A5082522262- T-cell and B-cell Immunology
- Cancer Cells and Metastasis
- RNA Research and Splicing
- Developmental Biology and Gene Regulation
- Immune Cell Function and Interaction
- Hematopoietic Stem Cell Transplantation
- Cell Adhesion Molecules Research
- MicroRNA in disease regulation
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Cancer-related molecular mechanisms research
- Cancer-related gene regulation
- Corneal Surgery and Treatments
- Liver physiology and pathology
- Hair Growth and Disorders
- Immunotherapy and Immune Responses
- IL-33, ST2, and ILC Pathways
- Hedgehog Signaling Pathway Studies
- Skin Protection and Aging
- Sperm and Testicular Function
- Cerebrovascular and genetic disorders
- Reproductive System and Pregnancy
- melanin and skin pigmentation
- Pluripotent Stem Cells Research
- Digestive system and related health
Genentech
2019
University of Münster
2018
Max Planck Institute for Molecular Biomedicine
2018
University of Oslo
2018
University of Oxford
2018
Oslo University Hospital
2018
Washington University in St. Louis
2010
Feinstein Institute for Medical Research
2010
Lawrence Berkeley National Laboratory
2005
Howard Hughes Medical Institute
2005
Notch signaling is known to regulate the proliferation and differentiation of intestinal stem progenitor cells; however, direct cellular targets specific functions signals had not been identified. We show here in mice that directly crypt base columnar (CBC) cell maintain activity. inhibition induced rapid CBC loss, with reduced proliferation, apoptotic death efficiency organoid initiation. Furthermore, expression cell-specific marker Olfm4 was dependent on signaling, transcription activated...
Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration multiple inputs. In mouse small intestine, Notch Wnt signaling are required both for cell maintenance a proper balance between secretory absorptive lineages. absence signaling, preferentially generate at expense cells. Here, we use function-blocking antibodies against receptors to demonstrate that blockade perturbs intestinal function by causing derepression pathway, leading...
The IRF8-dependent subset of classical dendritic cells (cDCs), termed cDC1, is important for cross-priming cytotoxic T cell responses against pathogens and tumors. Culture hematopoietic progenitors with DC growth factor FLT3 ligand (FLT3L) yields very few cDC1s (in humans) or only immature "cDC1-like" the mouse). We report that OP9 stromal expressing Notch Delta-like 1 (OP9-DL1) optimize FLT3L-driven development from murine immortalized primary bone marrow cells. Co-culture OP9-DL1 induced a...
Abstract NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting mutations drive clonal expansion impede carcinogenesis. Here we test this hypothesis. Sequencing aging reveals frequent biallelic that block signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced loss second allele. Widespread alters transcription has minimal effects...
The oncogene protein product (p21) of the ras gene has been implicated in mediating effects a variety growth factors and hormones. Microinjection monoclonal antibody 6B7, which is directed against synthetic peptide corresponding to highly conserved region p21 (amino acids 29 44) required for function, specifically inhibited Xenopus oocyte maturation induced by incubation with insulin. inhibition was dose-dependent specific since (i) same had no effect on progesterone-induced maturation, (ii)...
Delivery of siRNA is a key hurdle to realizing the therapeutic promise RNAi. By targeting internalizing cell surface antigens, antibody–siRNA complexes provide possible solution. However, initial reports relied on non-specific charged interactions and have not been broadly applicable. To assess improve this delivery method, we built an industrial platform antibodies called THIOMABs, engineered enable precise covalent coupling siRNAs. We report that such generates monomeric conjugates (ARCs)...
Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These are incompletely effective and decrease anticancer activity graft. We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived showed markedly decreased production inflammatory cytokines, but normal vivo proliferation, increased accumulation regulatory cells,...
Abstract The mechanisms underlying lymphocyte lineage stability and plasticity remain elusive. Recent work indicates that innate lymphoid cells (ILC) possess substantial plasticity. Whereas natural ILC2 (nILC2) produce type-2 cytokines, plastic inflammatory (iILC2) can coproduce both cytokines the ILC3-characteristic cytokine, IL-17. Mechanisms elicit this plasticity, importance in health disease, unclear. In study we show iILC2 are potent inducers of airway inflammation response to acute...
Primary liver cancer encompasses both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). The Notch signaling pathway, known to be important for the proper development of architecture, is also a potential driver primary cancer. However, with four receptors several ligands, it not clear which pathway members play predominant role in To address this question, we utilized antibodies specifically target Notch1, Notch2, Notch3, or jagged1 (Jag1) mouse model driven by v-akt murine thymoma...
Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, survival. Although aberrant activation has been implicated in numerous malignancies, including breast cancer, the importance individual distinct cancer subtypes mechanisms receptor remain unclear. Using a novel antibody detect active NOTCH3, we report here that NOTCH3 signals constitutively panel basal lines more than third tumors. Selective...
Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack animal models that faithfully recapitulate different subtypes impedes adequate preclinical testing stratified therapeutic concepts. Here, we demonstrate constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis Trp53ΔIEC mice...
Somatic inhibition restricts splicing of the Drosophila P-element third intron (IVS3) to germ line. We have exploited this simple system provide a model for mechanism alternative pre-mRNA splicing. Biochemical complementation experiments revealed that somatic extracts inhibited U1 snRNP binding 5' splice site. Using sensitive RNase protection and modification-interference assays, we found bound pseudo-5' site in exon multiprotein complexes an adjacent Binding these factors appeared mediate...
In eukaryotic cells alternative splicing of messenger RNA precursors (pre-mRNA's) is a means regulating gene expression. Although number the components that participate in some events have been identified by molecular genetic procedures, elucidation biochemical mechanisms governing requires vitro reaction systems. The tissue specificity P element transposition Drosophila depends on germline restriction pre-mRNA third intron (IVS3). IVS3 substrates were spliced accurately heterologous human...
Mammalian SR proteins are currently thought to function in mRNA export as well splicing. They contain multiple phosphorylated serine/arginine (RS/SR) dipeptides. Although domains can be by many kinases vitro, the physiologically relevant kinase(s), and role(s) of these modifications vivo have remained unclear. Npl3 is a shuttling protein budding yeast that we showed previously substrate for mammalian kinase, SRPK1, related Sky1. Here demonstrate Sky1p phosphorylates only one Npl3p's eight...
Binding of a multiprotein complex to 5' exon inhibitory element appears repress splicing the Drosophila P-element third intron (IVS3) in soma. We have purified 97- and 50-kD proteins that interact specifically with using RNA affinity chromatography. Antibodies specific for 97-kD protein relieve inhibition IVS3 somatic extracts, providing direct evidence requires this protein, inhibitor (PSI). identify as hrp48, similar mammalian factor hnRNP A1, show hrp48 recognizes nucleotides pseudo-5'...
Analysis of EST and cDNA collections from a number metazoan species has identified genes encoding long polyadenylated transcripts that do not contain ORFs lengths typical for protein-encoding mRNAs. Noncoding functions such have been elucidated in only few examples. The corresponding neither hallmark sequence motifs nor appear to conserved across phyla. Thus, it is impossible systematically identify new members this class gene by using homology traditional gene-finding algorithms depend on...
Notch has a well-defined role in controlling cell fate decisions the embryo and adult epidermis immune systems, yet emerging evidence suggests also directs non-cell-autonomous signalling tissues. Here, we show that Notch1 works as damage response signal. Epidermal induces recruitment of subsets including RORγ(+) ILC3s into wounded dermis; are potent sources IL17F wounds control immunological epidermal responses. Mice deficient for heal poorly resulting from delayed proliferation macrophage...