Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we investigated the function and the mechanism of action of RGS3, a member of a family of proteins called regulators of G protein signaling (RGS). Polyclonal antibodies against RGS3 were produced and characterized. An 80-kDa protein was identified as RGS3 by immunoprecipitation and immunoblotting with anti-RGS3 antibodies in a human mesangial cell line (HMC) stably transfected with RGS3 cDNA. Coimmunoprecipitation experiments in RGS3-overexpressing cell lysates revealed that RGS3 bound to aluminum fluoride-activated Galpha11 and to a lesser extent to Galphai3 and that this binding was mediated by the RGS domain of RGS3. A role of RGS3 in postreceptor signaling was demonstrated by decreased calcium responses and mitogen-activated protein (MAP) kinase activity induced by endothelin-1 in HMC stably overexpressing RGS3. Moreover, depletion of endogenous RGS3 by transfection of antisense RGS3 cDNA in NIH 3T3 cells resulted in enhanced MAP kinase activation induced by endothelin-1. The study of intracellular distribution of RGS3 indicated its unique cytosolic localization. Activation of G proteins by AlF4-, NaF, or endothelin-1 resulted in redistribution of RGS3 from cytosol to the plasma membrane as determined by Western blotting of the cytosolic and particulate fractions with RGS3 antiserum as well as by immunofluorescence microscopy. Agonist-induced translocation of RGS3 occurred by a dual mechanism involving both C-terminal (RGS domain) and N-terminal regions of RGS3. Thus, coexpression of RGS3 with a constitutively active mutant of Galpha11 (Galpha11-QL) resulted in the binding of RGS3, but not of its N-terminal fragment, to the membrane fraction and in its interaction with Galpha11-QL in vitro without any stimuli. However, both full-length RGS3 and its N-terminal domain translocated to the plasma membrane upon stimulation of intact cells with endothelin-1 as assayed by immunofluorescence microscopy. The effect of endothelin-1 was also mimicked by calcium ionophore A23187, suggesting the importance of Ca2+ in the mechanism of redistribution of RGS3. These data indicate that RGS3 inhibits G protein-coupled receptor signaling by a complex mechanism involving its translocation to the membrane in addition to its established function as a GTPase-activating protein.
Mol Cell Biol 1999 Jan
PMID:RGS3 inhibits G protein-mediated signaling via translocation to the membrane and binding to Galpha11. 985 94

The effect of feeding groups of mice with a diet containing 2000, 4000 and 6000 micrograms aluminum (Al3-/g) for two weeks (subacute) or 2000 and 4000 micrograms Al3+/g for eight weeks (subchronic) as well as the coadministration of vitamin E (alpha-tocopherol) 500 micrograms/g with Al3+, on the status of glutathione (GSH) and lipid peroxides as thiobarbituric acid reactive substances (TBARS) in whole brain tissues were evaluated. Changes in TBARS were further evaluated in vitro following the incubation of brain homogenates of the Al(3+)-fed mice in the presence of 50 microM FeSO4. The results of subacute experiments revealed that the brain levels of GSH were significantly decreased only in the group of mice that received 6000 micrograms Al3+/g diet (P < 0.05) and this effect was partially ameliorated when vitamin E was coadministered with Al3+. TBARS were significantly increased in vitro only in the presence of free iron ions and depended on the concentration of Al3+ in the diet. The effect was opposed by the vitamin E intake. Following subchronic Al3+ intake, the GSH content of the brain was significantly decreased only in the group of mice that received 4000 micrograms Al3+/g diet (P < 0.01), while TBARS were significantly increased in the brain tissues in vivo as well as in the presence of free iron ions in vitro. However, coadministration of vitamin E with Al3+ for eight weeks preserved GSH levels and decreased TBARS in the brain of mice in vivo and in the presence of free iron ions in vitro. It is concluded that the long term administration of vitamin E may prevent Al3(+)-stimulated oxidative injury in the brain.
Biochem Mol Biol Int 1998 Dec
PMID:Vitamin E protects the brain against oxidative injury stimulated by excessive aluminum intake. 989 50

Fluoride is an acknowledged bone anabolic agent. Nevertheless, a narrow therapeutic window and the adverse effects at higher therapeutic doses prevent broad clinical application of fluoride for treatment of diseases of bone loss, such as osteoporosis. The cellular and molecular mechanisms of fluoride action are poorly understood. recent advances in the elucidation of signal transduction pathways induced by fluoride in osteoblastic cells are reviewed. Fluoride and traces of aluminum form a complex, fluoroaluminate, which stimulates cellular heterotrimeric G proteins. Such complex can form in food, drinking water and in the organism after administration of sodium fluoride. Fluoroaluminate crosses the cell membrane and directly binds to the membrane-associated inactive G alpha protein subunits. Within the G alpha subunit, fluoroaluminate occupies the position next to GDP. The resulting G alpha-GDP-AlF4- complex assumes an active state conformation, which resembles that of G alpha-GTP complex. Under physiological conditions, G alpha-GTP complex is formed upon activation of seven transmembrane receptors that couple to heterotrimeric G proteins. Both fluoroaluminate-activated and receptor-activated G alpha subunits are capable of transmitting intracellular signals that lead to cellular responses. In bone-forming cells osteoblasts, fluoroaluminate stimulates pertussis toxin-sensitive G alpha i proteins. G alpha i activation leads to the reduction in cAMP (cyclic adenosine monophosphate) levels and to the activation of mitogen activated protein kinases, Erks (extracellular signal-regulated kinases) and p70 S6 kinase. These kinases are involved in the regulation of gene transcription and protein syntheses. Fluoroaluminate also stimulates pertussis toxin-insensitive proteins. Pertussis toxin-insensitive G proteins, most likely from G alpha 12 class, cause the activation of several cytoplasmic protein tyrosine kinases [Src, Pyk2 (proline-rich tyrosine kinase 2), and Fak (focal adhesion kinase)]. Activation of Erks can lead to osteoblast proliferation and differentiation, while activation of Src, Pyk2 and Fak can modulate the adhesion properties of osteoblasts. Osteoblast adhesion may, in turn, influence differentiation, migration, and apoptosis of these cells. The susceptibility of osteoblasts to fluoroaluminate can be achieved by their specific cellular context and by the rigidity of the surrounding bone tissue. In particular, higher levels of G alpha i proteins and of certain focal adhesion proteins are expressed by osteoblastic rather than by fibroblastic cells. The rigidity of adhesion substratum of osteoblasts may signal on its own and potentiate the signaling by fluoroaluminate. The information on mechanisms of intracellular signaling by fluoroaluminate can be utilized to identify a fluoroaluminate mimic, a drug that exhibits anabolic action on bone with a broader therapeutic range and less adverse effects than fluoride.
Int J Mol Med 1999 Feb
PMID:Heterotrimeric G proteins as fluoride targets in bone (review). 991 18

In an attempt to delineate the capacity of aluminum (Al) to promote pro-oxidant events, several indices of oxidative stress have been determined in brains and livers of rats exposed to an Al salt, either alone or in combination with an iron (Fe) compound. Treatment with Al over a 3-wk period increased both cortical levels of glutathione (GSH) and the rates of generation of reactive oxygen species (ROS). Dosing with an Fe compound resulted in no parallel changes, and concurrent exposure to Fe together with Al prevented these elevations. Both Fe and Al dosing elevated glutamine synthetase activity in the cortex. Levels of creatine kinase, another enzyme susceptible to oxidative stress, were also elevated in cortices of Al-treated rats. These data are in contrast to the changes found in liver fractions where exposure to Fe greatly enhanced hepatic pro-oxidant events as judged by changes in all three of the test indices used. Concurrent treatment with Al did not potentiate the pro-oxidant effects of Fe in liver. Al treatment had very minor effects on hepatic parameters of oxidative events. The results suggest that the presence of Al may exert deleterious pro-oxidant changes within the brain, which may be related to induction of oxidant species. These changes are tissue-specific and appear to be independent of any promotion of pro-oxidant status induced by exogenous Fe.
Mol Chem Neuropathol
PMID:Aluminum but not iron treatment induces pro-oxidant events in the rat brain. 1032 19

The induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Tolerance induction in the intestine has been studied extensively and therapeutic applications to autoimmunities are in progress, whereas tolerance in the respiratory tract is poorly investigated. We examined the immunoregulatory mechanisms for evading exaggerated inflammatory responses in the murine airway mucosa. Administration of an optimal dose of ovalbumin (OVA) to the trachea elicited eosinophilic inflammation in the trachea of OVA/aluminum hydroxide-sensitized BALB/c mice, whereas higher doses were unable to do so. This failure paralleled the downregulation of interleukin-4 production by mediastinal lymph node (LN) T cells. This high-dose tolerance was attributable to the mechanisms of antigen (Ag)-specific suppression, because the adoptive transfer of CD4(+) LN T cells from the OVA-tolerant mice inhibited the OVA-specific, but not irrelevant Ag KLH-specific, eosinophilic responses. The inhibitory effects were neutralized by the intratracheal administration of anti-transforming growth factor (TGF)-beta, but not that of anti-interferon (IFN)-gamma, monoclonal antibodies, indicating that the high-dose tolerance was mediated by secreted TGF-beta, but not by the dominance of transferred T helper (Th)1 cells over Th2 cells. The pivotal role of TGF-beta was reinforced by the finding that the LN cells from the OVA-tolerant mice produced TGF-beta in response to the in vitro Ag stimulation. These results demonstrate a novel regulatory mechanism in the airway: that TGF-beta secreted by T cells plays an important role in the downmodulation of the immune responses to high doses of Ag which might otherwise induce deleterious inflammation in the airway mucosal tissues.
Am J Respir Cell Mol Biol 1999 Aug
PMID:Transforming growth factor-beta secreted from CD4(+) T cells ameliorates antigen-induced eosinophilic inflammation. A novel high-dose tolerance in the trachea. 1042 11

Plasmodium falciparum malaria parasites actively remodel the host cell cytosol and plasma membrane during the erythrocytic cycle. The focus of this investigation was to characterize intra-parasitic and -erythrocytic secretory pathways. Electron-dense vesicles, similar in appearance to mammalian secretory vesicles were detected in proximity to smooth tubo-vesicular elements at the periphery of the parasite cytoplasm in mature parasites by transmission electron microscopy. Vesicles (60-100 nm diameter), which appeared to be coated, were visualized on the erythrocytic side of the parasite vacuolar membrane and in the erythrocyte cytosol. The vesicles seemed to bind to and fuse with the erythrocyte membrane, giving rise to cup-shaped electron-dense structures, which might be intermediates in knob structure formation. Treatment of mature parasites with aluminum tetrafluoride, an activator of GTP-binding proteins, resulted in the accumulation of the vesicles with an electron-dense limiting membrane in the erythrocyte cytosol into multiple vesicle strings. These vesicle complexes were often associated with and closely abutted the erythrocyte membrane, but were apparently prevented from fusing by the aluminum fluoride treatment. The parasite proteins PfEMP1 and PfEMP3 were found by immunoelectron microscopy to be associated with these vesicles, suggesting they are responsible for transporting these proteins to the erythrocyte membrane.
Mol Biochem Parasitol 2000 Feb 25
PMID:Evidence for vesicle-mediated trafficking of parasite proteins to the host cell cytosol and erythrocyte surface membrane in Plasmodium falciparum infected erythrocytes. 1074 17

We investigated the effects of interleukin (IL)-10 administration on allergen-induced Th2 cytokine production, eosinophilic inflammation, and airway reactivity. Mice were sensitized by intraperitoneal injection of ragweed (RW) adsorbed to Alum and challenged by intratracheal instillation of the allergen. Sensitization and challenge with RW increased concentrations of IL-10 in bronchoalveolar lavage (BAL) fluid from undetectable levels to 60 pg/ml over 72 h. Intratracheal instillation of 25 ng of recombinant murine IL-10 at the time of RW challenge further elevated BAL fluid IL-10 concentration to 440 pg/ml but decreased BAL fluid IL-4, IL-5, and interferon-gamma levels by 40-85% and eosinophil numbers by 70% (P < 0.0001). Unexpectedly, the same IL-10 treatment increased airway reactivity to methacholine in spontaneously breathing mice that had been sensitized and challenged with RW (P < 0.001). IL-10 treatment in naive animals or RW-sensitized mice challenged with PBS failed to increase airway reactivity, demonstrating that IL-10 induces an increase in airway reactivity only when it is administered in conjunction with allergic sensitization and challenge. The results demonstrate that IL-10 reduces Th2 cytokine levels and eosinophilic inflammation but augments airway hyperreactivity. Thus, despite its potent anti-inflammatory activity, IL-10 could contribute to the decline in pulmonary function observed in asthma.
Am J Physiol Lung Cell Mol Physiol 2000 Apr
PMID:IL-10 reduces Th2 cytokine production and eosinophilia but augments airway reactivity in allergic mice. 1074 43

The mechanism by which receptors activate G proteins is unclear because a connection between the receptor and the nucleotide binding site has not been established. To investigate this mechanism, we evaluated the roles in receptor interaction of three potential receptor contact sites in alpha(s): the alpha2/beta4, alpha3/beta5, and alpha4/beta6 loops. Substitutions of alpha(i2) homologs for alpha(s) residues in the alpha2/beta4 loop and alanine substitutions of residues in the alpha4/beta6 loop do not affect activation by the beta(2)-adrenergic receptor. However, replacement of five alpha(s) residues in the alpha3/beta5 loop region with the homologous alpha(i2) residues decreases receptor-mediated activation of alpha(s) and increases the affinity of G(s) for this receptor. The substitutions do not alter guanine nucleotide binding or hydrolysis, or activation by aluminum fluoride, indicating that the effects on receptor interaction are not due to a destabilization of the guanine-nucleotide bound state. In a model of the receptor-G protein complex, the alpha3/beta5 loop maps near the second and third intracellular loops of the receptor. The effects of the alpha3/beta5 substitutions suggest that the wild-type residues may be receptor contact sites that are optimized to ensure the reversibility of receptor-G protein interactions. Furthermore, the alpha3/beta5 region corresponds to an exchange factor contact site in both EF-Tu and Ras, suggesting that the mechanisms by which seven-transmembrane receptors and exchange factors catalyze nucleotide exchange may share common elements.
Mol Pharmacol 2000 Jun
PMID:A surface-exposed region of G(salpha) in which substitutions decrease receptor-mediated activation and increase receptor affinity. 1082 78

Aluminum (Al) is a simple trivalent cation incapable of redox changes. The toxicity of the metal has been the subject of much controversy in the past few decades. Although it has been generally believed that the metal is innocuous to human health, a causal role for Al has been established in dialysis dementia (Alfrey et al., 1976), osteomalacia (Bushinsky et al., 1995) and microcytic anemia without iron deficiency (Touam et al., 1983). Aluminum has also been implicated in Alzheimer's disease (AD) although a direct causal role has not been determined. The exact mechanism of Al toxicity is not known. However, there are several lines of evidence that show the metal's capacity to exacerbate oxidative events. The present review is intended to propose a coherent pathway linking Al-induced oxidative events to Alzheimer's disease. The preliminary segment is an introduction to reactive oxygen species and their potential involvement in the pathogenesis of AD and the generation of an inflammatory response. Evidence on the relation between AD and inflammatory processes is also presented. The epidemiological and clinical evidence of Al neurotoxicity is summarized in the second section of the review. Finally, a hypothesis indicating that aluminum can exacerbate AD by activating ROS generation and initiation of an inflammatory cascade is presented.
Cell Mol Biol (Noisy-le-grand) 2000 Jun
PMID:Aluminum induced oxidative events and its relation to inflammation: a role for the metal in Alzheimer's disease. 1087 35

In order to remedy the limitations of state-of-the-art methods for red blood cells grouping and antibody screening we have tried to develop a new type of immunosensors based upon a metallic substrate. The first two steps of the manufacturing of such a sensor consist in the anodization and in the silanization of the metal surface. Fourier transform infrared spectroscopy (FTIR) has been used to investigate aluminum samples treated with the above process. FTIR analysis allows the accurate determination of the grafted species, and thus to perform the optimization of the experimental parameters.
Spectrochim Acta A Mol Biomol Spectrosc 2000 Jul
PMID:Fourier transform infrared spectroscopic characterization of grafting of 3-aminopropyl silanol onto aluminum/alumina substrate. 1090 90


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