A5001933738- Cancer-related Molecular Pathways
- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Cancer Research and Treatments
- Phagocytosis and Immune Regulation
- Microtubule and mitosis dynamics
- Cellular Mechanics and Interactions
- Mitochondrial Function and Pathology
- Cancer, Hypoxia, and Metabolism
- Genetics, Aging, and Longevity in Model Organisms
- Hippo pathway signaling and YAP/TAZ
- Epigenetics and DNA Methylation
- Trace Elements in Health
- Hedgehog Signaling Pathway Studies
- Cardiovascular Effects of Exercise
- Animal Virus Infections Studies
- Immune cells in cancer
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Autophagy in Disease and Therapy
- Gene expression and cancer classification
- Genomic variations and chromosomal abnormalities
- Toxoplasma gondii Research Studies
- Wnt/β-catenin signaling in development and cancer
- Cancer Immunotherapy and Biomarkers
- SARS-CoV-2 and COVID-19 Research
Ludwig Cancer Research
2006-2024
University of Oxford
2011-2024
Ludwig Cancer Research
2004-2013
Analytical Biosciences (China)
2008
Dalian Institute of Chemical Physics
2008
Leiden University
2008
University College London
2004-2006
Trinity College Dublin
1999-2001
National University of Ireland, Maynooth
1998-2000
Sanford Burnham Prebys Medical Discovery Institute
1999
Exit of cytochrome c from mitochondria into the cytosol has been implicated as an important step in apoptosis. In cytosol, binds to CED-4 homologue, Apaf-1, thereby triggering Apaf-1–mediated activation caspase-9. Caspase-9 is thought propagate death signal by other caspase events, details which remain obscure. Here, we report that six additional caspases (caspases-2, -3, -6, -7, -8, and -10) are processed cell-free extracts response c, three others (caspases-1, -4, -5) failed be activated...
Apoptosis is orchestrated by a family of cysteine proteases known as the caspases. Fourteen mammalian caspases have been identified, three which (caspase-3, -6, and -7) are thought to coordinate execution phase apoptosis cleaving multiple structural repair proteins. However, relative contributions that "executioner" make demolition cell remains speculative. Here we used cell-free extracts immuno-depleted either caspase-3, or -7 examine caspase requirements for apoptosis-associated...
Interleukin-1β converting enzyme (ICE)-like proteases, which are synthesized as inactive precursors, play a key role in the induction of apoptosis. We now demonstrate that benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK), an ICE-like protease inhibitor, inhibits apoptosis by preventing processing CPP32 to its active form. These results suggest novel inhibitors can be developed prevent proforms proteases.
A reversed-phase liquid chromatography-linear ion trap-Fourier transform cyclotron resonance-mass spectrometric method was developed for the profiling of lipids in human and mouse plasma. With use a fused-core C8 column binary gradient, more than 160 belonging to eight different classes were detected single LC-MS run. The fully validated analytical characteristics such as linearity (R2, 0.994−1.000), limit detection (0.08−1.28 μg/mL plasma), repeatability (RSD, 2.7−7.9%) intermediate...
Apoptotic protease activating factor-1 (Apaf-1) has been identified as a proximal activator of caspase-9 in cell death pathways that trigger mitochondrial damage and cytochrome crelease. The mechanism Apaf-1 action is unclear but proposed to involve the clustering molecules, thereby facilitating autoprocessing adjacent zymogens. Here we show can dimerize via CED-4 homologous linker domains molecule providing means by which promote facilitate its activation. dimerization was repressed...
ASPP2 stimulates the apoptotic function of p53 family in vivo. We show here that −/− pups died before weaning. This postnatal lethality was significantly enhanced +/− background and both deletions are synthetic lethal. mice developed spontaneous tumors. The tumor onset accelerated by γ-irradiation or background. Tumors derived from retained wild-type allele even though some them lost . These provide first genetic evidence is a haploinsufficient suppressor shares overlapping function(s) with...
ABSTRACT The transmissible gastroenteritis coronavirus (TGEV), like many other viruses, exerts much of its cytopathic effect through the induction apoptosis host cell. Apoptosis is coordinated by a family cysteine proteases, called caspases, that are activated during and participate in dismantling cell cleaving key structural regulatory proteins. We have explored caspase activation events initiated upon infection human rectal tumor line HRT18 with TGEV. show TGEV results caspase-3, -6, -7,...
Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect growth under physiological conditions. Here we report that in aging mice factor-inhibiting (FIH), one the most studied negative HIF, haploinsufficient suppressor spontaneous B cell lymphomas, particular pulmonary...
During development, pseudostratified epithelia undergo large scale morphogenetic events associated with increased mechanical stress. Using a variety of genetic and imaging approaches, we uncover that in the mouse E6.5 epiblast, where apical tension is highest, ASPP2 safeguards tissue integrity. It achieves this by preventing most daughter cells from delaminating apically following division events. In context, maintains integrity organisation filamentous actin cytoskeleton at junctions. also...
An intriguing biological question relating to cell signaling is how the inflammatory mediator NF-kB and tumour suppressor protein p53 can be induced by similar triggers, like DNA damage or infection, yet have seemingly opposing sometimes cooperative functions. For example, NF-κB subunit RelA/p65 has been shown inhibit apoptosis, whereas induces apoptosis. One potential explanation may their co-regulation common cellular factors: inhibitor of Apoptosis Stimulating Protein (iASPP) one such...
The tumor suppressor p53 is a master sensor of stress, and posttranslational modifications are key in controlling its stability transcriptional activities. can be phosphorylated on at least 23 Ser/Thr residues, the majority which by stress-related kinases. An exception Ser315 human (Ser312 mouse), predominantly cell cycle-related To understand biological importance Ser312 phosphorylation vivo, we generated p53Ser312Ala knock-in mice. We show here that, although not essential for mouse life...
Abstract Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting following programmed cell death. Here we identify Inhibitor Apoptosis Stimulating Protein (iASPP), a negative regulator transcriptional activity, as tolerance. iASPP-deficiency promoted lung adenocarcinoma...
We reported recently that apoptosis-stimulating protein of p53 (ASPP) 2, an activator p53, co-operates with oncogenic RAS to enhance the transcription and apoptotic function p53. However, detailed mechanism remains unknown. Here we show ASPP2 is a novel substrate mitogen-activated kinase (MAPK). Phosphorylation by MAPK required for RAS-induced increased binding transactivation pro-apoptotic genes. In contrast, phosphorylation mutant exhibits reduced fails apoptosis. Thus RAS/MAPK pathway...
Abstract Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor p53, as a paradoxical suppressor oncogenic G12D -driven PC tumorigenesis. iASPP suppresses onset driven by alone or in combination with mutant R172H . deletion limits acinar-to-ductal metaplasia (ADM) vitro but accelerates -induced ADM, pancreatitis tumorigenesis vivo. /iASPP Δ8/Δ8 tumours well-differentiated classical PCs their...
The p53 tumour suppressor is activated in response to a wide variety of genotoxic stresses, frequently via post-translational modification. Using knock mouse model with Ser312 Ala mutation, we show here that phosphorylation on helps prevent induction by the alkylating agent MNU, which predominantly caused T cell lymphomas. This consistent our previous observation p53312A/A mice are more susceptible X-ray induced tumourigenesis. Phosphorylation aids p53's interaction E2F1 and enhances...