom Lee
We previously reported that palmitate induces receptor-interacting protein (RIP)1-dependent necrosis in RAW 264.7 macrophage cells. In response to death receptor stimuli, RIP1 is reported to activate RIP3, which causes the phosphorylation and translocation of mixed-lineage kinase domain-like (MLKL) protein to the plasma membrane, subsequent pore formation in the plasma membrane, and necrotic cell death. In the current study, we investigated the role of MLKL in palmitate-induced, RIP1/RIP3-dependent necrotic cell death in RAW 264...
January 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27834956/a-bak-dependent-mitochondrial-amplification-step-contributes-to-smac-mimetic-glucocorticoid-induced-necroptosis
#18
Katharina Rohde, Lara Kleinesudeik, Stefanie Roesler, Oliver Löwe, Juliana Heidler, Katrin Schröder, Ilka Wittig, Stefan Dröse, Simone Fulda
Necroptosis is a form of programmed cell death that critically depends on RIP3 and MLKL. However, the contribution of mitochondria to necroptosis is still poorly understood. In the present study, we discovered that mitochondrial perturbations play a critical role in Smac mimetic/Dexamethasone (Dexa)-induced necroptosis independently of death receptor ligands. We demonstrate that the Smac mimetic BV6 and Dexa cooperate to trigger necroptotic cell death in acute lymphoblastic leukemia (ALL) cells that are deficient in caspase activation due to absent caspase-8 expression or pharmacological inhibition by the caspase inhibitor zVAD...
January 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27832137/atp-competitive-mlkl-binders-have-no-functional-impact-on-necroptosis
#19
Bin Ma, Doug Marcotte, Murugan Paramasivam, Klaus Michelsen, Ti Wang, Andrea Bertolotti-Ciarlet, John Howard Jones, Ben Moree, Margaret Butko, Joshua Salafsky, Xin Sun, Timothy McKee, Laura F Silvian
MLKL is a pore forming pseudokinase involved in the final stage of necroptosis, a form of programmed cell death. Its phosphorylation by RIPK3 is necessary for triggering necroptosis but not for triggering apoptosis, which makes it a unique target for pharmacological inhibition to block necroptotic cell death. This mechanism has been described as playing a role in disease progression in neurodegenerative and inflammatory diseases. A type II kinase inhibitor (cpd 1) has been described that reportedly binds to the MLKL pseudokinase domain and prevents necroptosis...
2016: PloS One
https://www.readbyqxmd.com/read/27819682/ripk1-inhibits-zbp1-driven-necroptosis-during-development
#20
Kim Newton, Katherine E Wickliffe, Allie Maltzman, Debra L Dugger, Andreas Strasser, Victoria C Pham, Jennie R Lill, Merone Roose-Girma, Søren Warming, Margaret Solon, Hai Ngu, Joshua D Webster, Vishva M Dixit
Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL...
December 1, 2016: Nature
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