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PubMed1997

Effect of dimerization on signal transduction and biological function of oncogenic Ros, insulin, and insulin-like growth factor I receptors.

The avian sarcoma virus UR2 codes for an oncogenic Gag-Ros fusion protein-tyrosine kinase (PTK). We have previously derived two retroviruses, T6 and NM1, coding for oncogenic Gag-insulin receptor and Gag-insulin-like growth factor I receptor (IGFR) fusion proteins, respectively. The Gag-IGFR fusion protein dimerizes, whereas Gag-Ros does not. To identify sequences affecting dimerization and the effect of dimerization on signaling and biological functions, we generated recombinants exchanging the extracellular and transmembrane sequences among the three fusion receptors. The presence of multiple cysteines in the Gag sequence appears to preclude dimerization, since deletion of the 3' cysteine residue allows for dimerization. Most of the chimeric receptors retain high PTK activity and induce transformation regardless of their configuration on the cell surface. UT, a UR2/T6 chimera, retained mitogenic activity but has a markedly reduced transforming ability, while UN7, a UR2/NM1 recombinant, which also harbors Y950F and F951S mutations in IGFR, exhibits dramatic reductions in both activities. All of the fusion receptors can phosphorylate insulin receptor substrate 1 and activate PI 3-kinase. UT protein induces Shc phosphorylation, whereas UN7 protein does not, but both are unable to activate mitogen-activated protein kinase. Our results show that overexpressed oncogenic Gag-fusion receptors do not require dimerization for their signaling and transforming functions and that the extracellular and transmembrane sequences of a receptor PTK can affect its specific substrate interactions.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Stat3 plays an important role in oncogenic Ros- and insulin-like growth factor I receptor-induced anchorage-independent growth.

The role of signal transducers and activators of transcription (STATs) in receptor protein-tyrosine kinase (PTK)-induced cell growth and transformation was investigated using an inducible epidermal growth factor receptor-Ros chimeric receptor called ER2 and a constitutively activated insulin-like growth factor I receptor called NM1, both of which are able to induce anchorage-independent growth of NIH 3T3 cells. ER2 and NM1 receptor PTKs are able to cause Stat3 activation. Co-expressing the dominant negative Stat3 mutant with ER2 or NM1 in transiently or stable transfected cells resulted in a dramatic inhibition of colonies induced by these receptor PTKs and a moderate inhibition of their mitogenicity in monolayer. Therefore, Stat3 is not only important for initiation of transformation, as demonstrated by inhibition of the epidermal growth factor-inducible colony formation of the ER2 cells by the mutant, but it is also required for the maintenance of transformation, as evidenced by reversion of the NM1 transformed cells. The DNA binding and transcriptional activities of the endogenous Stat3 were greatly inhibited in the ER2 and NM1 cells co-expressing the Stat3 mutants. We conclude that activated function of Stat3 is required for the establishment and maintenance of Ros and insulin-like growth factor I receptor PTK-induced cell transformation.

3T3 Cells↗

PubMed2006

Antioxidant protective mechanisms against reactive oxygen species (ROS) generated by mitochondrial P450 systems in steroidogenic cells.

Mitochondrial P450 type enzymes catalyze central steps in steroid biosynthesis, including cholesterol conversion to pregnenolone, 11beta and 18 hydroxylation in glucocorticoid and mineralocorticoid synthesis, C-27 hydroxylation of bile acids, and 1alpha and 24 hydroxylation of 25-OH-vitamin D. These monooxygenase reactions depend on electron transfer from NADPH via FAD adrenodoxin reductase and 2Fe-2S adrenodoxin. These systems can function as a futile NADPH oxidase, oxidizing NADPH in absence of substrate, and leak electrons via adrenodoxin and P450 to O(2), producing superoxide and other reactive oxygen species (ROS). The degree of uncoupling depends on the P450 and steroid substrate. Studies with purified proteins and overexpression in cultured cells show consistently that adrenodoxin, but not reductase, is responsible for ROS production that can lead to apoptosis. In the ovary and corpus luteum, antioxidant enzyme activities superoxide dismutase, catalase, and glutathione peroxidase parallel steroidogenesis. Antioxidant beta-carotene, alpha-tocopherol, and ascorbate can protect against oxidative damages of P450 systems. In testis Leydig cells, steroidogenesis is associated with aging of the steroidogenic capacity.

Adrenodoxin↗

PubMed2006

Ros-induced histone modifications and their role in cell survival and cell death.

Much is known about the distal DNA damage repair response. In particular, many of the enzymes and auxiliary proteins that participate in DNA repair have been characterized. In addition, knowledge of signaling pathways activated in response to DNA damage is increasing. In contrast, comparatively less is known of DNA damage-sensing molecules or of the specific alterations to chromatin structure recognized by such DNA damage sensors. Thus, precisely how chromatin structure is altered in response to DNA damage and how such alterations regulate DNA repair processes remain important unanswered questions. In vertebrates, phosphorylation of the histone variant H2A.X occurs rapidly after double-strand break formation, extends over megabase chromatin domains, and is required for stable accumulation of repair proteins at damage foci. We have shown that reactive oxygen species (ROS)-induced DNA single-strand breaks induce the incorporation of 32P specifically into histone H3. ADP-Ribosylation of histones may stimulate local chromatin relaxation to facilitate the repair process, and, indeed, histone ribosylation preceded DNA damage-induced histone H3 phosphorylation. However, H3 phosphorylation occurred concomitant with overall chromatin condensation, as revealed by decreased sensitivity of chromatin to digestion by micrococcal nuclease and by DAPI staining of nuclei. Inhibitors of the ERK and p38MAPK pathways and inhibition of poly(ADP-ribose) polymerase all reduced ROS-induced H3 phosphorylation, chromatin condensation, and cell death. Precisely how changes in the post-translational modification of histone H3 regulate the survival response remains unclear. Attempts to determine the precise site of histone H3 phosphorylation, putative histone H3 kinases, and histone H3 interacting proteins are underway.

Animals↗

PubMed2005

Differential DNA strand breaking abilities of *OH and ROS generating radiomimetic chemicals and gamma-rays: study of plasmid DNA, pMTa4, in vitro.

Reactive oxygen species (ROS) interact with components of a living cell. Among them *OH is known to cause major oxidative damage to living cells and is proposed to be involved in pathogenesis including carcinogenesis. Proper understanding of consequences of such damage is, therefore, medically relevant. In this report, aqueous solution of plasmid DNA, pMTa4, has been exposed to Fenton oxidant and Haber-Weiss oxidant mediated free radical generating chemical systems, and 60Co gamma-rays in vitro either alone or in combination to study their strand breaking abilities. The exposed pMTa4 was analyzed by agarose gel electrophoresis. The results show qualitative differences in the induction of strand breaks on the plasmid pMTa4 molecule by the iron (Fe2+), copper (Cu2+) or gamma-rays mediated *OH and other ROS.

Chelating Agents↗

PubMed2006

Cobalt induces hypoxia-inducible factor-1alpha (HIF-1alpha) in HeLa cells by an iron-independent, but ROS-, PI-3K- and MAPK-dependent mechanism.

The iron-chelator desferrioxamine (DFO) and the transition metal cobalt induce hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. DFO stabilizes HIF-1alpha from proteolysis by inhibiting the activity of iron-dependent prolyl hydroxylases, but the mechanism of action of cobalt is not fully elucidated. The purpose of this study was to examine the regulation of HIF-1alpha induction and HeLa cell proliferation by cobalt and the role of iron in these processes. Our results show that, unlike DFO, induction of transcriptionally active HIF-1alpha by CoCl2 cannot be abrogated by the addition of excess Fe3+, but involves the production of reactive oxygen species (ROS) and the operation of the phosphatidylinositol-3 kinase (PI-3K) and MAPK pathways. CoCl2, as well as DFO, decreased HeLa cell proliferation, but these effects were reversed by the addition of Fe3+. We conclude that the effect of cobalt on cell proliferation is iron-dependent, while its effects on HIF-1alpha induction are ROS- and signaling pathways-dependent, but iron-independent.

Cell Proliferation↗

PubMedDate not supplied

How to clean the dirtiest place in the cell: cationic antioxidants as intramitochondrial ROS scavengers.

Membrane-penetrating triphenyl alkyl phosphonium cations have been suggested for many years in our group as having the ability to measure mitochondrial potential were recently used by Murphy as vehicles to specifically target CoQ to mitochondria. As was shown in our group, the phosphonium derivative of CoQ (MitoQ) easily penetrates a planar bilayer phospholipid membrane as a cation, generating 60 mV electric potential (Deltapsi) per a 10-fold MitoQ gradient. This means that MitoQ should be unequally distributed across the inner mitochondrial membrane, the intramitochondrial [MitoQ] = extramitochondrial [MitoQ] x 10(3) at 180 mV Deltapsi. In line with such a calculation, Murphy and his colleagues reported that antioxidant efficiency of MitoQ added to mitochondria or cells appears to be very much higher than of CoQ. It was found that H2O2-induced apoptosis (Murphy) and the H2O2-mediated bystander killing of the cultivated cells (our group) are completely arrested by pretreatement of the cells with 10(-10) - 10(-8) M MitoQ. These effects indicate that MitoQ and similar compounds may be promising in treatment of heart attack, stroke and other diseases accompanied by massive apoptosis in the injured tissue. The very fact that: (i) MitoQ is not only accumulated by mitochondria but also can be regenerated in its reduced form by mitochondrial respiratory chain, (ii) it is the mitochondrial interior that produces a large portion of reactive oxygen species (ROS) in our body, and (iii) the most sensitive ROS targets are localized in the mitochondrial matrix suggest the MitoQ-like compounds are promising tools of molecular therapy of aerobic cells. In line with this suggestion, we found that addition of MitoQ strongly improves structural and biochemical parameters of cultivated cells. As to cationic tetrapeptides, recently advertised as mitochondrially-targeted Deltapsi-independent antioxidants, their effect is most probably mediated by an opioid activity inherent in some of these substances.

Animals↗

PubMed2001

Antigenicity of poly(I) and ROS-poly(I) and their recognition of human anti-DNA autoantibodies.

The effect of hydroxyl radicals on polyinosinic acid [poly(I)] was studied. Strand breaks, base alteration and a decrease in absorbance at 248 nm (lambda max) were observed upon *OH modification of poly(I). The broad antigen specificity of the induced anti-poly(I) and anti-ROS-poly(I) antibodies showed diverse antigen binding characteristics similar to those of SLE autoantibodies. Recognition of both poly(I) and ROS-poly(I) by human SLE anti-DNA autoantibodies was observed. The possible significance of these findings in the etiology of SLE has been discussed.

Animals↗

PubMedDate not supplied

Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells.

Nuclear factor erythroid 2-related factor (Nrf2) confers protection against cell death induced by hyperoxia and other proapoptotic stimuli. Because phosphoinositide-3-kinase (PI3K)/Akt signaling promotes cell survival, the significance of this pathway in mediating reactive oxygen species (ROS)-dependent hyperoxia-induced Nrf2 activation was investigated in the murine pulmonary epithelial cell line, C10. Inhibition of the PI3K pathway markedly attenuated hyperoxia-induced Nrf2 translocation and ARE (antioxidant response element)-mediated transcription. Consistent with this, hyperoxia markedly stimulated the activation of PI3K pathway, while an NADPH oxidase inhibitor and an antioxidant prevented such activation. The inhibition of Akt activity using a pharmacological inhibitor markedly attenuated Nrf2 translocation and ARE-driven expression. Moreover, overexpression of a dominant-negative Akt mutant attenuated the transcription, whereas a constitutively active mutant stimulated it. These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia. Inhibition of the PI3K pathway prevented hyperoxia-stimulated Akt and ERK1/2 kinase activation, which is critical for Nrf2-mediated transcription. Likewise, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, blocked hyperoxia-stimulated Akt and ERK1/2 phosphorylation, Nrf2 nuclear accumulation, and ARE-driven transcription. Consistent with this result, an NADPH oxidase inhibitor blocked hyperoxia- stimulated EGFR phosphorylation, which was correlated with the attenuation of Akt and ERK activation. Collectively, our data suggest that EGFR-PI3K signaling through Akt and ERK kinases regulates ROS-dependent, hyperoxia-induced Nrf2 activation in pulmonary epithelial cells.

Animals↗

PubMed2002

ROS, stress-activated kinases and stress signaling in cancer.

Anticancer therapy is frequently efficient in early stages of the disease, whereas advanced tumors are usually resistant to the same treatments. The molecular basis for this change is not entirely understood. Many anticancer agents are DNA- or cytoskeleton-damaging drugs that show some specificity towards dividing cells. However, recent studies show that these agents also activate stress-signaling cascades that may play a role in eliciting the observed therapeutic effects. We discuss recent findings that suggest that induction of stress signaling in oncogenically transformed cells is integrated into apoptotic pathways. Reactive oxygen species (ROS) and stress-activated protein kinases (SAPKs), which are potentiated in recently transformed cells, emerge as key effectors of cell death. In advanced tumors, however, these agents are downregulated and, consequently, death signaling is suppressed. Such changes in ROS and SAPK activity levels during the course of tumor development may underlie the changes in responsiveness to anticancer therapy.

Animals↗

PubMed1998

Detection of reactive oxygen species (ROS) and apoptosis in human fragmented embryos.

In human in-vitro fertilization (IVF)-embryo transfer, the in-vitro culture environment differs from in-vivo conditions in that the oxygen concentration is higher, and in such conditions the mouse embryos show a higher concentration of reactive oxygen species (ROS) in simple culture media. ROS are believed to cause damage to cell membranes and DNA fragmentation in somatic cells. This study was conducted to ascertain the level of H2O2 concentration within embryos and the morphological features of cell damage induced by H2O2. A total of 62 human oocytes and embryos (31 fragmented, 15 non-fragmented embryos, 16 unfertilized oocytes) was obtained from the IVF-embryo transfer programme. The relative intensity of H2O2 concentrations within embryos was measured using 2',7'-dichlorodihydrofluorescein diacetate by Quanti cell 500 fluorescence imaging and DNA fragmentation was observed with transmission electron microscopy and an in-situ apoptosis detection kit. The H2O2 concentrations were significantly higher in fragmented embryos (72.21 +/- 9.62, mean +/- SEM) compared to non-fragmented embryos (31.30 +/- 3.50, P < 0.05) and unfertilized oocytes (30.75 +/- 2.67, P < 0.05). Apoptosis was observed only in fragmented embryos, and was absent in non-fragmented embryos. Electron microscopic findings confirmed apoptotic bodies and cytoplasmic condensation in the fragmented blastomeres. We conclude that there is a direct relationship between increased H2O2 concentration and apoptosis, and that further studies should be undertaken to confirm these findings.

Apoptosis↗

PubMedDate not supplied

Pleiotropic effects of regulatory ros mutants of Agrobacterium radiobacter and their interaction with Fe and glucose.

Four exo mutants of Agrobacterium radiobacter, defective in the synthesis of acidic exopolysaccharide were complemented by a gene from that species, which is similar to the transcriptional regulator, ros, of A. tumefaciens. It was confirmed that this A. radiobacter gene, which we term rosAR, like ros, repressed its own transcription as well as that of virC and virD, two loci involved in tumorigenesis. The sequence of RosAR suggested that it might bind to a transition metal and its repressor abilities were shown to require Fe in the medium; repression was also enhanced with increasing levels of glucose. Certain rosAR mutants, in which its 3' end was removed were dominant; i.e., when plasmids containing such mutant forms of the gene were introduced into wild-type A. radiobacter, the transconjugants were nonmucoid. Such effects were also seen in a wide range of bacteria, including Escherichia coli and Xanthomonas. Several mutants that were complementd by rosAR also accumulated protoporphyrin, suggesting a defect in haem synthesis.

Alleles↗

PubMed2003

Gene and protein expression in the epididymis of infertile c-ros receptor tyrosine kinase-deficient mice.

Transgenic male mice bearing inactive mutations of the receptor tyrosine kinase c-ros lack the initial segment of the epididymis and are infertile. Several techniques were applied to determine differences in gene expression in the epididymal caput of heterozygous fertile (HET) and infertile homozygous knockout (KO) males that may explain the infertility. Complementary DNA arrays, gene chips, Northern and Western blots, and immunohistochemistry indicated that some proteins were downregulated, including the initial segment/proximal caput-specific genes c-ros, cystatin-related epididymal-spermatogenic (CRES), and lipocalin mouse epididymal protein 17 (MEP17), whereas other caput-enriched genes (glutathione peroxidase 5, a disintegrin and metalloproteinase [ADAM7], bone morphogenetic proteins 7 and 8a, A-raf, CCAAT/enhancer binding protein beta, PEA3) were unchanged. Genes normally absent from the initial segment (gamma-glutamyltranspeptidase, prostaglandin D2 synthetase, alkaline phosphatase) were expressed in the undifferentiated proximal caput of the KO. More distally, lipocalin 2 (24p3), CRISP1 (formerly MEP7), PEBP (MEP9), and mE-RABP (MEP10) were unchanged in expression. Immunohistochemistry and Western blots confirmed the absence of CRES in epididymal tissue and fluid and the continued presence of CRES in spermatozoa of the KO mouse. The glutamate transporters EAAC1 (EAAT3) and EAAT5 were downregulated and upregulated, respectively. The genes of over 70 transporters, channels, and pores were detected in the caput epididymidis, but in the KO, only three were downregulated and six upregulated. The changes in these genes could affect sperm function by modifying the composition of epididymal fluid and explain the infertility of the KO males. These genes may be targets for a posttesticular contraceptive.

Animals↗

PubMed2000

The cause of infertility of male c-ros tyrosine kinase receptor knockout mice.

Male homozygous transgenic c-ros knockout mice are sterile by natural mating, lack a part of their epididymis, and the epididymal sperm exhibit tail angulation in vivo and in vitro. To ascertain if this abnormal tail form caused the infertility, the number and nature of sperm in the tract of females mated to knockout and wild-type mice were determined. Percentage motility and numbers of sperm in the uterus 1 h after mating were similar between genotypes. The majority of the uterine sperm from the wild-type males had straight flagella, whereas 46-86% of knockout sperm were bent at the cytoplasmic droplet even when motile. Motile knockout sperm showed a 54 and 37% reduction in the straightline and curvilinear velocities compared with straight wild-type sperm. Sequential flushings of the oviduct 4 h after mating with the wild-type males contained sperm: 591 +/- 119 free, 371 +/- 70 loosely, and 122 +/- 47 tightly bound to the epithelium, but no knockout sperm were recovered from the oviduct or observed within the uterotubal junction in tissue sections. The infertility of c-ros knockout male mice can be explained by the sperm's inability to enter the oviduct, as a result of their bent tails forming the entangled sperm mass and their compromised flagellar vigor within the uterus.

Animals↗

PubMed2005

A new hypertrophic mechanism of serotonin in cardiac myocytes: receptor-independent ROS generation.

Reactive oxygen species (ROS) play a critical role in cardiac hypertrophy. We have recently shown that the serotonin-degrading enzyme monoamine oxidase A (MAO A) is an important source of hydrogen peroxide in rat heart. In the present study, we investigated the potential role of hydrogen peroxide generated by MAO A in cardiomyocyte hypertrophy by serotonin. Serotonin (5 microM, 48 h) induced hypertrophy in cultured adult rat ventricular myocytes, as reflected by increased 3H-leucine incorporation (+43%, P<0.001) and total protein content (+22%, P<0.001). Serotonin also increased intracellular hydrogen peroxide and oxidative stress production, measured respectively by DCF fluorescence intensity and GSH/GSSG ratio, and promoted ERK1/2 phosphorylation (P<0.001). Serotonin effects were only partially inhibited by the 5-HT2B receptor antagonist SB 206553. In contrast, they were extensively (>80%) prevented by the amine uptake inhibitor imipramine, the MAO inhibitor pargyline and the MEK inhibitor PD 98059. Cardiomyocyte hypertrophy and ERK activation were also inhibited by decreasing intracellular ROS by adenoviral overexpression of catalase or cardiomyocytes treatment with the iron chelator deferoxamine. These data suggest that part of cardiac hypertrophic effect of serotonin requires hydrogen peroxide production by MAO A and ERK1/2 activation. This newly recognized, receptor-independent mechanism of serotonin may contribute to myocardial remodeling and failure.

Adrenergic Uptake Inhibitors↗

PubMed1991

Expression of platelet-derived growth factors, transforming growth factors, and the ros gene in a variety of primary human brain tumors.

Ribonucleic acid was isolated from a wide spectrum of central nervous system tumors to examine the expression of platelet-derived growth factors (PDGF) A and B, tumor growth factors (TGF-beta) 1 and 2, and ros messenger ribonucleic acid. Eight glioblastoma cell lines were examined as well as cell cultures from 22 tumor explants. The explants included 6 glioblastomas, 4 anaplastic astrocytomas, 5 astrocytomas, 3 ependymal tumors, 2 meningiomas, 1 medulloblastoma. and 1 ganglioglioma. For comparison, 2 nontumor glial cell cultures were included. The PDGF B-chain was expressed in 5 of 8 glioblastoma cell lines, 2 of 6 glioblastomas, and in 3 of 4 anaplastic astrocytoma explants. There was no PDGF B expression in 4 astrocytomas, 3 ependymomas of varying malignancy, in the remainder of the tumors, or in the nontumor glial cells. The PDGF A-chain was expressed in all of the tumors, with the exception of the malignant ependymoma and in both nontumor glial cell cultures. TGF-beta 1 was expressed in all of the tumors and in nontumor glial cells. The expression of TGF-beta 2 was expressed in many of the benign and malignant tumors and also in both nontumor glial cell cultures. The ros messenger ribonucleic acid was expressed in 1 of 5 glioblastoma cell lines and in 2 of 6 glioblastoma cell explants, but in none of the other tumors or in the nontumor glial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Neoplasms↗

PubMed2003

ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy.

Oxidative stress has emerged as an important pathogenic factor in the development of long-term complications, such as atherosclerosis and nephropathy, in patients with diabetes. Whereas multiple enzymes and processes can contribute to oxidative stress, recent studies indicate that a multicomponent phagocyte-type NADPH oxidase is a major source of reactive oxygen species (ROS) production in many nonphagocytic cells, including fibroblasts, vascular smooth muscle cells, endothelial cells, renal mesangial cells, and tubular cells. Under physiologic conditions, nonphagocytic NADPH oxidases have very low-level constitutive activity. However, enzyme activity can be upregulated both acutely and chronically in response to stimuli such as growth factors, cytokines, high glucose, and hyperlipidemia. ROS production by the oxidase may serve a signaling role or may lead to oxidative damage. This article reviews current knowledge of the nonphagocyte-NADPH oxidases at both structural and biochemical levels and discusses the possible role of these enzymes in the pathophysiology of diabetic nephropathy.

Animals↗

PubMed1988

Regulation of the virC and virD promoters of pTiC58 by the ros chromosomal mutation of Agrobacterium tumefaciens.

The virC and virD operons of the virulence region of the Ti plasmid are highly regulated, requiring a transcriptional regulator that is encoded by virG and is activated by the product of virA and plant phenolics such as acetosyringone. Full expression of virC and virD of octopine and nopaline Ti plasmids is also obtained by a mutation in the ros gene of the Agrobacterium tumefaciens chromosome. S1-nuclease analysis, in vitro transcription, and DNase I protection experiments with A. tumefaciens RNA polymerase revealed virD promoters tandemly arranged, both of which are functional in the Ros mutant, while only one is functional in the presence of acetosyringone. A third (overlapping) promoter appears to be responsible for transcription of virC. Expression of virC and virD appears to be modulated by factors within the bacterium by means of a mechanism that is independent of factors produced during infection of the host plant.

Acetophenones↗