Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis
Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAFV600E melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti-tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single-cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to r...
Source: Molecular Systems Biology - March 26, 2015 Category: Molecular Biology Authors: Fallahi-Sichani, M., Moerke, N. J., Niepel, M., Zhang, T., Gray, N. S., Sorger, P. K. Tags: Cancer, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Phospho-tyrosine dependent protein-protein interaction network
Post-translational protein modifications, such as tyrosine phosphorylation, regulate protein–protein interactions (PPIs) critical for signal processing and cellular phenotypes. We extended an established yeast two-hybrid system employing human protein kinases for the analyses of phospho-tyrosine (pY)-dependent PPIs in a direct experimental, large-scale approach. We identified 292 mostly novel pY-dependent PPIs which showed high specificity with respect to kinases and interacting proteins and validated a large fraction in co-immunoprecipitation experiments from mammalian cells. About one-sixth of the interactions are ...
Source: Molecular Systems Biology - March 26, 2015 Category: Molecular Biology Authors: Grossmann, A., Benlasfer, N., Birth, P., Hegele, A., Wachsmuth, F., Apelt, L., Stelzl, U. Tags: Network Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Growth-dependent bacterial susceptibility to ribosome-targeting antibiotics
Bacterial growth environment strongly influences the efficacy of antibiotic treatment, with slow growth often being associated with decreased susceptibility. Yet in many cases, the connection between antibiotic susceptibility and pathogen physiology remains unclear. We show that for ribosome-targeting antibiotics acting on Escherichia coli, a complex interplay exists between physiology and antibiotic action; for some antibiotics within this class, faster growth indeed increases susceptibility, but for other antibiotics, the opposite is true. Remarkably, these observations can be explained by a simple mathematical model tha...
Source: Molecular Systems Biology - March 19, 2015 Category: Molecular Biology Authors: Greulich, P., Scott, M., Evans, M. R., Allen, R. J. Tags: Articles Source Type: research
T160-phosphorylated CDK2 defines threshold for HGF-dependent proliferation in primary hepatocytes
In conclusion, we identified CDK2 phosphorylation as a gate-keeping mechanism to maintain hepatocyte quiescence in the absence of HGF. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - March 14, 2015 Category: Molecular Biology Authors: Mueller, S., Huard, J., Waldow, K., Huang, X., D'Alessandro, L. A., Bohl, S., Borner, K., Grimm, D., Klamt, S., Klingmuller, U., Schilling, M. Tags: Cell Cycle, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Bridging the knowledge gap: from microbiome composition to function
Despite the wealth of metagenomic sequencing data, the functions of most bacterial genes from the mammalian microbiota have remained poorly understood. In their recent study (Yaung et al 2015), Wang, Gerber, and colleagues present a platform which allows functional mining of bacterial genomes for genes that contribute to fitness in vivo and holds great potential for forward engineering microbes with enhanced colonization abilities in the microbiota. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - March 11, 2015 Category: Molecular Biology Authors: Faith, J. J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Synthetic Biology & Biotechnology News [amp ] Views Source Type: research
Improving microbial fitness in the mammalian gut by in vivo temporal functional metagenomics
We present Temporal FUnctional Metagenomics sequencing (TFUMseq), a platform to functionally mine bacterial genomes for genes that contribute to fitness of commensal bacteria in vivo. Our approach uses metagenomic DNA to construct large-scale heterologous expression libraries that are tracked over time in vivo by deep sequencing and computational methods. To demonstrate our approach, we built a TFUMseq plasmid library using the gut commensal Bacteroides thetaiotaomicron (Bt) and introduced Escherichia coli carrying this library into germfree mice. Population dynamics of library clones revealed Bt genes conferring significa...
Source: Molecular Systems Biology - March 11, 2015 Category: Molecular Biology Authors: Yaung, S. J., Deng, L., Li, N., Braff, J. L., Church, G. M., Bry, L., Wang, H. H., Gerber, G. K. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Synthetic Biology & Biotechnology Articles Source Type: research
Cell shape and the microenvironment regulate nuclear translocation of NF-{kappa}B in breast epithelial and tumor cells
In this study, we used high-content image analysis and Bayesian network modeling to ask whether cell shape and context features influence NF-B activation using the inherent variability present in unperturbed populations of breast tumor and non-tumor cell lines. Cell–cell contact, cell and nuclear area, and protrusiveness all contributed to variability in NF-B localization in the absence and presence of TNFα. Higher levels of nuclear NF-B were associated with mesenchymal-like versus epithelial-like morphologies, and RhoA-ROCK-myosin II signaling was critical for mediating shape-based differences in NF-B localiza...
Source: Molecular Systems Biology - March 3, 2015 Category: Molecular Biology Authors: Sero, J. E., Sailem, H. Z., Ardy, R. C., Almuttaqi, H., Zhang, T., Bakal, C. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia
High-throughput omics have proven invaluable in studying human disease, and yet day-to-day clinical practice still relies on physiological, non-omic markers. The metabolic syndrome, for example, is diagnosed and monitored by blood and urine indices such as blood cholesterol levels. Nevertheless, the association between the molecular and the physiological manifestations of the disease, especially in response to treatment, has not been investigated in a systematic manner. To this end, we studied a mouse model of diet-induced dyslipidemia and atherosclerosis that was subject to various drug treatments relevant to the disease ...
Source: Molecular Systems Biology - March 3, 2015 Category: Molecular Biology Authors: Wagner, A., Cohen, N., Kelder, T., Amit, U., Liebman, E., Steinberg, D. M., Radonjic, M., Ruppin, E. Tags: Computational Biology, Systems Medicine Reports Source Type: research
Cell dynamics and gene expression control in tissue homeostasis and development
During tissue and organ development and maintenance, the dynamic regulation of cellular proliferation and differentiation allows cells to build highly elaborate structures. The development of the vertebrate retina or the maintenance of adult intestinal crypts, for instance, involves the arrangement of newly created cells with different phenotypes, the proportions of which need to be tightly controlled. While some of the basic principles underlying these processes developing and maintaining these organs are known, much remains to be learnt from how cells encode the necessary information and use it to attain those complex bu...
Source: Molecular Systems Biology - February 25, 2015 Category: Molecular Biology Authors: Rue, P., Martinez Arias, A. Tags: Development & Differentiation, Quantitative Biology & Dynamical Systems, Stem Cells Reviews Source Type: research
Targeting a cell state common to triple-negative breast cancers
Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their ‘basal-like’ transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly agg...
Source: Molecular Systems Biology - February 19, 2015 Category: Molecular Biology Authors: Muellner, M. K., Mair, B., Ibrahim, Y., Kerzendorfer, C., Lechtermann, H., Trefzer, C., Klepsch, F., Muller, A. C., Leitner, E., Macho-Maschler, S., Superti-Furga, G., Bennett, K. L., Baselga, J., Rix, U., Kubicek, S., Colinge, J., Serra, V., Nijman, S. M Tags: Cancer, Genome-Scale & Integrative Biology, Pharmacology & Drug Discovery Articles Source Type: research
Quantitative proteomic analysis reveals a simple strategy of global resource allocation in bacteria
A central aim of cell biology was to understand the strategy of gene expression in response to the environment. Here, we study gene expression response to metabolic challenges in exponentially growing Escherichia coli using mass spectrometry. Despite enormous complexity in the details of the underlying regulatory network, we find that the proteome partitions into several coarse-grained sectors, with each sector's total mass abundance exhibiting positive or negative linear relations with the growth rate. The growth rate-dependent components of the proteome fractions comprise about half of the proteome by mass, and their mut...
Source: Molecular Systems Biology - February 13, 2015 Category: Molecular Biology Authors: Hui, S., Silverman, J. M., Chen, S. S., Erickson, D. W., Basan, M., Wang, J., Hwa, T., Williamson, J. R. Tags: Genome-Scale & Integrative Biology, Metabolism, Quantitative Biology & Dynamical Systems Articles Source Type: research
A multi-scale approach reveals that NF-{kappa}B cRel enforces a B-cell decision to divide
Understanding the functions of multi-cellular organs in terms of the molecular networks within each cell is an important step in the quest to predict phenotype from genotype. B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically. Based on tracking single-cell time-lapse trajectories of hundreds of B cells, single-cell transcriptome, and immunofluorescence analyses, we constructed an agent-based multi-modular computational model to simulate lymphocyte population dynamics in terms of the mol...
Source: Molecular Systems Biology - February 13, 2015 Category: Molecular Biology Authors: Shokhirev, M. N., Almaden, J., Davis-Turak, J., Birnbaum, H. A., Russell, T. M., Vargas, J. A. D., Hoffmann, A. Tags: Autophagy & Cell Death, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA
The human PYHIN proteins, AIM2, IFI16, IFIX, and MNDA, are critical regulators of immune response, transcription, apoptosis, and cell cycle. However, their protein interactions and underlying mechanisms remain largely uncharacterized. Here, we provide the interaction network for all PYHIN proteins and define a function in sensing of viral DNA for the previously uncharacterized IFIX protein. By designing a cell-based inducible system and integrating microscopy, immunoaffinity capture, quantitative mass spectrometry, and bioinformatics, we identify over 300 PYHIN interactions reflective of diverse functions, including DNA da...
Source: Molecular Systems Biology - February 9, 2015 Category: Molecular Biology Authors: Diner, B. A., Li, T., Greco, T. M., Crow, M. S., Fuesler, J. A., Wang, J., Cristea, I. M. Tags: Immunology, Network Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Quantitative variability of 342 plasma proteins in a human twin population
The degree and the origins of quantitative variability of most human plasma proteins are largely unknown. Because the twin study design provides a natural opportunity to estimate the relative contribution of heritability and environment to different traits in human population, we applied here the highly accurate and reproducible SWATH mass spectrometry technique to quantify 1,904 peptides defining 342 unique plasma proteins in 232 plasma samples collected longitudinally from pairs of monozygotic and dizygotic twins at intervals of 2–7 years, and proportioned the observed total quantitative variability to its roo...
Source: Molecular Systems Biology - February 4, 2015 Category: Molecular Biology Authors: Liu, Y., Buil, A., Collins, B. C., Gillet, L. C., Blum, L. C., Cheng, L.-Y., Vitek, O., Mouritsen, J., Lachance, G., Spector, T. D., Dermitzakis, E. T., Aebersold, R. Tags: Genetics, Gene Therapy & Genetic Disease, Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Negative feedback buffers effects of regulatory variants
Mechanisms conferring robustness against regulatory variants have been controversial. Previous studies suggested widespread buffering of RNA misexpression on protein levels during translation. We do not find evidence that translational buffering is common. Instead, we find extensive buffering at the level of RNA expression, exerted through negative feedback regulation acting in trans, which reduces the effect of regulatory variants on gene expression. Our approach is based on a novel experimental design in which allelic differential expression in a yeast hybrid strain is compared to allelic differential expression in a poo...
Source: Molecular Systems Biology - January 29, 2015 Category: Molecular Biology Authors: Bader, D. M., Wilkening, S., Lin, G., Tekkedil, M. M., Dietrich, K., Steinmetz, L. M., Gagneur, J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription Articles Source Type: research
