L Vardimon

Tel Aviv University, Tel Aviv, Tel Aviv, Israel

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Publications (42)234.66 Total impact

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    ABSTRACT: Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here, we show that c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or the half-life of the c-Jun protein but, rather, in the translatability of the transcript. The c-Jun 5'UTR harbors a potent internal ribosomal entry site (IRES) with a virus-like IRES domain that directs cap-independent translation in glioblastoma cells. Accumulation of c-Jun is not dependent on MAPK activity but can be stimulated by a cytoskeleton-dependent pathway. Our findings provide evidence that human c-Jun is an IRES-containing cellular transcript that contributes to cancer development through translational activation. This previously undescribed mechanism of c-Jun regulation might also be relevant to other types of human cancer and offers unique potential targets for therapy.
    Proceedings of the National Academy of Sciences 10/2012; 109(42):E2875-84. · 9.81 Impact Factor
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    ABSTRACT: A fundamental event in the development and progression of malignant melanoma is the deregulation of cancer-relevant transcription factors. We recently showed that c-Jun is a main regulator of tumor progression in melanoma and thus the most important member of the AP-1 transcription factor family for this disease. Interestingly, we revealed that c-Jun expression was regulated on the post-transcriptional level and therefore speculated that miRNAs could be involved in c-Jun regulation. We determined seed sequences for miR-125b and miR-527 in the coding region of c-Jun mRNA that hints at the direct involvement of miRNA-dependent regulation on the protein level. We found that the expression of miR-125b was significantly reduced in malignant melanoma cell lines and tissue samples compared with melanocytes, whereas miR-527 remained unchanged. In further functional experiments, treatment of melanoma cells with pre-miR-125b resulted in strong suppression of cellular proliferation and migration, supporting the role of miR-125b in melanoma. In addition, transfection of pre-miR-125b led to strong downregulation of c-Jun protein but not mRNA expression in melanoma cells. Luciferase assays using reporter plasmids containing the miR-125b seed sequence in the luciferase coding region confirmed the direct interaction with miR-125b. Furthermore, immunoprecipitation of Ago-2 revealed that c-Jun mRNA accumulated in the RNA-induced silencing complex after pre-miR-125b transfection in melanoma cells. In summary, we identified an important role for miR-125b in malignant melanoma. Moreover, we demonstrated post-transcriptional regulation of c-Jun by this miRNA and showed that c-Jun is a main mediator of the effects of miR-125b on melanoma cells.Oncogene advance online publication, 16 July 2012; doi:10.1038/onc.2012.307.
    Oncogene 07/2012; · 8.56 Impact Factor
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    ABSTRACT: Recently, we discovered that the loss of E-cadherin induces c-Jun protein expression, which is a member of the AP-1 transcription factor family and a key player in the processes of cell proliferation and tumor development and also found in elevated levels in melanomas. Notably, the mRNA level of c-Jun was not affected, suggesting that c-Jun is regulated at post-transcriptional level. Here, we present data that suggest that the dynamic cytoskeletal network, linked to E-cadherin, is involved in the regulation of the c-Jun protein and transcriptional activity. In a signaling cascade, the loss of E-cadherin activates the transcriptional regulator ETS-1 and consequently leads to the induction of RhoC expression that stabilizes c-Jun in melanoma. The link between RhoC and c-Jun seems to be indirect via the cytoskeleton. We conclude that the loss of E-cadherin mediated cell-adhesion induces c-Jun protein expression in a multistep process, offering several possibilities for therapeutic intervention.
    International Journal of Cancer 07/2011; 130(12):2801-11. · 6.20 Impact Factor
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    ABSTRACT: A central event in the development of malignant melanoma is the loss of the tumor-suppressor protein E-cadherin. Here, we report that this loss is linked to the activation of the proto-oncogene c-Jun, a key player in tumorigenesis. In vivo, malignant melanomas show strong expression of the c-Jun protein in contrast to melanocytes. Interestingly, c-Jun mRNA levels did not differ in the melanoma cell lines when compared to melanocytes, suggesting that c-Jun could be regulated at the post-transcriptional level. To uncover the link between E-cadherin and c-Jun, we re-expressed E-cadherin in melanoma cells and detected decreased protein expression and activity of c-Jun. Furthermore, c-Jun accumulation is dependent on active E-cadherin-mediated cell-cell adhesion and regulated via the cytoskeleton. Additionally, we determined that, with respect to c-Jun regulation, there are two melanoma subgroups. One subgroup regulates c-Jun expression via the newly discovered E-cadherin-dependent signaling pathway, whereas the other subgroup uses the MAPKinases to regulate its expression. In summary, our data provide novel insights into the tumor-suppressor function of E-cadherin, which contributes to the suppression of c-Jun protein translation and transcriptional activity independent of MAPKinases.
    Pigment Cell & Melanoma Research 10/2010; 24(1):148-64. · 5.84 Impact Factor
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    ABSTRACT: Evolution of the uricotelic system for ammonia detoxification required a mechanism for tissue-specific subcellular localization of glutamine synthetase (GS). In uricotelic vertebrates, GS is mitochondrial in liver cells and cytoplasmic in brain. Because these species contain a single copy of the GS gene, it is not clear how tissue-specific subcellular localization is achieved. Here we show that in chicken, which utilizes the uricotelic system, the GS transcripts of liver and brain cells are identical and, consistently, there is no difference in the amino acid sequence of the protein. The N-terminus of GS, which constitutes a 'weak' mitochondrial targeting signal (MTS), is sufficient to direct a chimeric protein to the mitochondria in hepatocytes and to the cytoplasm in astrocytes. Considering that a weak MTS is dependent on a highly negative mitochondrial membrane potential (DeltaPsi) for import, we examined the magnitude of DeltaPsi in hepatocytes and astrocytes. Our results unexpectedly revealed that DeltaPsi in hepatocytes is considerably more negative than that of astrocytes and that converting the targeting signal into 'strong' MTS abolished the capability to confer tissue-specific subcellular localization. We suggest that evolutional selection of weak MTS provided a tool for differential targeting of an identical protein by taking advantage of tissue-specific differences in DeltaPsi.
    Journal of Cell Science 02/2010; 123(Pt 3):351-9. · 5.88 Impact Factor
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    ABSTRACT: Loss of E-cadherin-mediated cell-cell contacts can elicit a signaling pathway that leads to acquisition of an invasive phenotype. Here, we show that at the receiving end of this pathway is the proto-oncogene c-Jun, a member of the activator protein-1 family of transcription factors that play a key role in stimulation of cell proliferation and tumor promotion. Cell separation or abrogation of E-cadherin-mediated cell-cell contacts both cause a dramatic increase in accumulation of the c-Jun protein. Unlike growth factors that enhance the expression of c-Jun by activating the transcription of the c-jun gene, the cell contact-dependent increase in c-Jun accumulation is not accompanied by a corresponding increase in c-Jun mRNA or c-Jun protein stability but rather in the translatability of the c-Jun transcript. Consistently, the increase in c-Jun accumulation is not dependent on activation of the mitogen-activated protein kinase or beta-catenin pathways but is mediated by signals triggered by the restructured cytoskeleton. Depolymerization of the cytoskeleton can mimic the effect of cell separation and cause a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase. This novel mechanism of c-Jun regulation seems to underlie the robust overexpression of c-Jun in tumor cells of patients with colon carcinoma.
    Molecular biology of the cell 03/2009; 20(7):2121-9. · 5.98 Impact Factor
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    ABSTRACT: Restriction of glutamine synthetase to the nervous system is mainly achieved through the mutual function of the glucocorticoid receptor and the neural restrictive silencing factor, NRSF/REST. Glucocorticoids induce glutamine synthetase expression in neural tissues while NRSF/REST represses the hormonal response in non-neural cells. NRSF/REST is a modular protein that contains two independent repression domains, at the N and C termini of the molecule, and is dominantly expressed in nonneural cells. Neural tissues express however splice variants, REST4/5, which contain the repression domain at the N, but not at the C terminus of the molecule. Here we show that full-length NRSF/REST or its C-terminal domain can inhibit almost completely the induction of gene transcription by glucocorticoids. By contrast, the N-terminal domain not only fails to repress the hormonal response but rather stimulates it markedly. The inductive activity of the N-terminal domain is mediated by hBrm, which is recruited to the promoter only in the concomitant presence of GR. Importantly, a similar inductive activity is also exerted by the splice variant REST4. These findings raise the possibility that NRSF/REST exhibits a dual role in regulation of glutamine synthetase. It represses gene induction in nonneural cells and enhances the hormonal response, via its splice variant, in the nervous system.
    Journal of Biological Chemistry 02/2008; 283(1):110-9. · 4.65 Impact Factor
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    ABSTRACT: The cytoskeleton is a dynamic network that undergoes restructuring during a variety of cellular events including cell contact formation, cell invasion and the mitotic phase of the cell cycle. Here, we review the contribution of the cytoskeletal network to the inductive activity of glucocorticoids by focusing on the hormonal control of glutamine synthetase in the chick neural retina. Depolymerization of the cytoskeleton in cells of the intact retinal tissue inhibits the hormonal induction of glutamine synthetase, but does not alter the cellular amount of the glucocorticoid-receptor protein or the ability of the receptor molecules to translocate into the nucleus. Inhibition of glutamine synthetase induction occurs via a mechanism that involves elevation of c-Jun protein accumulation and repression of glucocorticoid-receptor transcriptional activity. Unlike growth factors and other c-Jun inducing stimuli that control the transcription of the c-Jun gene, depolymerization of the cytoskeleton elevates c-Jun accumulation by upregulating the translation of the c-Jun transcript. We postulate that the cytoskeletal-dependent increase in c-Jun accumulation is involved in cell contact control of both cell proliferation and transcriptional activity of the glucocorticoid-receptor protein.
    Molecular and Cellular Endocrinology 07/2006; 252(1-2):142-7. · 4.04 Impact Factor
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    ABSTRACT: The cytoskeleton is a dynamic network that undergoes restructuring during various cellular events, influencing cell proliferation, differentiation, and apoptosis. Here, we report that accumulation of c-Jun, a member of the AP1 family of transcription factors that play a key role in normal and aberrant cell growth, dramatically increases upon depolymerization of the cytoskeleton, and that, unexpectedly, this increase is controlled translationally. Depolymerization of the actin or microtubule network induces an increase in c-Jun accumulation with no corresponding increase in c-Jun mRNA or in the half-life of the c-Jun protein, but rather in the translatability of its transcript. This increase is mediated by the untranslated regions (UTRs) of c-Jun mRNA, and is not dependent on activated mitogen-activated protein kinase pathways. This novel mechanism of c-Jun regulation might be relevant to physiological conditions in which c-Jun plays a pivotal role.
    Oncogene 03/2006; 25(5):665-76. · 8.56 Impact Factor
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    ABSTRACT: Glutamine synthetase (GS) plays a key role in two major biochemical pathways: In liver GS catalyzes ammonia detoxification, whereas in neural tissues it also functions in recycling of the neurotransmitter glutamate. In most species the GS gene gives rise to a cytoplasmic protein in both liver and neural tissues. However, in species that utilize the ureosmotic or uricotelic system for ammonia detoxification, the enzyme is cytoplasmic in neural tissues, but mitochondrial in liver cells. Since most vertebrates have a single copy of the GS gene, it is not clear how tissue-specific subcellular localization is achieved. Here we show that in the ureosmotic elasmobranch, Squalus acanthias (spiny dogfish), two different GS transcripts are generated by tissue-specific alternative splicing. The liver transcript contains an alternative exon that is not present in the neural one. This exon leads to acquisition of an upstream in-frame start codon and formation of a mitochondrial targeting signal (MTS). Therefore, the liver product is targeted to the mitochondria while the neural one is retained in the cytoplasm. These findings present a mechanism in which alternative splicing of an MTS-encoding exon is used to generate tissue-specific subcellular localization.
    FEBS Letters 11/2005; 579(25):5527-34. · 3.58 Impact Factor
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    Iftach Shaked, Iris Ben-Dror, Lily Vardimon
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    ABSTRACT: Clearance of synaptic glutamate by glial cells is required for the normal function of excitatory synapses and for prevention of neurotoxicity. Although the regulatory role of glial glutamate transporters in glutamate clearance is well established, little is known about the influence of glial glutamate metabolism on this process. This study examines whether glutamine synthetase (GS), a glial-specific enzyme that amidates glutamate to glutamine, affects the uptake of glutamate. Retinal explants were incubated in the presence of [(14)C]glutamate and glutamate uptake was assessed by measurement of the amount of radioactively labeled molecules within the cells and the amount of [(14)C]glutamine released to the medium. An increase in GS expression in Müller glial cells, caused by induction of the endogenous gene, did not affect the amount of glutamate accumulated within the cells, but led to a dramatic increase in the amount of glutamine released. This increase, which was directly correlated with the level of GS expression, was dependent on the presence of external sodium ions, and could be completely abolished by methionine sulfoximine, a specific inhibitor of GS activity. Our results demonstrate that GS activity significantly influences the uptake of glutamate by the neural retina and suggest that this enzyme may represent an important target for neuroprotective strategies.
    Journal of Neurochemistry 12/2002; 83(3):574-80. · 3.97 Impact Factor
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    ABSTRACT: Glutamine synthetase (GS) constitutes an endogenous mechanism for protection against glutamate neurotoxicity in neural tissues by catalyzing the amidation of the neurotoxic amino acid glutamate to the non-toxic amino acid glutamine. Expression of GS is regulated by systemic glucocorticoids, which induce transcription of the GS gene in glial cells only. This cell type specificity is established through the mutual activity of positive and negative regulatory elements, the glucocorticoid response element (GRE) and the neural restrictive silencing element (NRSE), respectively. Glial cell proliferation, which often occurs at the site of neural injury (gliosis), results in a marked decline in GS expression. This decline is mediated by the c-Jun protein, which accumulates in the proliferating cells and blocks the transcriptional activity of the glucocorticoid receptor. Disruption of glia-neuron cell contacts or supply of bFGF can also cause a decline in GS by a mechanism that involves the activation of the c-Jun signaling pathway in glial cells. Considering the detoxificating role of GS, stimulation of glial cell proliferation at the site of injury may exacerbate glutamate-mediated neurotoxicity through direct downregulation of GS.
    Gene Function & Disease 10/2001; 2:83-88.
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    ABSTRACT: Basic fibroblast growth factor (bFGF) was recently shown to promote the survival of neural cells and tissues, raising hopes for its therapeutic potential in degenerative disorders of the CNS. Here we examine the effect of bFGF on the expression of glutamine synthetase, a key enzyme in the detoxification of the neurotransmitter glutamate. Expression of this enzyme is regulated by systemic glucocorticoids and, in chick neural retina tissue, is restricted to Müller glial cells. We report that exogenous supply of bFGF to retinal explants inhibits hormonal induction of glutamine synthetase expression. This inhibition appears to be mediated by the c-Jun protein which accumulated, in response to bFGF, exclusively in Müller glial cells. Ischemic conditions, which reportedly stimulate the release of endogenous bFGF, also led to an increase in c-Jun protein and a decline in glutamine synthetase expression. This decline could be competitively prevented by a soluble fibroblast growth factor receptor but not by a soluble epidermal growth factor receptor. The finding that endogenous release of bFGF or its exogenous supply down-regulates glutamine synthetase expression suggests that in addition to its reported neuroprotective effect, bFGF may exacerbate glutamate mediated neurotoxicity through direct down-regulation of glutamine synthetase.
    Journal of Neurochemistry 07/2001; 77(6):1641-9. · 3.97 Impact Factor
  • L Vardimon
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    ABSTRACT: Glutamine synthetase constitutes an endogenous mecha- nism of protection against glutamate neurotoxicity in neural tissues by catalyzing the amidation of the neuro- toxic amino acid glutamate to the non-toxic amino acid glutamine. Expression of GS is regulated by glucocorti- coids that activate transcription of the gene exclusively in glial cells. Glial cell proliferation, which often occurs at the site of neuronal injury, causes a marked decline in GS expression via a mechanism mediated by the c-Jun pro- tein. A decline in GS expression might impair the ability of glial cells to cope with glutamate neurotoxicity. This is evidenced by the finding that an increase in GS expres- sion, achieved by activation of the endogenous gene or a supply of purified GS to injured tissue, has neuroprotec- tive benefits. Glutamate neurotoxicity The amino acid glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system. When released at synaptic terminals, glutamate activates several subtypes of receptorionophore com- plexes, including the N-methyl-D-aspartate subtype. Binding of glutamate to NMDA or non-NMDA (kainate or quisqualate) receptors causes opening of ion channels, alteration of membrane conductance, and further trans- duction of the neuronal signal. Removal of the neuro- transmitter from the extracellular fluid is a critical step in synaptic transmission because without it no new signal can get through. Also, removal of glutamate is of particular importance because its accumulation in the postsynaptic region is neurotoxic, causing death of neighboring cells. Glutamate is a remarkably potent and rapidly acting neurotoxin. Exposure to only 100 µM glutamate for 5 minutes results in the destruction of large numbers of cultured cortical neurons (1). Three main lines of evi- dence support the concept of glutamate-mediated neuro- toxicity: a) neuronal insult leads to accumulation of rela- tively large amounts of glutamate in the extracellular fluid, b) administration of glutamate (systemically or in vitro) leads to neuronal cell death, and c) glutamate receptor antagonists can protect against neuronal degeneration. Glutamate neurotoxicity is a self-propagating process: The GS = glutmine synthetase NMDA = N-methyl-D-aspartate
    The Israel Medical Association journal: IMAJ 08/2000; 2 Suppl:46-51. · 0.98 Impact Factor
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    ABSTRACT: The glucocorticoid signaling pathway is responsive to a considerable number of internal and external signals and can therefore establish diverse patterns of gene expression. A glial-specific pattern, for example, is shown by the glucocorticoid-inducible gene glutamine synthetase. The enzyme is expressed at a particularly high level in glial cells, where it catalyzes the recycling of the neurotransmitter glutamate, and at a low level in most other cells, for housekeeping duties. Glial specificity of glutamine synthetase induction is achieved by the use of positive and negative regulatory elements, a glucocorticoid response element and a neural restrictive silencer element. Though not glial specific by themselves, these elements may establish a glial-specific pattern of expression through their mutual activity and their combined effect. The inductive activity of glucocorticoids is markedly repressed by the c-Jun protein, which is expressed at relatively high levels in proliferating glial cells. The signaling pathway of c-Jun is activated by the disruption of glia-neuron cell contacts, by transformation with v-src, and in proliferating retinal cells of early embryonic ages. The c-Jun protein inhibits the transcriptional activity of the glucocorticoid receptor and thus represses glutamine synthetase expression. This repressive mechanism might also affect the ability of glial cells to cope with glutamate neurotoxicity in injured tissues.
    Journal of Neurobiology 10/1999; 40(4):513-27. · 3.05 Impact Factor
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    ABSTRACT: Leptin regulates food intake and other activities through its hypothalamic receptor. Leptin receptors are also found in other organs, including the ovary. Direct effects of leptin in ovarian steroid production were studied in primary rat granulosa cells and in rat and human granulosa cell lines. Leptin (0.6-18 nM) suppressed ovarian steroid synthesis costimulated by FSH and dexamethasone. Production of pregnenolone, progesterone, and 20alpha-hydroxy-4-pregnen-3-one was inhibited by leptin. This inhibition was due at least in part to reduced expression of adrenodoxin, a component of the P450scc system enzyme. Costimulation of progesterone production by forskolin and dexamethasone was also inhibited by leptin, whereas the forskolin-induced cAMP production was not affected. We find that leptin induces c-Jun expression and attenuates the transcriptional activity of the glucocorticoid receptor (GR) in granulosa cells. Elevation of c-Jun expression by other means, e.g. 12-O tetradecanoyl-phorbol-13-acetate or transfecting with a c-Jun expression vector, abolished the transcriptional activity of the GR. A leptin-induced elevation of c-Jun modulates the transcriptional activity of the GR, possibly leading to the observed attenuation of steroidogenesis. It was recently shown that glucocorticoids stimulate leptin expression in vivo, which in turn, inhibits cortisol synthesis. A direct action of leptin on the ovary is an additional element of a regulatory network that maintains the homeostasis of steroid production.
    Endocrinology 05/1999; 140(4):1731-8. · 4.72 Impact Factor
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    ABSTRACT: Glutamine synthetase is a key enzyme in the recycling of the neurotransmitter glutamate. Expression of this enzyme is regulated by glucocorticoids, which induce a high level of glutamine synthetase in neural but not in various non-neural tissues. This is despite the fact that non-neural cells express functional glucocorticoid receptor molecules capable of inducing other target genes. Sequencing and functional analysis of the upstream region of the glutamine synthetase gene identified, 5' to the glucocorticoid response element (GRE), a 21-base pair glutamine synthetase silencer element (GSSE), which showed considerable homology with the neural restrictive silencer element NRSE. The GSSE was able to markedly repress the induction of gene transcription by glucocorticoids in non-neural cells and in embryonic neural retina. The repressive activity of the GSSE could be conferred on a heterologous GRE promoter and was orientation- and position-independent with respect to the transcriptional start site, but appeared to depend on a location proximal to the GRE. Gel-shift assays revealed that non-neural cells and cells of early embryonic retina contain a high level of GSSE binding activity and that this level declines progressively with age. Our results suggest that the GSSE might be involved in the restriction of glutamine synthetase induction by glucocorticoids to differentiated neural tissues.
    Journal of Biological Chemistry 05/1999; 274(16):11399-407. · 4.65 Impact Factor
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    ABSTRACT: The physical and functional link between adhesion molecules and the cytoskeletal network suggests that the cytoskeleton might mediate the transduction of cell-to-cell contact signals, which often regulate growth and differentiation in an antagonistic manner. Depolymerization of the cytoskeleton in confluent cell cultures is reportedly sufficient to initiate DNA synthesis. Here we show that depolymerization of the cytoskeleton is also sufficient to repress differentiation-specific gene expression. Glutamine synthetase is a glia-specific differentiation marker gene whose expression in the retinal tissue is regulated by glucocorticoids and is ultimately dependent on glia-neuron cell contacts. Depolymerization of the actin or microtubule network in cells of the intact retina mimics the effects of cell separation, repressing glutamine synthetase induction by a mechanism that involves induction of c-Jun and inhibition of glucocorticoid receptor transcriptional activity. Depolymerization of the cytoskeleton activates JNK and p38 mitogen-activated protein kinase and induces c-Jun expression by a signaling pathway that depends on tyrosine kinase activity. Induction of c-Jun expression is restricted to Müller glial cells, the only cells in the tissue that express glutamine synthetase and maintain the ability to proliferate upon cell separation. Our results suggest that the cytoskeletal network might play a part in the transduction of cell contact signals to the nucleus.
    Molecular and Cellular Biology 04/1999; 19(3):1742-50. · 5.37 Impact Factor
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    ABSTRACT: The neurotransmitter glutamate is neurotoxic when it is accumulated in a massive amount in the extracellular fluid. Excessive release of glutamate has been shown to be a major cause of neuronal degeneration after central nervous system injury. Under normal conditions, accumulation of synaptically released glutamate is prevented, at least in part, by a glial uptake system in which the glia-specific enzyme glutamine synthetase (GS) plays a key role. We postulated that glial cells cannot cope with glutamate neurotoxicity because the level of GS is not high enough to catalyze the excessive amounts of glutamate released by damaged neurons. We examined whether elevation of GS expression in glial cells protects against neuronal degeneration in injured retinal tissue. Analysis of lactate dehydrogenase efflux, DNA fragmentation, and histological sections revealed that hormonal induction of the endogenous GS gene in retinal glial cells correlates with a decline in neuronal degeneration, whereas inhibition of GS activity by methionine sulfoximine leads to increased cell death. A supply of purified GS enzyme to the culture medium of retinal explants or directly to the embryo in ovo causes a dose-dependent decline in the extent of cell death. These results show that GS is a potent neuroprotectant and that elevation of GS expression in glial cells activates an endogenous mechanism whereby neurons are protected from the deleterious effects of excess glutamate in extracellular fluid after trauma or ischemia. Our results suggest new approaches to the clinical handling of neuronal degeneration.
    Proceedings of the National Academy of Sciences 07/1997; 94(13):7024-9. · 9.81 Impact Factor
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    ABSTRACT: Two isoforms of the glucocorticoid receptor, with apparent molecular mass of 90 and 95 kDa, are expressed in embryonic chicken neural retina. The 95-kDa receptor represents a hyperphosphorylated form of the 90-kDa receptor. Activation of the glucocorticoid receptor by cortisol results in a dose-dependent increase in receptor phosphorylation, translocation of receptor molecules into the nucleus and a decline in the total amount of the receptor. Activation of the glucocorticoid receptor can also be observed in the developing retinal tissue in ovo. At late embryonic ages, when the systemic level of glucocorticoids increases, a substantial quantity of receptor molecules becomes translocated into the nucleus, the relative level of the 95-kDa isoform increases, and the total amount of receptor declines. Activation of the receptor molecules in ovo correlates directly with an increase in transcription of the glucocorticoid-inducible gene, glutamine synthetase. The close correlation between the increase in systemic glucocorticoids, activation of glucocorticoid receptor molecules and induction of glutamine synthetase gene transcription suggests that glucocorticoids are directly involved in the developmental control of glutamine synthetase expression. Long-term organ culturing of embryonic retinal tissue in the absence of hormone results in an increase in glutamine synthetase expression. This increase, which is only 5 to 10% of that observed in ovo, is not mediated by activated receptor molecules and represents a mechanism for non-hormonal regulation of glutamine synthetase.
    Molecular Brain Research 01/1997; 43(1-2):321-9. · 2.00 Impact Factor

Publication Stats

992 Citations
234.66 Total Impact Points

Institutions

  • 1993–2012
    • Tel Aviv University
      • Department of Biochemistry and Molecular Biology
      Tel Aviv, Tel Aviv, Israel
  • 1991
    • University of Illinois at Chicago
      • Department of Biochemistry and Molecular Genetics (Chicago)
      Chicago, IL, United States
  • 1988
    • University of Chicago
      • Department of Molecular Genetics & Cell Biology
      Chicago, IL, United States
  • 1980–1984
    • University of Cologne
      • Institute for Genetics
      Köln, North Rhine-Westphalia, Germany