A5076858197- Gene Regulatory Network Analysis
- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- Single-cell and spatial transcriptomics
- RNA modifications and cancer
- Bioinformatics and Genomic Networks
- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- TGF-β signaling in diseases
- Cell death mechanisms and regulation
- Ovarian cancer diagnosis and treatment
- Microtubule and mitosis dynamics
- Circadian rhythm and melatonin
- Light effects on plants
- Pluripotent Stem Cells Research
- Mathematical Biology Tumor Growth
- Bacterial Genetics and Biotechnology
- Protein Tyrosine Phosphatases
- CRISPR and Genetic Engineering
- Endoplasmic Reticulum Stress and Disease
- Lymphoma Diagnosis and Treatment
- Genomics and Chromatin Dynamics
- Melanoma and MAPK Pathways
- Cellular Mechanics and Interactions
- Developmental Biology and Gene Regulation
University of Stuttgart
2021-2024
Institute of Molecular Biology
2013-2023
Johannes Gutenberg University Mainz
2022
Boehringer Ingelheim (Australia)
2022
Digital Science (United States)
2022
Center for Systems Biology
2022
German Cancer Research Center
2011-2012
Heidelberg University
2012
National Academy of Sciences of Armenia
2011
DKFZ-ZMBH Alliance
2011
The intrinsic, or mitochondrial, pathway of caspase activation is essential for apoptosis induction by various stimuli including cytotoxic stress. It depends on the cellular context, whether cytochrome c released from mitochondria induces gradually in an all-or-none fashion, and irreversibly commits cells to apoptosis. By analyzing a quantitative kinetic model, we show that inhibition caspase-3 (Casp3) Casp9 inhibitors (IAPs) results implicit positive feedback, since cleaved Casp3 augments...
Article7 April 2009Open Access Systems-level interactions between insulin–EGF networks amplify mitogenic signaling Nikolay Borisov Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA Search for more papers by this author Edita Aksamitiene Anatoly Kiyatkin Stefan Legewie Institute Theoretical Humboldt Berlin, Germany Jan Berkhout Maiwald Freiburg Advanced Science, University Freiburg, Nikolai P Kaimachnikov Biophysics, Russian Academy...
The building blocks of most signal transduction pathways are pairs enzymes, such as kinases and phosphatases, that control the activity protein targets by covalent modification. It has previously been shown [Goldbeter A & Koshland DE (1981) Proc Natl Acad Sci USA 78 , 6840–6844] these systems can be highly sensitive to changes in stimuli if their catalysing enzymes saturated with target substrates. This mechanism, termed zero‐order ultrasensitivity, may set thresholds filter out...
Article23 February 2018Open Access Transparent process Estrogen-dependent control and cell-to-cell variability of transcriptional bursting Christoph Fritzsch Institute Molecular Biology, Mainz, Germany Search for more papers by this author Stephan Baumgärtner Monika Kuban Daria Steinshorn George Reid Corresponding Author [email protected] orcid.org/0000-0002-0298-693X European Biology Laboratory, Heidelberg, Stefan Legewie orcid.org/0000-0003-4111-0567 Information Fritzsch1,‡,...
Abstract Even though proteins are produced from mRNA, the correlation between mRNA levels and protein abundances is moderate in most studies, occasionally attributed to complex post-transcriptional regulation. To address this, we generate a paired transcriptome/proteome time course dataset with 14 points during Drosophila embryogenesis. Despite limited mRNA-protein ( ρ = 0.54), mathematical models describing translation degradation explain 84% of time-courses based on measured dynamics...
Dual modes of activation caspase-8 enable precise control apoptosis.
Alternative splicing generates distinct mRNA isoforms and is crucial for proteome diversity in eukaryotes. The RNA-binding protein (RBP) U2AF2 central to decisions, as it recognizes 3′ splice sites recruits the spliceosome. We establish “in vitro iCLIP” experiments, which recombinant RBPs are incubated with long transcripts, study how RNA sequences this modulated by trans -acting RBPs. measure affinities at hundreds of binding compare vivo landscapes mathematical modeling. find that...
Article25 January 2018Open Access Transparent process Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels Jette Strasen Berlin Institute for Medical Systems Biology, Max Delbrueck Center Helmholtz Association, Berlin, Germany Search more papers this author Uddipan Sarma of Molecular Biology (IMB), Mainz, Marcel Jentsch Department Technische Universität Darmstadt, Stefan Bohn Caibin Sheng Daniel Horbelt Chemistry and Biochemistry, Freie Petra Knaus...
Abstract Following CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope can be caused by aberrant exon 2 processing, we herein investigate regulatory code that controls splicing. We combine high-throughput mutagenesis with mathematical modelling quantitatively disentangle effects all mutations in region comprising exons 1-3. Thereupon, identify ~200 single point alter splicing and thus could...
Splicing of pre-mRNAs critically contributes to gene regulation and proteome expansion in eukaryotes, but our understanding the recognition pairing splice sites during spliceosome assembly lacks detail. Here, we identify multidomain RNA-binding protein FUBP1 as a key splicing factor that binds hitherto unknown cis-regulatory motif. By collecting NMR, structural, vivo interaction data, demonstrate stabilizes U2AF2 SF1, components at 3' site, through multivalent binding interfaces located...
What makes embryogenesis a robust and canalized process is an important question in developmental biology. A bone morphogenetic protein (BMP) morphogen gradient plays key role embryonic development, we are beginning to understand how the self-regulating properties of its signaling circuitry ensure patterning. An unexplored why BMP circuit organized as modular synexpression group, with prevalence feedback inhibitors. Here, provide evidence from direct experimentation mathematical modeling...
Mutations causing aberrant splicing are frequently implicated in human diseases including cancer. Here, we establish a high-throughput screen of randomly mutated minigenes to decode the cis-regulatory landscape that determines alternative exon 11 proto-oncogene MST1R (RON). Mathematical modelling kinetics enables us identify more than 1000 mutations affecting RON skipping, which corresponds pathological isoform RON∆165. Importantly, effects correlate with cancer patients bearing same...
Alternative pre-mRNA splicing is an essential step in human gene regulation, and mutation- induced aberrant frequently found diseases therapy resistance. Splicing regulation highly dependent on sequence cellular context, posing a challenge to predict outcomes of splicing-related disease mutations. Here, we use kinetic modeling derive the underlying quantitative principles, describing splice site competition downstream effects wide spectrum isoforms. Employing statistical learning large-scale...
Mitogen‐activated protein kinase (MAPK) signaling determines crucial cell fate decisions in most types, and mediates cellular transformation many types of cancer. The activity MAPK is controlled by reversible phosphorylation, the quantitative characteristics activation determine response. Many systems biological studies have analyzed kinetics dose–response behavior pathway. Here we investigate how pathway transcriptional feedback loops. Initially, predict that regulates phosphatases,...
Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with deficiency or overload. A key role this process plays ferroportin, the only known mammalian transmembrane exporter, which releases from duodenal enterocytes, hepatocytes, iron-recycling macrophages into blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms response hypoxia, deficiency, heme inflammatory cues cell-autonomous...
Stimulation of CD95/Fas/APO-1 results in the induction both apoptotic and non-apoptotic signaling pathways. The processes regulating these two opposing pathways have not been thoroughly elucidated to date. In this study, using quantitative immunoblots, imaging, mathematical modeling, we addressed dynamics DED proteins death-inducing complex (DISC), procaspase-8, cellular FLICE inhibitory (c-FLIPs) onset CD95-mediated ERK1/2 p38 mitogen-activated protein kinase (MAPK) activation. We found...
Circadian rhythms are generated by complex interactions among genes and proteins. Self-sustained ∼24 hour oscillations require negative feedback loops sufficiently strong nonlinearities that the product of molecular network switches. Here we review common mechanisms to obtain switch-like behavior, including cooperativity, antagonistic enzymes, multisite phosphorylation, positive feedback, sequestration. We discuss how switches play a crucial role as essential components in cellular circadian...
Ultrasensitive responses are common in cellular information transfer because they allow cells to decode extracellular stimuli an all‐or‐none manner. Biochemical usually analyzed by fitting the Hill equation, and estimated coefficient is taken as a measure of sensitivity. However, this approach not appropriate if response under consideration significantly deviates from best‐fit equation. In addition, coefficients greater than unity do necessarily imply ultrasensitive behaviour basal...
Abstract Alternative splicing is an important step in eukaryotic mRNA pre-processing which increases the complexity of gene expression programs, but frequently altered disease. Previous work on regulation alternative has demonstrated that controlled by RNA-binding proteins (RBPs) and epigenetic DNA/histone modifications affect changing speed polymerase-mediated pre-mRNA transcription. The interplay these different layers poorly understood. In this paper, we derived mathematical models...