Cdc42 regulates arsenic-induced NADPH oxidase activation and cell migration through actin filament reorganization. 2005

Yong Qian, and Ke Jian Liu, and Yan Chen, and Daniel C Flynn, and Vince Castranova, and Xianglin Shi
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA. YAQ2@CDC.GOV

Although arsenic is a human carcinogen, the molecular mechanisms of its action remain to be understood. The present study reports that exposure to arsenic induced actin filament reorganization, resulting in lamellipodia and filopodia structures through the activation of Cdc42 in SVEC4-10 endothelial cells. It was also found that arsenic induced the formation of the superoxide anion (O2*) in SVEC4-10 cells. Immunoprecipitation and Western blotting analysis demonstrated that arsenic stimulation induced serine phosphorylation of p47phox, a key component of NADPH oxidase, indicating that arsenic induces O2* formation through NADPH oxidase activation. Inhibition of arsenic-induced actin filament reorganization by either overexpression of a dominant negative Cdc42 or pretreatment of an actin filament stabilizing regent, jasplakinolide, abrogated arsenic-induced NADPH oxidase activation, showing that the activation of NADPH oxidase was regulated by Cdc42-mediated actin filament reorganization. This study also showed that overexpression of a dominant negative Rac1 was sufficient to abolish arsenic-induced O2*- production, implying that Rac1 activities are required for Cdc42-mediated NADPH oxidase activation in response to arsenic stimulation. Furthermore, arsenic stimulation induced cell migration, which can be inhibited by the inactivation of either Cdc42 or NADPH oxidase. Taken together, the results indicate that arsenic is able to activate NADPH oxidase through Cdc42-mediated actin filament reorganization, leading to the induction of an increase in cell migration in SVEC4-10 endothelial cells.

UI MeSH Term Description Entries
D008841 Actin Cytoskeleton Fibers composed of MICROFILAMENT PROTEINS, which are predominately ACTIN. They are the smallest of the cytoskeletal filaments. Actin Filaments,Microfilaments,Actin Microfilaments,Actin Cytoskeletons,Actin Filament,Actin Microfilament,Cytoskeleton, Actin,Cytoskeletons, Actin,Filament, Actin,Filaments, Actin,Microfilament,Microfilament, Actin,Microfilaments, Actin
D011554 Pseudopodia A dynamic actin-rich extension of the surface of an animal cell used for locomotion or prehension of food. Axopodia,Filopodia,Lamellipodia,Lobopodia,Microspikes, Cell Surface,Reticulopodia,Pseudopodium,Cell Surface Microspike,Cell Surface Microspikes,Lamellipodias,Microspike, Cell Surface,Surface Microspike, Cell,Surface Microspikes, Cell
D002461 Cell Line, Transformed Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals. Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D002465 Cell Movement The movement of cells from one location to another. Distinguish from CYTOKINESIS which is the process of dividing the CYTOPLASM of a cell. Cell Migration,Locomotion, Cell,Migration, Cell,Motility, Cell,Movement, Cell,Cell Locomotion,Cell Motility,Cell Movements,Movements, Cell
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001151 Arsenic A shiny gray element with atomic symbol As, atomic number 33, and atomic weight 75. It occurs throughout the universe, mostly in the form of metallic arsenides. Most forms are toxic. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), arsenic and certain arsenic compounds have been listed as known carcinogens. (From Merck Index, 11th ed) Arsenic-75,Arsenic 75
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D019255 NADPH Oxidases A family of membrane-associated flavoprotein NADPH-dependent oxidoreductases that catalyze the univalent reduction of OXYGEN to create SUPEROXIDES. Structurally, they are characterized by six N-terminal transmembrane ALPHA-HELICES, a FLAVIN-ADENINE DINUCLEOTIDE (FAD)-binding region, and a C-terminal NADPH-binding region. They are expressed primarily by EPITHELIAL CELLS in gut, kidney, colon, and smooth muscle tissues, as well as GRANULOCYTES and function to transfer electrons across membranes to molecular oxygen. Defects in the production of superoxide ions by some NADPH oxidases result in GRANULOMATOUS DISEASE, CHRONIC. NADPH Oxidase,NAD(P)H Oxidases,NAD(P)H oxidase,Nox Proteins,Oxidase, NADPH,Oxidases, NADPH
D020764 cdc42 GTP-Binding Protein A member of the Rho family of MONOMERIC GTP-BINDING PROTEINS. It is associated with a diverse array of cellular functions including cytoskeletal changes, filopodia formation and transport through the GOLGI APPARATUS. This enzyme was formerly listed as EC 3.6.1.47. G25K GTP-Binding Protein, Placental Isoform,G25K Protein,cdc42 Protein,p21 cdc42,Cell Division Control Protein 42 Homolog,Cell Division Cycle 42 Protein,G25K GTP-Binding Protein,G25K GTP Binding Protein,G25K GTP Binding Protein, Placental Isoform,GTP-Binding Protein, G25K,GTP-Binding Protein, cdc42,cdc42 GTP Binding Protein,cdc42, p21

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