Covalent inhibitor of the Rho family inhibits the migration of breast cancer cells
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ABSTRACT:
PROVIDER: PRJNA417393 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6263606_1.fastq.gz | Fastqsanger.gz | |||
| SRR6263606_2.fastq.gz | Fastqsanger.gz | |||
| SRR6263607_1.fastq.gz | Fastqsanger.gz | |||
| SRR6263607_2.fastq.gz | Fastqsanger.gz | |||
| SRR6263608_1.fastq.gz | Fastqsanger.gz |
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Project description:Small GTPase proteins usually serve as molecular switches in various biological process, such as the proliferation, survival, and migration of cells. Mutations or aberrant activations of small GTPase proteins, such as Ras, are frequently observed in various kinds of cancers. Drug discovery efforts that target the Ras family proteins are making breakthroughs, while the discovery of efficient inhibitors that target the Rho family proteins is still stagnant. Protein members from the Rho family, such as RhoA and Cdc42, are key regulators of the migration and invasion of cancer cells. Thus inhibitors of the Rho family proteins are promising to become drug candidates that target cancer metastasis, which is a principal cause of cancer recurrence and chemotherapy failure. Here we show the discovery and characterization of a novel covalent inhibitor named DC-RC-063 that targets the Rho family proteins, using a combined approach of computations and experiments. Revealed by solved crystal structures, compound DC-RC-063 inhibited the activation of RhoA, by disrupting protein-protein interactions, in an allosteric manner. As compound DC-RC-063 inhibited the migration and invasion of breast cancer MDA-MB-231 cells, our findings proved that the Rho family proteins are targetable for covalent inhibitors via an allosteric mechanism. The novel binding site revealed by this inhibitor can be exploited for further development of anti-cancer drugs that target cancer metastasis.
2017-12-07 | GSE106605 | GEO
Project description:Although Rho GTPases are essential molecular switches involved in many cellular processes, an unbiased experimental comparison of their interaction partners was not yet performed. Here, we develop quantitative GTPase affinity purification (qGAP) to systematically identify interaction partners of six Rho GTPases (Cdc42, Rac1, RhoA, RhoB, RhoC, RhoD) depending on their nucleotide loading state. We use Stable isotope labeling by Amino acids in cell culture (SILAC) and label free quantification (LFQ). Our interaction network contains many new proteins, reveals highly promiscuous binding of several effectors and mirrors evolutionary relationships of Rho GTPases.
2016-12-23 | PXD004190 | Pride
Project description:LSD1 inhibits the invasion and migration of breast cancer through exosomes
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Project description:Describing the architecture of robust, nonlinear cell signaling networks is essential to gain a predictive understanding of cellular behavior. The structure of the Drosophila Rho-signaling network, comprised of Rho-family GTPases, RhoGTP Exchange Factors (RhoGEFs), and RhoGTPase Activating Proteins (RhoGAPs), has been particularly difficult to infer due to the highly overlapping function and substrate specificity of network components. We developed a parameterized modeling approach to predict connectivity amongst components of the Rho-signaling network that was driven by hundreds of mRNA expression profiles derived from RNAi-mediated inhibition or overexpression of component genes. Our model incorporated rate kinetics, transcriptional feedback, and noise. We biochemically validated several novel predicted connections, and used this model to predict Rho-signaling response to particular conditions. While functional redundancy is a feature of all signaling systems that often prevents classical genetic methods from elucidating relationships between components, the methods described here provide the basis for describing any complex network architecture. Keywords: Genetic modification, RNAi-mediated gene inhibition
2012-12-31 | GSE18307 | GEO
Project description:Transcription profiling of E. coli MG1655Δrac, comparing the effect Rho mutants (SBS: N340S, G324D) with WT Rho
2016-03-28 | GSE77177 | GEO
Project description:Background: Cancer metastasis is dependent on cell migration. Several mechanisms, including epithelial-to-mesenchymal transition (EMT) and actin fiber formation, could be involved in cancer cell migration. As a downstream effector of the Hippo signaling pathway, transcriptional coactivator with PDZbinding motif (TAZ) is recognized as a key mediator of the metastatic ability of breast cancer cells. We aimed to examine whether TAZ affects the migration of breast cancer cells through the regulation of EMT or actin cytoskeleton. Methods: MCF-7 and MDA-MB-231 cells were treated with siRNA to attenuate TAZ abundance. Transwell migration assay and scratch wound healing assay were performed to study the effects of TAZ knockdown on cancer cell migration. Fluorescence microscopy was conducted to examine the vinculin and phalloidin. Semiquantitative immunoblotting and quantitative real-time PCR were performed to study the expression of small GTPases and kinases. Changes in the expression of genes associated with cell migration were examined through next-generation sequencing. Results: TAZ-siRNA treatment reduced TAZ abundance in MCF-7 and MDA-MB- 231 breast cancer cells, which was associated with a significant decrease in cell migration. TAZ knockdown increased the expression of fibronectin, but it did not exhibit the typical pattern of EMT progression. TGF-b treatment in MDA-MB-231 cells resulted in a reduction in TAZ and an increase in fibronectin levels. However, it paradoxically promoted cell migration, suggesting that EMT is unlikely to be involved in the decreased migration of breast cancer cells in response to TAZ suppression. RhoA, a small Rho GTPase protein, was significantly reduced in response to TAZ knockdown. This caused a decrease in the expression of the Rho-dependent downstream pathway, i.e., LIM kinase 1 (LIMK1), phosphorylated LIMK1/2, and phosphorylated cofilin, leading to actin depolymerization. Furthermore, myosin light chain kinase (MLCK) and phosphorylated MLC2 were significantly decreased in MDA-MB-231 cells with TAZ knockdown, inhibiting the assembly of stress fibers and focal adhesions. Conclusion: TAZ knockdown inhibits the migration of breast cancer cells by regulating the intracellular actin cytoskeletal organization. This is achieved, in part, by reducing the abundance of RhoA and Rho-dependent downstream kinase proteins, which results in actin depolymerization and the disassembly of stress fibers and focal adhesions.
2024-04-27 | GSE264547 | GEO
Project description:Describing the architecture of robust, nonlinear cell signaling networks is essential to gain a predictive understanding of cellular behavior. The structure of the Drosophila Rho-signaling network, comprised of Rho-family GTPases, RhoGTP Exchange Factors (RhoGEFs), and RhoGTPase Activating Proteins (RhoGAPs), has been particularly difficult to infer due to the highly overlapping function and substrate specificity of network components. We developed a parameterized modeling approach to predict connectivity amongst components of the Rho-signaling network that was driven by hundreds of mRNA expression profiles derived from RNAi-mediated inhibition or overexpression of component genes. Our model incorporated rate kinetics, transcriptional feedback, and noise. We biochemically validated several novel predicted connections, and used this model to predict Rho-signaling response to particular conditions. While functional redundancy is a feature of all signaling systems that often prevents classical genetic methods from elucidating relationships between components, the methods described here provide the basis for describing any complex network architecture. Keywords: Genetic modification, RNAi-mediated gene inhibition 129 samples analyzed. Experiments were peformed in batches of 4 containing 1 control/reference sample (transfection of GFP alone) that was prepared in parallel with experimental samples. There are 30 reference samples. The majority of experiments were replicated 2-6 times.
2012-12-31 | E-GEOD-18307 | biostudies-arrayexpress
Project description:Transcription termination factor Rho is essential in enterobacteria. We inhibited Rho activity with bicyclomycin and used microarray experiments to assess Rho function on a genome-wide scale. Rho is a global regulator of gene expression that matches E. coli transcription to translational needs. Remarkably, genes that are most repressed by Rho are prophages and other horizontally-acquired portions of the genome. Elimination of these foreign DNA elements increases resistance to bicyclomycin. Although rho remains essential, such reduced-genome bacteria no longer require Rho cofactors NusA and NusG. Thus, Rho termination, supported by NusA and NusG, is required to suppress the toxic activity of foreign DNA. Global regulation of transcription termination by Rho, NusA, and NusG. Experiment Overall Design: Two sets of experiments are presented. First, treatment of E. coli with Rho inhibitor bicyclomycin was performed in strains MG1655 and O157:H7 EDL933 for twenty minutes at concentrations of 10, 25, or 100 micrograms/milliliter. In the second set of experiments the reduced-genome strain MDS42 was treated with bicyclomycin as well as having deletions of the genes nusA and nusG. Total RNA was extracted and hybridized to the Affymetrix E. coli Genome 2.0 array, which contains complete genome coverage of four strains of E. coli.
2008-06-20 | E-GEOD-10345 | biostudies-arrayexpress
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