A5061151378- Biochemical and Molecular Research
- Microtubule and mitosis dynamics
- Protein Degradation and Inhibitors
- RNA Research and Splicing
- HER2/EGFR in Cancer Research
- Immune Response and Inflammation
- Cancer Treatment and Pharmacology
- RNA and protein synthesis mechanisms
- interferon and immune responses
- Breast Cancer Treatment Studies
- Streptococcal Infections and Treatments
- Cancer-related molecular mechanisms research
- Cancer-related gene regulation
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- RNA regulation and disease
- Immune Cell Function and Interaction
- Viral Infections and Immunology Research
- Inflammasome and immune disorders
- Genetic Associations and Epidemiology
- Cancer Genomics and Diagnostics
- Fetal and Pediatric Neurological Disorders
- Protein Kinase Regulation and GTPase Signaling
- Nutrition, Genetics, and Disease
- Cancer Mechanisms and Therapy
Boehringer Ingelheim (Austria)
2020-2024
Ablynx (Belgium)
2022
University of Vienna
2011-2020
Max Perutz Labs
2011-2020
Vienna Biocenter
2016-2020
Medical University of Vienna
2020
Helios Amper-Klinikum Dachau
2018
Diakonie-Klinikum Stuttgart
2012
Caritas-Krankenhaus Bad Mergentheim
2012
Breast Center
2012
Article20 December 2011Open Access Tristetraprolin-driven regulatory circuit controls quality and timing of mRNA decay in inflammation Franz Kratochvill Max F. Perutz Laboratories, Center for Molecular Biology, University Vienna, Austria Search more papers by this author Christian Machacek Claus Vogl Institute Animal Breeding Genetics, Veterinary Medicine Florian Ebner Vitaly Sedlyarov Andreas R Gruber Department Theoretical Chemistry, Harald Hartweger Raimund Vielnascher Marina Karaghiosoff...
Abstract HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. binding to AU-rich elements within the 3′ untranslated region of mRNAs encoding oncogenes, growth factors, cytokines leads message stability translation. In this study, we evaluated as a small-molecule target for preventing cancer high-risk groups such those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). human specimens, levels cytoplasmic...
Precise regulation of mRNA decay is fundamental for robust yet not exaggerated inflammatory responses to pathogens. However, a global model integrating and functional consequences inflammation-associated remains be established. Using time-resolved high-resolution RNA binding analysis the mRNA-destabilizing protein tristetraprolin (TTP), an inflammation-limiting factor, we qualitatively quantitatively characterize TTP positions in transcriptome immunostimulated macrophages. We identify...
Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation multidrug resistant strains. Understanding immune responses orchestrating K. clearance by host utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with launching bacterial growth-controlling interactions between alveolar macrophages natural killer (NK) cells. Type IFNs are important but disparate incompletely understood...
We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using collection of German cases and matched controls >25,000 single nucleotide polymorphisms located within 16,000 genes. One the candidate loci identified was on chromosome 19p13.2 [odds ratio (OR) = 1.5, P 0.001]. The effect substantially stronger in subset with reported family history (OR 3.4, 0.001). finding subsequently replicated two independent collections (combined OR 1.4, <...
The RNA-editing protein ADAR is essential for early development in the mouse. Genetic evidence suggests that A to I editing marks endogenous RNAs as 'self'. Today, different Adar knockout alleles have been generated show a common phenotype of apoptosis, liver disintegration, elevated immune response and lethality at E12.5. All can be rescued by concomitant deletion innate immunity genes Mavs or Ifih1 (MDA5), albeit extents. This multiple functions ADAR. We analyze AdarΔ7-9 mice unique growth...
<p>PRISM platform–based high-throughput screen with more than 900 cancer cell lines shows sensitivity of BI-2493 across a wide range <i>KRAS</i>-altered lines. <b>A,</b> Sensitivity data 801 after quality control are shown (Supplementary Table S1). Cancer ranked from the highest (left) to lowest (right) using measure 1 − AUC (area under dose–response curve). Red bars highlight lines, including <i>KRAS</i> mutations (point mutations, insertions, and...
<p><i>KRAS</i> WT–amplified tumors are enriched in gastroesophageal cancers. <b>A,</b> TCGA cohort was queried for <i>KRAS</i> patients. Frequency of patients is shown, stratified by different thresholds relative CNs. Only the top 10 altered cancer types shown CN 2 to 3. <b>B,</b> Stratified Cox regression grouped thresholds. For each analysis, were a variable interest (e.g., > 7) and compared with all other OR plots show log scale...
<div>Abstract<p>KRAS<sup>G12C</sup> selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other <i>KRAS</i>-mutant alleles in patients with cancer. We report that <i>KRAS</i> wild-type (WT)–amplified tumor models are sensitive to treatment the small-molecule KRAS inhibitors BI-2493 BI-2865. These pan-KRAS directly target “OFF” state result potent antitumor activity preclinical cancers driven by KRAS-mutant...
<p>Supplementary Figure 1: Cellular sensitivity to BI-2493 integrated with CRISPR and RNAi gene dependency data. (Top) CRISPR: Drug-target associations show selectivity of for KRAS but not HRAS NRAS. Panel left, mid right effect (or dependency) scores derived from Chronos KRAS, NRAS, respectively on the x-axis. A low score indicates that a cell line is likely depend given gene. equal or close 0 genes are non-essential, whereas -1 defined as median all common essential commonly used...
<p>Supplementary Figure 9: BI-2493 and BI-2865 treatment induces cell cycle arrest apoptosis in KRAS wild-type amplified cancer lines. (A) Upper panel: Representative flow blots of states determined by EdU incorporation into newly synthesized DNA total content staining FxCycle indicated lines treated for 48 h with DMSO (mock), 3 µM BI-2493, 0.3 trametinib. Cells were pre-gated based on scattering properties content. Numbers indicate frequency parent population. Lower Impact or...
<p>Supplementary Figure 6: Relationship between KRAS wild-type amplification and oncogenic activity in TCGA patient data. RAS activation signatures MPAS (3), RAS_addiction Ras84 (1). Enrichment scores were estimated using single sample enrichment (ssGSEA) A one-sided Wilcox-test was used to test for significance relative copy number of 2-7 or >7.</p>
<p><i>KRAS</i> WT–amplified cancer cell lines are sensitive to pan-KRAS inhibitors BI-2493 and BI-2865. <b>A,</b> Cell tested for sensitivity were ranked according <i>KRAS</i> WT relative CN. Tumor of origin gene expression [log<sub>2</sub>(TPM + 1)] indicated. <b>B, </b><i>In vitro</i> shown in <b>A</b> BI-2493, BI-2865, trametinib (<i>n</i> = 3, means ± SD). Control lines, with CN < 7,...
<p>Supplementary Figure 7. Gastroesophageal cancers are enriched in KRAS wild-typeWT amplified tumors. (n=3464) were selected from the AACR Genie MSK and DFCI cohort (version v16.0-public). Only patients with any alterations above listed genes shown (1498 unaltered not shown). Co-alterations ranked by frequency. samples defined a GISTIC score of 2 according to GENIE as exact copy number thresholds available cohort.</p>
<p>Supplementary Figure 5. Anti-proliferative activity of RMC-7977 across different KRAS altered cell lines. (Left) (2) mutant or wild-type amplified Cell lines are sorted by median sensitivity alleles. Note: AUC values relative measures drug and therefore suitable to compare for a single compound but do not allow comparison compounds. (Right) Comparison with dependency on either KRAS, HRAS NRAS. Chronos score (gene effect score) less than -1 were considered dependent. Sensitivity...
<p>Supplementary Figure 3. Relationship between KRAS wild-type amplification and oncogenic activity in cell lines. RAS activation signatures (1,3) MSigDB, KrasLA, KRASG13D134, HRAS, MPAS, ras84 addiction amplified lines (relative copy number >7) compared to with a lower relative (2-7) mutated without amplification. Enrichment scores were estimated using single sample enrichment (ssGSEA). A one-sided Wilcox-test was used test for significance of 2-7 or >7. Adjusted P-values...
<p>Supplementary Figure 10. BI-2493 treatment in animal models is tolerated. % bodyweight change xenograft treated with control vehicle or BI-2493. Data represent the mean +/- SEM of mice grafted with: (A) DMS 53 cells (N=7); (B) MKN1 (N=7). One group had to be sacrificed earlier (d11) due loss. (C) ES11082 PDX model (N=8). Two animals and three (d18, d18, d15, d12, d7, respectively). (D) GA6871 2 (d7 d16, d30, respectively) loss.</p>
<p>BI-2493 suppresses tumor growth in xenograft models of <i>KRAS</i> WT–amplified cancers. <b>A,</b> Antitumor activity BI-2493 the DMS 53 small cell lung cancer (SCLC) CDX model (left) and MKN1 gastric (GC) (right). was administered orally twice daily at 30 or 90 mg/kg. Data represent mean volume ± SEM (<i>N</i> = 7). Statistical significance assessed on day 20. *, <i>P</i> < 0.05 vs. vehicle control (Wilcoxon test Bonferroni–Holm...
<p>Supplementary Figure 4. Correlation between signatures for KRAS activation and sensitivity to BI-2493 across the wild-type amplified cell panel. RAS were obtained from East et al. (1). coefficient enrichment scores estimated using a Pearson R.</p>
<p>Supplementary Figure 8: KRAS wild-type amplified cancer cell lines are sensitive to pan-KRAS inhibitors BI-2493 and BI-2865. (A) Inhibition of pERK by BI-2493, BI-2865 trametinib at the indicated timepoints for (n=2, means ± SD). Control lines, with CN<7 CN>7 colored in black, blue, red, respectively. (B) Quantification down regulation from 1M concentration P-values were calculated using two-way ANOVA, followed Tukey’s multiple comparisons test.</p>
<p>Supplementary Figure 2: KRAS expression as a function of copy number alteration. (Left) increases with number. (Mid) High correlation and (Pearson R=0.904, P=4.85e-20). The vertical dotted line marks relative threshold 7. Only cell lines >2 are shown. (Right) Ranking across all 800 from the PRISM screen. Vertical left to right mark thresholds 10, 7, 2 1, respectively.</p>
Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether lifespan pathogen-engaged is regulated differently from that in circulating steady-state pool. Here, we have found under homeostatic conditions, mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis numbers infiltrating murine but not neutrophil cellularity....