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Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells.
Dos Santos AA, López-Granero C, Farina M, Rocha JBT, Bowman AB, Aschner M
(2018) Food Chem Toxicol 113: 328-336
MeSH Terms: Animals, Astrocytes, Caspase 3, Caspase 9, Cell Death, Cells, Cultured, Enzyme Activation, Lim Kinases, Methylmercury Compounds, Mice, Inbred C57BL, Myosin-Light-Chain Phosphatase, Oxidative Stress, Phosphorylation, Proteolysis, rho-Associated Kinases
Show Abstract · Added April 11, 2018
Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 μM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD/NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA.
Copyright © 2018. Published by Elsevier Ltd.
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15 MeSH Terms
Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2.
Jerrell RJ, Parekh A
(2016) Biomaterials 84: 119-129
MeSH Terms: Biomechanical Phenomena, Cell Line, Tumor, Cell Movement, Extracellular Matrix, Humans, Isoenzymes, Lim Kinases, Myosin Type II, Neoplasm Invasiveness, Phosphorylation, Pseudopodia, Signal Transduction, rho-Associated Kinases
Show Abstract · Added February 23, 2016
ROCK activity increases due to ECM rigidity in the tumor microenvironment and promotes a malignant phenotype via actomyosin contractility. Invasive migration is facilitated by actin-rich adhesive protrusions known as invadopodia that degrade the ECM. Invadopodia activity is dependent on matrix rigidity and contractile forces suggesting that mechanical factors may regulate these subcellular structures through ROCK-dependent actomyosin contractility. However, emerging evidence indicates that the ROCK1 and ROCK2 isoforms perform different functions in cells suggesting that alternative mechanisms may potentially regulate rigidity-dependent invadopodia activity. In this study, we found that matrix rigidity drives ROCK signaling in cancer cells but that ROCK1 and ROCK2 differentially regulate invadopodia activity through separate signaling pathways via contractile (NM II) and non-contractile (LIMK) mechanisms. These data suggest that the mechanical rigidity of the tumor microenvironment may drive ROCK signaling through distinct pathways to enhance the invasive migration required for cancer progression and metastasis.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Leukotrienes target F-actin/cofilin-1 to enhance alveolar macrophage anti-fungal activity.
Morato-Marques M, Campos MR, Kane S, Rangel AP, Lewis C, Ballinger MN, Kim SH, Peters-Golden M, Jancar S, Serezani CH
(2011) J Biol Chem 286: 28902-13
MeSH Terms: Actins, Animals, Candida albicans, Candidiasis, Cofilin 1, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Female, Immunity, Innate, Lectins, C-Type, Leukotriene B4, Lim Kinases, Macrophages, Alveolar, Membrane Proteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Phagocytosis, Phosphatidylinositol 3-Kinases, Protein Kinase C-delta, Rats, Rats, Wistar
Show Abstract · Added May 4, 2017
Candida albicans is the most common opportunistic fungal pathogen and causes local and systemic disease in immunocompromised patients. Alveolar macrophages (AMs) are pivotal for the clearance of C. albicans from the lung. Activated AMs secrete 5-lipoxygenase-derived leukotrienes (LTs), which in turn enhance phagocytosis and microbicidal activity against a diverse array of pathogens. Our aim was to investigate the role of LTB(4) and LTD(4) in AM antimicrobial functions against C. albicans and the signaling pathways involved. Pharmacologic and genetic inhibition of LT biosynthesis as well as receptor antagonism reduced phagocytosis of C. albicans when compared with untreated or WT controls. Conversely, exogenous LTs of both classes augmented base-line C. albicans phagocytosis by AMs. Although LTB(4) enhanced mainly mannose receptor-dependent fungal ingestion, LTD(4) enhanced mainly dectin-1 receptor-mediated phagocytosis. LT enhancement of yeast ingestion was dependent on protein kinase C-δ (PKCδ) and PI3K but not PKCα and MAPK activation. Both LTs reduced activation of cofilin-1, whereas they enhanced total cellular F-actin; however, LTB(4) accomplished this through the activation of LIM kinases (LIMKs) 1 and 2, whereas LTD(4) did so exclusively via LIMK-2. Finally, both exogenous LTB(4) and LTD(4) enhanced AM fungicidal activity in an NADPH oxidase-dependent manner. Our data identify LTB(4) and LTD(4) as key mediators of innate immunity against C. albicans, which act by both distinct and conserved signaling mechanisms to enhance multiple antimicrobial functions of AMs.
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22 MeSH Terms
Drosophila MMP2 regulates the matrix molecule faulty attraction (Frac) to promote motor axon targeting in Drosophila.
Miller CM, Liu N, Page-McCaw A, Broihier HT
(2011) J Neurosci 31: 5335-47
MeSH Terms: Age Factors, Animals, Animals, Genetically Modified, Axons, Bone Morphogenetic Proteins, Calcium-Binding Proteins, Drosophila, Drosophila Proteins, Embryo, Nonmammalian, Extracellular Matrix Proteins, Gene Expression Regulation, Developmental, Green Fluorescent Proteins, Helix-Loop-Helix Motifs, Humans, Lim Kinases, Matrix Metalloproteinase 2, Microfilament Proteins, Models, Biological, Motor Neurons, Mutation, Neuroglia, Oligodeoxyribonucleotides, Antisense, RNA, Signal Transduction, Two-Hybrid System Techniques
Show Abstract · Added March 5, 2014
Matrix metalloproteinases (MMPs) are widely hypothesized to regulate signaling events through processing of extracellular matrix (ECM) molecules. We previously demonstrated that membrane-associated Mmp2 is expressed in exit glia and contributes to motor axon targeting. To identify possible substrates, we undertook a yeast interaction screen for Mmp2-binding proteins and identified the novel ECM protein faulty attraction (Frac). Frac encodes a multidomain extracellular protein rich in epidermal growth factor (EGF) and calcium-binding EGF domains, related to the vertebrate Fibrillin and Fibulin gene families. It is expressed in mesodermal domains flanking Mmp2-positive glia. The juxtaposition of Mmp2 and Frac proteins raises the possibility that Frac is a proteolytic target of Mmp2. Consistent with this hypothesis, levels of full-length Frac are increased in Mmp2 loss-of-function (LOF) and decreased in Mmp2 gain-of-function (GOF) embryos, indicating that Frac cleavage is Mmp2 dependent. To test whether frac is necessary for axon targeting, we characterized guidance in frac LOF mutants. Motor axons in frac LOF embryos are loosely associated and project ectopically, a phenotype essentially equivalent to that of Mmp2 LOF. The phenotypic similarity between enzyme and substrate mutants argues that Mmp2 activates Frac. In addition, Mmp2 overexpression pathfinding phenotypes depend on frac activity, indicating that Mmp2 is genetically upstream of frac. Last, overexpression experiments suggest that Frac is unlikely to have intrinsic signaling activity, raising the possibility that an Mmp2-generated Frac fragment acts as a guidance cue cofactor. Indeed, we present genetic evidence that Frac regulates a non-canonical LIM kinase 1-dependent bone morphogenetic protein signaling pathway in motoneurons necessary for axon pathfinding during embryogenesis.
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25 MeSH Terms
An essential role for p120-catenin in Src- and Rac1-mediated anchorage-independent cell growth.
Dohn MR, Brown MV, Reynolds AB
(2009) J Cell Biol 184: 437-50
MeSH Terms: Actin Depolymerizing Factors, Actins, Adherens Junctions, Animals, Cadherins, Catenins, Cell Adhesion Molecules, Cell Line, Cell Physiological Phenomena, Dogs, Enzyme Activation, Genes, ras, Humans, Lim Kinases, Phosphoproteins, RNA Interference, Signal Transduction, rac1 GTP-Binding Protein, ras Proteins, rho-Associated Kinases, src-Family Kinases
Show Abstract · Added March 5, 2014
p120-catenin regulates epithelial cadherin stability and has been suggested to function as a tumor suppressor. In this study, we used anchorage-independent growth (AIG), a classical in vitro tumorigenicity assay, to examine the role of p120 in a different context, namely oncogene-mediated tumorigenesis. Surprisingly, p120 ablation by short hairpin RNA completely blocked AIG induced by both Rac1 and Src. This role for p120 was traced to its activity in suppression of the RhoA-ROCK pathway, which appears to be essential for AIG. Remarkably, the AIG block associated with p120 ablation was completely reversed by inhibition of the downstream RhoA effector ROCK. Harvey-Ras (H-Ras)-induced AIG was also dependent on suppression of the ROCK cascade but was p120 independent because its action on the pathway occurred downstream of p120. The data suggest that p120 modulates oncogenic signaling pathways important for AIG. Although H-Ras bypasses p120, a unifying theme for all three oncogenes is the requirement to suppress ROCK, which may act as a gatekeeper for the transition to anchorage independence.
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21 MeSH Terms