A5003120183- Inflammasome and immune disorders
- Cell death mechanisms and regulation
- interferon and immune responses
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Cancer Genomics and Diagnostics
- CRISPR and Genetic Engineering
- Immune Response and Inflammation
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Pluripotent Stem Cells Research
- Epigenetics and DNA Methylation
- Immune cells in cancer
- NF-κB Signaling Pathways
- Monoclonal and Polyclonal Antibodies Research
- IL-33, ST2, and ILC Pathways
- Immunotherapy and Immune Responses
- Cancer Cells and Metastasis
- RNA modifications and cancer
- Viral Infectious Diseases and Gene Expression in Insects
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- HER2/EGFR in Cancer Research
- Cytokine Signaling Pathways and Interactions
- Autophagy in Disease and Therapy
- Phagocytosis and Immune Regulation
Roche (United States)
2021
Genentech
2009-2019
MRC Laboratory of Molecular Biology
2009
Life and Cell Death Trying to protect animals from one form of cell death may lead by another. Two protein kinases, known as RIPK1 RIPK3 promote signaling that leads necroptosis. However, Newton et al. (p. 1357 , published online 20 February; see the Perspective Zhang Chan ) found inhibition was not always beneficial. Instead, mice expressing a with no catalytic activity died increased apoptotic death, but lacking entirely, did die perhaps because restrains apoptosis mediated caspase-8 an...
Necroptosis is a caspase-independent form of cell death that triggered by activation the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation its pseudokinase substrate mixed lineage kinase-like (MLKL), which then translocates to membranes promotes lysis. Activation RIPK3 regulated RIPK1. Here we analyze contribution RIPK1, RIPK3, or MLKL several mouse disease models. Loss had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis,...
LRRK2 kinase inhibitors, under development for Parkinson’s disease, have an effect on type II pneumocytes in nonhuman primate lung, suggesting that pulmonary toxicity may be a critical safety liability.
Abstract Recent single-cell studies of cancer in both mice and humans have identified the emergence a myofibroblast population specifically marked by highly restricted leucine-rich-repeat-containing protein 15 (LRRC15) 1–3 . However, molecular signals that underlie development LRRC15 + cancer-associated fibroblasts (CAFs) their direct impact on anti-tumour immunity are uncharacterized. Here mouse models pancreatic cancer, we provide vivo genetic evidence TGFβ receptor type 2 signalling...
Pyroptosis requires the induction of gasdermin D expression by transcription factor IRF2.
Significance Statement Single-cell transcriptomics techniques have revolutionized the ability to characterize cells from heterogeneous organs like kidney. Although glomerular disorders are an important cause of CKD, a thorough characterization in glomerulus has remained challenging due technical difficulties isolating undamaged cells, especially glomeruli diseased animals. This study provides comprehensive single-cell atlas, based on approximately 75,000 healthy mice and injured four ways,...
Intracellular LPS sensing by caspase-4/5/11 triggers proteolytic activation of pore-forming gasdermin D (GSDMD), leading to pyroptotic cell death in Gram-negative bacteria-infected cells. Involvement and GSDMD inflammatory responses, such as lethal sepsis, makes them highly desirable drug targets. Using knock-in (KI) mouse strains, we herein provide genetic evidence show that caspase-11 auto-cleavage at the inter-subunit linker is essential for optimal catalytic activity subsequent cleavage...
Many important signaling pathways rely on multiple ligands. It is unclear if this a mechanism of safeguard via redundancy or it serves other functional purposes. In study, we report unique insight into question by studying the activin receptor-like kinase 1 (ALK1) pathway. Despite its importance in vascular development, physiological ligand ligands for ALK1 remain to be determined. Using conventional knockout and specific antibodies against bone morphogenetic protein 9 (BMP9) BMP10, showed...
CDK8 is a cyclin-dependent kinase that mediates transcriptional control of pathways linked to both cancer and stem cells. In this study, we show required for tumor growth maintenance dedifferentiation in vivo uncover common role controlling cell function. Acute loss strongly inhibited promoted differentiation. Transcriptional profiling identified set embryonic cell-related genes are activated by cancer. Consistent with this, found expression correlated the pluripotency state caused cells...
RIPK1, RIPK3, ZBP1 and TRIF, the four mammalian proteins harboring RIP homotypic interaction motif (RHIM) domains, are key components of inflammatory signaling programmed cell death. RHIM-domain protein activation is mediated by their oligomerization; however, mechanisms that promote a return to homeostasis remain unknown. Here we show autophagy critical for turnover all proteins. Macrophages lacking gene Atg16l1accumulated highly insoluble forms TRIF ZBP1. Defective enhanced necroptosis...
Despite the development of effective therapies, a substantial proportion asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, rodents, TRPA1 is involved induction airway inflammation hyperreactivity. Here, discovery early clinical GDC-0334, highly potent, selective, orally bioavailable antagonist, described. GDC-0334 inhibited function on smooth...
Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example, BAP1 encodes a widely expressed deubiquitinase for histone H2A, but germline mutations are predominantly associated with uveal melanomas and mesotheliomas. We show that inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, pancreatic not melanocytes mesothelial cells. Ubiquitin ligase RNF2, which silences genes by monoubiquitinating promoted BAP1-deficient cells...