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  • 1
    Keywords: CANCER ; EXPRESSION ; CELL ; Germany ; KINASE ; MODEL ; PATHWAY ; CLASSIFICATION ; SUPPORT ; SYSTEM ; SYSTEMS ; GENE ; GENE-EXPRESSION ; PROTEIN ; MICE ; ACTIVATION ; animals ; RATS ; BIOLOGY ; fibroblasts ; PHOSPHORYLATION ; PROTEIN-KINASE ; SEQUENCE ; gene expression ; HUMANS ; PROMOTER ; REQUIRES ; SIGNALING PATHWAY ; DOSE-RESPONSE ; TRANSFORMATION ; PREDICTION ; KINETICS ; SELECTION ; REVEALS ; systems biology ; BEHAVIOR ; Ras ; signaling ; MAPK ; regulation ; mRNA ; PHOSPHATASE ; EXTENT ; Oligonucleotide Array Sequence Analysis ; RNA Stability ; INVESTIGATE ; Extracellular ; cellular response ; CELLULAR-RESPONSE ; SEQUENCE DATA ; hypothesis ; *Genes,ras ; *Models,Biological ; Cells,Cultured ; *Feedback,Biochemical ; Dual Specificity Phosphatase 6/*physiology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Fibroblasts/metabolism ; MAP Kinase Signaling System/physiology ; RNA,Messenger/metabolism ; Signal Transduction/physiology
    Abstract: Mitogen-activated protein kinase (MAPK) signaling determines crucial cell fate decisions in most cell types, and mediates cellular transformation in many types of cancer. The activity of MAPK is controlled by reversible phosphorylation, and the quantitative characteristics of MAPK activation determine the cellular response. Many systems biological studies have analyzed the activation kinetics and the dose-response behavior of the MAPK signaling pathway. Here we investigate how the pathway activity is controlled by transcriptional feedback loops. Initially, we predict that MAPK signaling regulates phosphatases, by integrating promoter sequence data and ontology-based classification of gene function. From this, we deduce that MAPK signaling might be controlled by transcriptional negative feedback regulation via dual-specificity phosphatases (DUSPs), and implement a mathematical model to further test this hypothesis. Using time-resolved measurements of pathway activity and gene expression, we employ a model selection approach, and select DUSP6 as a highly likely candidate for shaping the activity of the MAPK pathway during cellular transformation caused by oncogenic RAS. Two predictions from the model were confirmed: first, feedback regulation requires that DUSP6 mRNA and protein are unstable; and second, the activation kinetics of MAPK are ultrasensitive. Taken together, an integrated systems biological approach reveals that transcriptional negative feedback controls the kinetics and the extent of MAPK activation under both physiological and pathological conditions.
    Type of Publication: Journal article published
    PubMed ID: 19154344
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  • 2
    Abstract: Colorectal cancer is driven by cooperating oncogenic mutations. In this study, we use organotypic cultures derived from transgenic mice inducibly expressing oncogenic beta-catenin and/or PIK3CAH1047R to follow sequential changes in cancer-related signaling networks, intestinal cell metabolism, and physiology in a three-dimensional environment mimicking tissue architecture. Activation of beta-catenin alone results in the formation of highly clonogenic cells that are nonmotile and prone to undergo apoptosis. In contrast, coexpression of stabilized beta-catenin and PIK3CAH1047R gives rise to intestinal cells that are apoptosis-resistant, proliferative, stem cell-like, and motile. Systematic inhibitor treatments of organoids followed by quantitative phenotyping and phosphoprotein analyses uncover key changes in the signaling network topology of intestinal cells after induction of stabilized beta-catenin and PIK3CAH1047R We find that survival and motility of organoid cells are associated with 4EBP1 and AKT phosphorylation, respectively. Our work defines phenotypes, signaling network states, and vulnerabilities of transgenic intestinal organoids as a novel approach to understanding oncogene activities and guiding the development of targeted therapies.
    Type of Publication: Journal article published
    PubMed ID: 28442534
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  • 3
    Keywords: GROWTH-FACTOR RECEPTOR ; COLORECTAL-CANCER ; ACQUIRED-RESISTANCE ; PROTEIN PHOSPHATASE ; BREAST-CANCER CELLS ; ERK ACTIVATION ; AZD6244 ARRY-142886 ; negative feedback ; MEK INHIBITION ; REGULATED KINASE
    Abstract: The epidermal growth factor receptor (EGFR) signaling network is activated in most solid tumors, and small-molecule drugs targeting this network are increasingly available. However, often only specific combinations of inhibitors are effective. Therefore, the prediction of potent combinatorial treatments is a major challenge in targeted cancer therapy. In this study, we demonstrate how a model-based evaluation of signaling data can assist in finding the most suitable treatment combination. We generated a perturbation data set by monitoring the response of RAS/PI3K signaling to combined stimulations and inhibitions in a panel of colorectal cancer cell lines, which we analyzed using mathematical models. We detected that a negative feedback involving EGFR mediates strong cross talk from ERK to AKT. Consequently, when inhibiting MAPK, AKT activity is increased in an EGFR-dependent manner. Using the model, we predict that in contrast to single inhibition, combined inactivation of MEK and EGFR could inactivate both endpoints of RAS, ERK and AKT. We further could demonstrate that this combination blocked cell growth in BRAF- as well as KRAS-mutated tumor cells, which we confirmed using a xenograft model.
    Type of Publication: Journal article published
    PubMed ID: 23752269
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