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Results: 1 to 10 of 197

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Muscle-specific stress fibers give rise to sarcomeres in cardiomyocytes.
Fenix AM, Neininger AC, Taneja N, Hyde K, Visetsouk MR, Garde RJ, Liu B, Nixon BR, Manalo AE, Becker JR, Crawley SW, Bader DM, Tyska MJ, Liu Q, Gutzman JH, Burnette DT
(2018) Elife 7:
MeSH Terms: Actin Cytoskeleton, Actins, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Microfilament Proteins, Microscopy, Confocal, Molecular Motor Proteins, Muscle Fibers, Skeletal, Myocytes, Cardiac, Myosin Heavy Chains, Nonmuscle Myosin Type IIB, RNA Interference, Sarcomeres, Stress Fibers
Show Abstract · Added March 27, 2019
The sarcomere is the contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating actin and myosin filament assembly during sarcomere formation. Therefore, we developed an assay using human cardiomyocytes to monitor sarcomere assembly. We report a population of muscle stress fibers, similar to actin arcs in non-muscle cells, which are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from muscle stress fibers. This requires formins (e.g., FHOD3), non-muscle myosin IIA and non-muscle myosin IIB. Furthermore, we show short cardiac myosin II filaments grow to form ~1.5 μm long filaments that then 'stitch' together to form the stack of filaments at the core of the sarcomere (i.e., the A-band). A-band assembly is dependent on the proper organization of actin filaments and, as such, is also dependent on FHOD3 and myosin IIB. We use this experimental paradigm to present evidence for a unifying model of sarcomere assembly.
© 2018, Fenix et al.
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16 MeSH Terms
Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis.
Stoletov K, Willetts L, Paproski RJ, Bond DJ, Raha S, Jovel J, Adam B, Robertson AE, Wong F, Woolner E, Sosnowski DL, Bismar TA, Wong GK, Zijlstra A, Lewis JD
(2018) Nat Commun 9: 2343
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Chick Embryo, Collagen, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, Mice, SCID, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Phenotype, Prostatic Neoplasms, RNA Interference, RNA, Small Interfering
Show Abstract · Added April 10, 2019
Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.
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The C-terminal region of A-kinase anchor protein 350 (AKAP350A) enables formation of microtubule-nucleation centers and interacts with pericentriolar proteins.
Kolobova E, Roland JT, Lapierre LA, Williams JA, Mason TA, Goldenring JR
(2017) J Biol Chem 292: 20394-20409
MeSH Terms: A Kinase Anchor Proteins, Biomarkers, Cell Line, Centrosome, Cytoskeletal Proteins, Humans, Imaging, Three-Dimensional, Intracellular Signaling Peptides and Proteins, Luminescent Proteins, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, Microtubule-Organizing Center, Models, Molecular, Nerve Tissue Proteins, Peptide Fragments, Phosphoproteins, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Multimerization, Proteomics, RNA Interference, Recombinant Fusion Proteins, Recombinant Proteins, Two-Hybrid System Techniques
Show Abstract · Added April 3, 2018
Microtubules in animal cells assemble (nucleate) from both the centrosome and the cis-Golgi cisternae. A-kinase anchor protein 350 kDa (AKAP350A, also called AKAP450/CG-NAP/AKAP9) is a large scaffolding protein located at both the centrosome and Golgi apparatus. Previous findings have suggested that AKAP350 is important for microtubule dynamics at both locations, but how this scaffolding protein assembles microtubule nucleation machinery is unclear. Here, we found that overexpression of the C-terminal third of AKAP350A, enhanced GFP-AKAP350A(2691-3907), induces the formation of multiple microtubule-nucleation centers (MTNCs). Nevertheless, these induced MTNCs lacked "true" centriole proteins, such as Cep135. Mapping analysis with AKAP350A truncations demonstrated that AKAP350A contains discrete regions responsible for promoting or inhibiting the formation of multiple MTNCs. Moreover, GFP-AKAP350A(2691-3907) recruited several pericentriolar proteins to MTNCs, including γ-tubulin, pericentrin, Cep68, Cep170, and Cdk5RAP2. Proteomic analysis indicated that Cdk5RAP2 and Cep170 both interact with the microtubule nucleation-promoting region of AKAP350A, whereas Cep68 interacts with the distal C-terminal AKAP350A region. Yeast two-hybrid assays established a direct interaction of Cep170 with AKAP350A. Super-resolution and deconvolution microscopy analyses were performed to define the association of AKAP350A with centrosomes, and these studies disclosed that AKAP350A spans the bridge between centrioles, co-localizing with rootletin and Cep68 in the linker region. siRNA-mediated depletion of AKAP350A caused displacement of both Cep68 and Cep170 from the centrosome. These results suggest that AKAP350A acts as a scaffold for factors involved in microtubule nucleation at the centrosome and coordinates the assembly of protein complexes associating with the intercentriolar bridge.
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MeSH Terms
Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin.
Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, Hayward SW, Li D, Webb DJ
(2017) J Cell Biol 216: 3799-3816
MeSH Terms: Cancer-Associated Fibroblasts, Cell Communication, Cell Line, Tumor, Cell Movement, Coculture Techniques, Extracellular Matrix, Fibronectins, Humans, Integrin alpha5beta1, Male, Mechanotransduction, Cellular, Neoplasm Invasiveness, Nonmuscle Myosin Type IIA, Prostatic Neoplasms, RNA Interference, Receptor, Platelet-Derived Growth Factor alpha, Time Factors, Transfection, Tumor Cells, Cultured, Tumor Microenvironment
Show Abstract · Added March 14, 2018
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α-mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
© 2017 Erdogan et al.
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20 MeSH Terms
RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks.
Dungrawala H, Bhat KP, Le Meur R, Chazin WJ, Ding X, Sharan SK, Wessel SR, Sathe AA, Zhao R, Cortez D
(2017) Mol Cell 67: 374-386.e5
MeSH Terms: A549 Cells, Animals, BRCA2 Protein, CRISPR-Cas Systems, DNA Breaks, Double-Stranded, DNA Repair, DNA, Neoplasm, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Genomic Instability, HEK293 Cells, Humans, Mice, Models, Molecular, Mutation, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Protein Binding, RNA Interference, Rad51 Recombinase, Replication Origin, Transfection
Show Abstract · Added March 24, 2018
RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability.
Copyright © 2017 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Endoglin Mediates Vascular Maturation by Promoting Vascular Smooth Muscle Cell Migration and Spreading.
Tian H, Ketova T, Hardy D, Xu X, Gao X, Zijlstra A, Blobe GC
(2017) Arterioscler Thromb Vasc Biol 37: 1115-1126
MeSH Terms: Animals, CRISPR-Cas Systems, Cell Movement, Cell Shape, Cells, Cultured, Coculture Techniques, Endoglin, Endothelial Cells, Focal Adhesion Kinase 1, Gene Expression Regulation, Humans, Integrins, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Phenotype, RNA Interference, Signal Transduction, Transfection
Show Abstract · Added March 22, 2018
OBJECTIVE - Endoglin, a transforming growth factor-β superfamily coreceptor, is predominantly expressed in endothelial cells and has essential roles in vascular development. However, whether endoglin is also expressed in vascular smooth muscle cells (VSMCs), especially in vivo, remains controversial. Furthermore, the roles of endoglin in VSMC biology remain largely unknown. Our objective was to examine the expression and determine the function of endoglin in VSMCs during angiogenesis.
APPROACH AND RESULTS - Here, we determine that endoglin is robustly expressed in VSMCs. Using CRISPR/CAS9 knockout and short hairpin RNA knockdown in the VSMC/endothelial coculture model system, we determine that endoglin in VSMCs, but not in endothelial cells, promotes VSMCs recruitment by the endothelial cells both in vitro and in vivo. Using an unbiased bioinformatics analysis of RNA sequencing data and further study, we determine that, mechanistically, endoglin mediates VSMC recruitment by promoting VSMC migration and spreading on endothelial cells via increasing integrin/FAK pathway signaling, whereas endoglin has minimal effects on VSMC adhesion to endothelial cells. In addition, we further determine that loss of endoglin in VSMCs inhibits VSMC recruitment in vivo.
CONCLUSIONS - These studies demonstrate that endoglin has an important role in VSMC recruitment and blood vessel maturation during angiogenesis and also provide novel insights into how discordant endoglin function in endothelial and VSMCs may regulate vascular maturation and angiogenesis.
© 2017 The Authors.
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19 MeSH Terms
Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
Ando K, Shah AK, Sachdev V, Kleinstiver BP, Taylor-Parker J, Welch MM, Hu Y, Salgia R, White FM, Parvin JD, Ozonoff A, Rameh LE, Joung JK, Bharti AK
(2017) Oncotarget 8: 43733-43751
MeSH Terms: BRCA1 Protein, Camptothecin, Cell Line, Tumor, DNA Topoisomerases, Type I, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Editing, Humans, Ku Autoantigen, Multiprotein Complexes, PTEN Phosphohydrolase, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Proteolysis, RNA Interference, Topoisomerase I Inhibitors, Ubiquitin
Show Abstract · Added November 26, 2018
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.
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PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.
Iwata H, Goettsch C, Sharma A, Ricchiuto P, Goh WW, Halu A, Yamada I, Yoshida H, Hara T, Wei M, Inoue N, Fukuda D, Mojcher A, Mattson PC, Barabási AL, Boothby M, Aikawa E, Singh SA, Aikawa M
(2016) Nat Commun 7: 12849
MeSH Terms: ADP-Ribosylation, Animals, Apoptosis, Atherosclerosis, Cell Survival, Coronary Artery Disease, Female, Humans, Inflammation, Interferon-gamma, Interleukin-4, Lipopolysaccharide Receptors, Macrophage Activation, Male, Mice, Mice, Inbred C57BL, Neoplasm Proteins, Phosphorylation, Plaque, Atherosclerotic, Poly(ADP-ribose) Polymerases, RAW 264.7 Cells, RNA Interference, Ribose, STAT1 Transcription Factor, THP-1 Cells
Show Abstract · Added March 14, 2018
Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9-PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.
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25 MeSH Terms
Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans.
Gitschlag BL, Kirby CS, Samuels DC, Gangula RD, Mallal SA, Patel MR
(2016) Cell Metab 24: 91-103
MeSH Terms: Animals, Caenorhabditis elegans, DNA, Mitochondrial, Gene Deletion, Gene Dosage, Genome, Mitochondrial, Homeostasis, Mitochondrial Dynamics, Mutation, RNA Interference, Transcription, Genetic, Unfolded Protein Response
Show Abstract · Added March 21, 2018
Mutant mitochondrial genomes (mtDNA) can be viewed as selfish genetic elements that persist in a state of heteroplasmy despite having potentially deleterious metabolic consequences. We sought to study regulation of selfish mtDNA dynamics. We establish that the large 3.1-kb deletion-bearing mtDNA variant uaDf5 is a selfish genome in Caenorhabditis elegans. Next, we show that uaDf5 mutant mtDNA replicates in addition to, not at the expense of, wild-type mtDNA. These data suggest the existence of a homeostatic copy-number control that is exploited by uaDf5 to "hitchhike" to high frequency. We also observe activation of the mitochondrial unfolded protein response (UPR(mt)) in uaDf5 animals. Loss of UPR(mt) causes a decrease in uaDf5 frequency, whereas its constitutive activation increases uaDf5 levels. UPR(mt) activation protects uaDf5 from mitophagy. Taken together, we propose that mtDNA copy-number control and UPR(mt) represent two homeostatic response mechanisms that play important roles in regulating selfish mitochondrial genome dynamics.
Copyright © 2016 Elsevier Inc. All rights reserved.
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12 MeSH Terms
p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network.
Marshall CB, Mays DJ, Beeler JS, Rosenbluth JM, Boyd KL, Santos Guasch GL, Shaver TM, Tang LJ, Liu Q, Shyr Y, Venters BJ, Magnuson MA, Pietenpol JA
(2016) Cell Rep 14: 2289-300
MeSH Terms: Animals, Bronchioles, Cell Differentiation, Cells, Cultured, Cilia, Epithelial Cells, Epithelium, Female, Forkhead Transcription Factors, Gene Regulatory Networks, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phosphoproteins, RNA Interference, Sequence Analysis, RNA, Trachea, Trans-Activators, Transcriptome, Tumor Protein p73
Show Abstract · Added March 17, 2016
We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus; hippocampal dysgenesis; sterility; and chronic inflammation/infection of lung, middle ear, and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells and suggest that p73 marks these cells for MCC differentiation. In summary, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation, and, like p63, has an essential role in development of tissues.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms