A5017954465- Cell death mechanisms and regulation
- NF-κB Signaling Pathways
- interferon and immune responses
- Immune Response and Inflammation
- Ubiquitin and proteasome pathways
- PARP inhibition in cancer therapy
- Cytokine Signaling Pathways and Interactions
- Toxin Mechanisms and Immunotoxins
- Melanoma and MAPK Pathways
- Cancer-related Molecular Pathways
- Protein Tyrosine Phosphatases
- Computational Drug Discovery Methods
- Calcium signaling and nucleotide metabolism
- Synthesis and biological activity
- Protein Kinase Regulation and GTPase Signaling
- Cancer Mechanisms and Therapy
- Virus-based gene therapy research
- Phagocytosis and Immune Regulation
- RNA Interference and Gene Delivery
- Retinoids in leukemia and cellular processes
- Viral Infections and Immunology Research
- Viral Infectious Diseases and Gene Expression in Insects
- Inflammasome and immune disorders
- Signaling Pathways in Disease
- RNA regulation and disease
Walter and Eliza Hall Institute of Medical Research
2012-2022
The University of Melbourne
2013-2020
University of Hong Kong
2016
La Trobe University
2007-2012
TetraLogic Pharmaceuticals (United States)
2007
Otto-von-Guericke University Magdeburg
2007
University of Birmingham
2003
TNF is an inflammatory cytokine that upon binding to its receptor, TNFR1, can drive production, cell survival, or death. TNFR1 stimulation causes activation of NF-κB, p38α, and downstream effector kinase MK2, thereby promoting transcription, mRNA stabilization, translation target genes. Here we show TNF-induced MK2 results in global RIPK1 phosphorylation. directly phosphorylates at residue S321, which inhibits ability bind FADD/caspase-8 induce RIPK1-kinase-dependent apoptosis necroptosis....
Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor κB (NF-κB) signaling, and sensitize cells to tumor necrosis α (TNFα). The physiological relevance these discoveries cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1–Tnf receptor-associated 2 (TRAF2) complex. Unlike cause rapid proteasomal cIAP1, signaling by promotes lysosomal...
Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated activation cytokine production. Here we develop characterize a selective RIPK2 inhibitor, WEHI-345, which delays ubiquitylation downstream NOD engagement. Despite only...
Abstract MLKL is the essential effector of necroptosis, a form programmed lytic cell death. We have isolated mouse strain with single missense mutation, Mlkl D139V , that alters two-helix ‘brace’ connects killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation salivary glands mediastinum. The normal embryonic development homozygotes until birth, absence...
Both of the TNF superfamily ligands, and LT α, can bind signal through TNFR 1 2, yet mice mutant for each have different phenotypes. Part this difference is because α but not activate Herpes Virus Entry Mediator also heterotrimerise with β to βR, which consistent similar phenotypes βR deficient mice. However, it has been reported that LTα 3 homotrimer signals differently than 1, unique roles in initiation exacerbation some inflammatory diseases. Our modeling / interface compared structure...
Abstract Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy preclinical Smac-mimetic compound A and clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity triple-negative (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using vivo PDX models TNBC estrogen receptor-positive (ER + ) cancer....
Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production other cytokines via membrane-bound complex 1 or induces cell death cytosolic 2. To understand how TNF-induced regulated, we performed mass spectrometry 2 and identified tankyrase-1 as native that, upon stimulus, mediates poly-ADP-ribosylation (PARylation). PARylation recruitment E3 ligase RNF146, resulting in proteasomal degradation 2, thereby limiting...
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a "death ligand"—a member of the TNF superfamily that binds to receptors bearing death domains. As well causing apoptosis certain types tumor cells, TRAIL can activate both NF-κB and JNK signalling pathways. To determine role TGF-β-Activated Kinase-1 (TAK1) in signalling, we analyzed effects adding mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice. TAK1−/− MEFs were significantly...
Use of the cre transgene in vivo mouse models to delete a specific 'floxed' allele is well-accepted method for studying effects spatially or temporarily regulated genes. During course our investigation into effect cyclic adenosine 3',5'-monophosphate-dependent protein kinase A (PKA) expression on cell death, we found that either cultured lines transgenic mice results global changes PKA target phosphorylation. This consequently alters gene profile and cytokine secretion such as IL-6. These...
MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal p53-deficiency. While TP53 deletion rare glioblastomas, these tumors often carry mutations. Here, we show that strongly attenuated glioblastoma cell proliferation through p53wt stabilization and senescence. The senescence-inducing efficacy of was particularly strong when cells were co-treated with the standard-of-care temozolomide. However, also increased...
SUMMARY We have isolated a mouse strain with single missense mutation in the gene encoding MLKL, essential effector of necroptotic cell death. The resulting substitution lies within two-helix ‘brace’ and confers constitutive, RIPK3 independent, killing activity to MLKL. Mice homozygous for Mlkl D139V develop lethal inflammation days birth, implicating salivary glands pericardium as hotspots necroptosis inflammatory infiltration. normal development homozygotes until absence any overt...
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a ''death ligand''-a member of the TNF superfamily that binds to receptors bearing death domains.As well causing apoptosis certain types tumor cells, TRAIL can activate both NF-kB and JNK signalling pathways.To determine role TGF-b-Activated Kinase-1 (TAK1) in signalling, we analyzed effects adding mouse embryonic fibroblasts (MEFs) derived from TAK1 conditional knockout mice.TAK12/2 MEFs were significantly...