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PubMed2004

Molecular mimicry in translational regulation: the case of ribosomal protein S15.

Ribosomal protein S15 is highly conserved among prokaryotes. It plays a pivotal role in the assembly of the central domain of the small ribosomal subunit and regulates its own expression by a feedback mechanism at the translational level. The protein recognizes two RNA targets (rRNA and mRNA) that share only partial similarity. Its interaction with 16S rRNA has been fully characterized, while mRNA interactions and regulatory mechanisms have been extensively studied in E. coli and in T. thermophilus. Recently, we have characterized which aminoacids are involved in E. coli mRNA recognition, using an in vivo assay allowing to identify S15 mutations affecting the S15-mRNA interactions without altering 30S subunit assembly. Here, we address the following questions: Are common determinants used by S15 to recognize its rRNA and mRNA targets? What is the extent of molecular mimicry? Is the regulatory mechanism conserved? Our results indicate that specific recognition of mRNA and rRNA relies on both mimicry and site differentiation. They also highlight the high plasticity of RNA to adapt to evolutionary constraints.

Base Sequence↗
PubMed1989

Association of lysosomal activity with sensitivity and resistance to tumor necrosis factor in murine L929 cells.

The cytotoxic mechanism of action of tumor necrosis factor (TNF) was examined using murine L929 fibrosarcoma cells in vitro. Two cell lines were evaluated: parental TNF sensitive (L929S) (50% cytotoxic concentration, 2-6 ng/ml); and TNF resistant (L929R) (50% cytotoxic concentration, greater than 10,000 ng/ml). The latter resistant cell line was developed by serial passage in increasing concentrations of recombinant human TNF. Sensitive cells demonstrated cytolytic and cytostatic effects at TNF concentrations between 2 and 6 ng/ml, respectively. However, TNF failed to show any selective depression of RNA, DNA, or protein synthesis or ATP content in these cells until general cell death was apparent, as defined by the cell rounding and lifting off the plastic surface. The cytokine also failed to cause DNA single-strand breaks, as detected by alkaline elution techniques. TNF was also found to be no more active in glutathione-depleted cells than in target cells containing normal glutathione levels. In contrast, various nonspecific lysosomotropic agents such as ammonium chloride and D-saccharic acid lactone led to a marked inhibition of the cytotoxic action of TNF in vitro. Furthermore, significant differences in lysosomal enzyme activity were noted between L929S and L929R cells. The changes in L929R cells involved a 50% reduction in total lysosomal protein levels and a marked depression of beta-glucuronidase activity. In contrast, L929R lysosomal hexosaminidase activity was significantly elevated over the L929S cells. From these studies it is concluded that the antitumor activity of TNF does not involve specific inhibition of macromolecular synthesis, ATP production, or the level of reduced thiols. Instead, TNF cytotoxicity appears to require functional lysosomes, which are altered when TNF resistance develops in vitro.

Adenosine Triphosphate↗
PubMed1986

Natural cytotoxicity against mouse hepatitis virus-infected cells. II. A cytotoxic effector cell with a B lymphocyte phenotype.

The effector cell in mouse spleen which mediates natural cytotoxicity against mouse hepatitis virus (MHV)-infected target cells was characterized. The target cells were MHV-infected BALB/c 3T3, and the assay time was 3 hr. The effector cell, designated virus killer (VK) cell for the purpose of discussion, had the following phenotype: lymphocyte morphology, plastic-nonadherent, nylon wool-adherent, nonphagocytic, cyclophosphamide-sensitive; by antibody plus complement (C) depletion studies, it was asialo GM1-, NK 1.2 alloantigen-negative, Thy-1.2-, Lyt-5-, and macrophage antigen-negative; by rosetting techniques, it was Fc receptor-positive and surface Fab+; by flow cytometry (FACS) analysis, it was Lyt-2-, MAC-1-, Ia+, IgG (gamma)+, IgM (mu)+, IgD (delta)+, and B cell lineage antibody B-220+. NK cells, measured for cytotoxicity on YAC-1 cells, were similarly tested and were found to differ from the VK cell in the following properties: nylon wool-nonadherent, asialo GM1+, NK alloantigen-positive, Lyt-5+, surface Fab-, MAC-1+, Ia-, IgG-, IgM-, IgD-, and B-220-. The VK effector cell had a phenotype highly distinguishable from NK cells, effectors most commonly associated with antiviral natural cytotoxicity. The VK cell had a phenotype identical to that of a B lymphocyte and was identified as such. Although the effector cells displayed cell surface antibody, the antibody did not appear to be involved in lysis, because lysis could not be blocked by F(ab)'2 directed against Fab, mu, or delta. Cytotoxicity was more likely associated with recognition of the B lymphocyte surface by the MHV glycoprotein E2, as shown in the accompanying companion paper. This is the first demonstration that natural cytotoxicity can be mediated by B lymphocytes.

Animals↗
PubMed2006

Regulation of neuronal PKA signaling through AKAP targeting dynamics.

Central to organization of signaling pathways are scaffolding, anchoring and adaptor proteins that mediate localized assembly of multi-protein complexes containing receptors, second messenger-generating enzymes, kinases, phosphatases, and substrates. At the postsynaptic density (PSD) of excitatory synapses, AMPA (AMPAR) and NMDA (NMDAR) glutamate receptors are linked to signaling proteins, the actin cytoskeleton, and synaptic adhesion molecules on dendritic spines through a network of scaffolding proteins that may play important roles regulating synaptic structure and receptor functions in synaptic plasticity underlying learning and memory. AMPARs are rapidly recruited to dendritic spines through NMDAR activation during induction of long-term potentiation (LTP) through pathways that also increase the size and F-actin content of spines. Phosphorylation of AMPAR-GluR1 subunits by the cAMP-dependent protein kinase (PKA) helps stabilize AMPARs recruited during LTP. In contrast, induction of long-term depression (LTD) leads to rapid calcineurin-protein phosphatase 2B (CaN) mediated dephosphorylation of PKA-phosphorylated GluR1 receptors, endocytic removal of AMPAR from synapses, and a reduction in spine size. However, mechanisms for coordinately regulating AMPAR localization, phosphorylation, and synaptic structure by PKA and CaN are not well understood. A kinase-anchoring protein (AKAP) 79/150 is a PKA- and CaN-anchoring protein that is linked to NMDARs and AMPARs through PSD-95 and SAP97 membrane-associated guanylate kinase (MAGUK) scaffolds. Importantly, disruption of PKA-anchoring in neurons and functional analysis of GluR1-MAGUK-AKAP79 complexes in heterologous cells suggests that AKAP79/150-anchored PKA and CaN may regulate AMPARs in LTD. In the work presented at the "First International Meeting on Anchored cAMP Signaling Pathways" (Berlin-Buch, Germany, October 15-16, 2005), we demonstrate that AKAP79/150 is targeted to dendritic spines by an N-terminal basic region that binds phosphatidylinositol-4,5-bisphosphate (PIP(2)), F-actin, and actin-linked cadherin adhesion molecules. Thus, anchoring of PKA and CaN as well as physical linkage of the AKAP to both cadherin-cytoskeletal and MAGUK-receptor complexes could play roles in coordinating changes in synaptic structure and receptor signaling functions underlying plasticity. Importantly, we provide evidence showing that NMDAR-CaN signaling pathways implicated in AMPAR regulation during LTD lead to a disruption of AKAP79/150 interactions with actin, MAGUKs, and cadherins and lead to a loss of the AKAP and anchored PKA from postsynapses. Our studies thus far indicate that this AKAP79/150 translocation depends on activation of CaN, F-actin reorganization, and possibly Ca(2+)-CaM binding to the N-terminal basic regions. Importantly, this tranlocation of the AKAP79/150-PKA complex from spines may shift the balance of PKA kinase and CaN/PP1 phosphatase activity at the postsynapse in favor of the phosphatases. This loss of PKA could then promote actions of CaN and PP1 during induction of LTD including maintaining AMPAR dephosphorylation, promoting AMPAR endocytosis, and preventing AMPAR recycling. Overall, these findings challenge the accepted notion that AKAPs are static anchors that position signaling proteins near fixed target substrates and instead suggest that AKAPs can function in more dynamic manners to regulate local signaling events.

A Kinase Anchor Proteins↗
PubMed2003

Calmodulin-regulated adenylyl cyclases: cross-talk and plasticity in the central nervous system.

Gene disruption studies have shown that the Ca(2+)-stimulated adenylyl cyclases, AC1 and AC8, are critical for some forms of synaptic plasticity, including long-term potentiation as well as long-term memory formation (LTM). It is hypothesized that these enzymes are required for LTM to support the increased expression of a family of genes regulated through the cAMP/Ca(2+) response element-binding protein/cAMP response element transcriptional pathway. In contrast to AC1 and AC8, AC3 is a Ca(2+)-inhibited adenylyl cyclase that plays an essential role in olfactory signal transduction. Coupling of odorant receptors to AC3 stimulates cAMP transients that function as the major second messenger for olfactory signaling. These cAMP transients are caused, at least in part, by Ca(2+) inhibition of AC3, which is mediated through calmodulin-dependent protein kinase II. The unique structure and regulatory properties of these adenylyl cyclases make them attractive drug target sites for modulation of a number of physiological processes including memory formation and olfaction.

Adenylyl Cyclases↗
PubMed2006

Neuroprotective effect of A20 on TNF-induced postischemic apoptosis.

Focal cerebral ischemia causes apoptosis in neural cells during the postischemia period. TNF is critically involved in such neuronal apoptosis mediated by caspase pathways. A20 can inhibit TNF-induced apoptosis in many cell types. However, little work has been carried out in central nervous system. In the present study, gene transfer of A20 resulted in reduction of infarct volume and improvement of neurological deficit in ischemia rats. Results of flow cytometry, TUNEL and DNA fragmentation assay all indicated A20 could inhibit TNF-induced apoptosis both in primary rat hippocampal neurons and SH-SY5Y cells. Moreover, we found A20 targeted the TNF apoptotic pathway by inhibiting proteolytic cleavage of caspase 8 and 3 in SH-SY5Y cells. These data demonstrated A20 could effectively protect neurons from postischemic apoptosis and may function partly on death receptor caspase pathway. Gene transfer of A20 may be a promising approach to gene therapy for cerebral ischemia in the future.

Animals↗
PubMed1995

Regulatory region in choline acetyltransferase gene directs developmental and tissue-specific expression in transgenic mice.

Acetylcholine, one of the main neurotransmitters in the nervous system, is synthesized by the enzyme choline acetyltransferase (ChAT; acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6). The molecular mechanisms controlling the establishment, maintenance, and plasticity of the cholinergic phenotype in vivo are largely unknown. A previous report showed that a 3800-bp, but not a 1450-bp, 5' flanking segment from the rat ChAT gene promoter directed cell type-specific expression of a reporter gene in cholinergic cells in vitro. Now we have characterized a distal regulatory region of the ChAT gene that confers cholinergic specificity on a heterologous downstream promoter in a cholinergic cell line and in transgenic mice. A 2342-bp segment from the 5' flanking region of the ChAT gene behaved as an enhancer in cholinergic cells but as a repressor in noncholinergic cells in an orientation-independent manner. Combined with a heterologous basal promoter, this fragment targeted transgene expression to several cholinergic regions of the central nervous system of transgenic mice, including basal forebrain, cortex, pons, and spinal cord. In eight independent transgenic lines, the pattern of transgene expression paralleled qualitatively and quantitatively that displayed by endogenous ChAT mRNA in various regions of the rat central nervous system. In the lumbar enlargement of the spinal cord, 85-90% of the transgene expression was targeted to the ventral part of the cord, where cholinergic alpha-motor neurons are located. Transgene expression in the spinal cord was developmentally regulated and responded to nerve injury in a similar way as the endogenous ChAT gene, indicating that the 2342-bp regulatory sequence contains elements controlling the plasticity of the cholinergic phenotype in developing and injured neurons.

Aging↗
PubMed1995

Plasticity in the development of neocortical areas.

Heterotopic transplantation analysis suggests that individual areas of the developing neocortex have the capacity to differentiate many of the architectural and connectional features normally characteristic of other neocortical areas. Many studies indicate a pivotal role for thalamocortical afferents in the differentiation of the area-specific features that distinguish neocortical areas. Both activity-dependent and activity-independent mechanisms contribute to the patterning of thalamocortical afferent terminations. The available evidence suggests that positional information is established in the cortical subplate and that this information controls the precise targeting of developing thalamocortical axons. In this way appropriate thalamocortical relationships can be established that allow these afferents to promote the differentiation of the functionally specialized and anatomically distinct areas of the adult neocortex.

Animals↗
PubMedDate not supplied

Learning by neurones: role of attention, reinforcement and behaviour.

The importance of the behavioural situation, attentional demands of the task, and stimulus-reinforcement contingencies in promoting or permitting experience-dependent neuronal plasticity is argued. Evidence is provided for the specific activation of the locus coeruleus noradrenergic system of the rat by novel stimuli encountered while investigating the environment, as well as during a formal learning situation. Noradrenergic neurons are particularly concerned with changes in the predictive value of the stimulus, when new learning should occur. Noradrenaline, released at LC terminals in target sensory systems, could facilitate shifts in attention, information processing and memory through its well-documented gating and tuning effects and its permissive role in long-term potentiation. Dopamine neurons, which fire persistently to reward during learning, could be involved in maintaining the behavioural response.

Animals↗
PubMed1991

[Medical and technical aspects of weapon effects. IV. Plastic bullets reduce the risk of the military assault rifle (StG 77)].

56 x 45 mm Rota-ammunition was introduced to meet the requirements of security personnel at prisons. The Austrian military assault rifle (StG 77) can be used for this ammunition. The bullet consists of an X-ray dense plastic material with a weight of 1.6 g. Therefore the kinetic energy of this projectile is lower than that of the standard ammunition, also on its flight it loses velocity at a higher rate. Thus, this bullet has the advantage of being less dangerous over long distances (500 m versus 2500 m or more) but still offers at short distances (fe 10 m) a reasonable capacity of incapacitation. Tests concerning ballistics, penetration and shooting at gelatine and soap targets were performed. By means of these tests we compared the wounding capacity of the standard ammunition (5.56 x 45 mm S-cartridge) and the investigated Rota-ammunition.

Animals↗
PubMed1998

Dynamic modulation of cerebral cortex synaptic function by nitric oxide.

Our experiments demonstrate that NO exerts several actions in the cerebral cortex (see Fig. 4). Its production is mediated by neuronal activity through at least two pathways, NMDA receptors and AMPA receptors. By virtue of its diffusion in extracellular space, NO can interact with synapses that are near the production site but not necessarily anatomically connected to the NO source by a conventional synaptic linkage. NO's primary action is amplification of the release of the excitatory neurotransmitter, L-glutamate, thus effectively creating a positive feed-forward gain system. However, a number of effective brakes, presumably activated under physiological conditions, serve to limit the cascade. These include NO's ability to inhibit NMDA receptors, its negative feedback on the rate limiting enzyme, NOS (Rengasamy and Johns, 1993; Park et al., 1994; Ravichandran et al., 1995) and other inhibitory actions (Figs. 3H and L). Under conditions of extremely strong activation or curtailment of the inhibitory feedback mechanisms, as might occur with a change in the local redox milieu (see Lipton, this volume), the amplification cascade may proceed unchecked leading to neurotoxicity (see Dawson, this volume). NO's ability to modulate synaptic function is indicated by both its positive and negative modulatory role in a form of activity-dependent synaptic plasticity, covariance-induced synaptic potentiation. These opposing effects may be due to NO's ability to amplify glutamate release and inhibit NMDA receptors, respectively. The actions of endogenous NO in vivo are primarily facilitatory in visual cortex (Fig. 4). However, inhibitory actions also occur in vivo. The targets for NO in vivo, are potentially more diverse including the neurotransmitter release process, NMDA receptors, other receptors and ion channels and the cerebral vasculature. However, regardless of the signaling pathways, the net result of endogenous NO production in the intact visual cortex is a potent modulation of cells' responses to visual stimulation. Thus, it is likely that this signal plays an important role in ongoing information processing in the mature cerebral cortex, dynamically altering the effective strength of cortical networks.

Animals↗
PubMed2003

Genes, neurons and codes: remarks on biological communication.

I examine critically the application of information-theoretic ideas to biological communication during embryonic development and in the functioning central nervous system (CNS). I show that intercellular communication relies mostly on simple signals whose role is to effect a selection among predetermined cellular states. Hence, a crucial role is played by cellular memory, which stabilizes such states. Memory in cells is partly located in the nuclear DNA; no less important however is (phenotypic) memory lying in the cell's organelles and compartments. Because of combinatorial effects in gene expression patterns, cell memory is an enormously powerful mechanism, which also underlies plasticity, and thus constitutes the factor unifying genetic determination, plasticity and learning. Communication in the CNS is analyzed in some detail: here, cellular memory is embodied in anatomy (i.e., cell shape) and neurochemistry. These are the major, relatively "static" factors affecting the routing of neural impulses in the adult CNS. In addition, however, faster channeling is also required: action potentials must be directed to their targets along a few of exponentially many paths, and this dynamic routing is crucial for proper operation. I suggest that collective oscillatory modes may play a role in solving this addressing problem, in the same way that the clock signal gates the operation of man-made computers.

Animals↗
PubMed2001

beta-catenin: molecular plasticity and drug design.

The protein beta-catenin is an essential component of intercellular junctions and the Wnt growth factor signaling pathway. In many cancers, mutation of Wnt pathway components leads to activation of oncogenes by the beta-catenin-Tcf transcription factor complex. This complex is therefore an attractive target for anti-cancer drugs, but any such compound must selectively interfere with the beta-catenin-Tcf complex without disrupting other essential interactions of beta-catenin. Recent structural and biochemical studies have probed the molecular basis of ligand interaction by beta-catenin, and highlighted the possibilities and challenges of designing inhibitors of the beta-catenin-Tcf complex.

Animals↗
PubMed2001

Targeting hyperthermia for renal cell carcinoma using human MN antigen-specific magnetoliposomes.

Magnetoliposomes (MLs) conjugated with an antibody fragment to give specificity to a tumor were applied to hyperthermia for cancer. The Fab' fragment of the G250 antibody, which binds to MN antigen on many types of human renal cell carcinoma, was cross-linked to N-(6-maleimidocaproyloxy)-dipalmitoyl phosphatidylethanolamine (EMC-DPPE) in liposomal membrane. The targetability of the G250-Fab' fragment-conjugating MLs (G250-FMLs) was investigated using the mouse renal cell carcinoma (mRCC) and MN antigen-presenting cell, MN-mRCC. The amount of G250-FMLs uptake reached 67 pg / cell against MN-mRCC cells in an in vitro experiment using plastic dishes and this value was about 6 times higher than that in the case of MLs. In an in vivo experiment using MN-mRCC-harboring mice, 1.5 mg of the FMLs per carcinoma tissue accumulated (tumor weight was 0.19 g), which corresponded to approximately 50% of the total injection. This value was 27 times higher than that of the MLs. After injection of the FMLs, mice were exposed to intracellular hyperthermia using alternating magnetic field irradiation. The temperature of tumor tissue increased to 43 degrees C and the growth of the carcinoma was strongly arrested for at least 2 weeks. These results indicate the G250-FMLs could target renal cell carcinoma cells in vitro and in vivo, and are efficiently applicable to the hyperthermic treatment of carcinoma.

Animals↗
PubMed1992

Estrogen receptors colocalize with low-affinity nerve growth factor receptors in cholinergic neurons of the basal forebrain.

The rodent and primate basal forebrain is a target of a family of endogenous peptide signaling molecules, the neurotrophins--nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3--and of the gonadal steroid hormone estrogen, both of which have been implicated in cholinergic function. To investigate whether or not these ligands may act on the same neurons in the developing and adult rodent basal forebrain, we combined autoradiography with 125I-labeled estrogen and either nonisotopic in situ hybridization histochemistry or immunohistochemistry. We now report colocalization of intranuclear estrogen binding sites with the mRNA and immunoreactive protein for the low-affinity nerve growth factor receptor, which binds all three neurotrophins, and for the cholinergic marker enzyme choline acetyltransferase (acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6). Colocalization of estrogen and low-affinity nerve growth factor receptors implies that their ligands may act on the same neuron, perhaps synergistically, to regulate the expression of specific genes or gene networks that may influence neuronal survival, differentiation, regeneration, and plasticity. That cholinergic neurons in brain regions subserving cognitive functions may be regulated not only by the neurotrophins but also by estrogen may have considerable relevance for the development and maintenance of neural substrates of cognition. If estrogen-neurotrophin interactions are important for survival of target neurons, then clinical conditions associated with estrogen deficiency could contribute to the atrophy or death of these neurons. These findings have implications for the subsequent decline in those differentiated neural functions associated with aging and Alzheimer disease.

Animals↗
PubMed2006

Delayed intervention with transplants and neurotrophic factors supports recovery of forelimb function after cervical spinal cord injury in adult rats.

The adult central nervous system is capable of considerable anatomical reorganization and functional recovery after injury. Functional outcomes, however, vary greatly, depending upon size and location of injury, type and timing of intervention, and type of recovery and plasticity evaluated. The present study was undertaken to assess the recovery of skilled and unskilled forelimb function in adult rats after a C5/C6 spinal cord over-hemisection and delayed intervention with fetal spinal cord transplants and neurotrophins. Recovery of forelimb function was evaluated during both target reaching (a skilled behavior) and vertical exploration (an unskilled behavior). Anatomical tracing and immunohistochemistry were used to assess the growth of descending raphespinal, corticospinal, and rubrospinal fibers at the injury site, tracts that normally confer forelimb function. Delayed intervention with transplants and either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) restored skilled left forelimb reaching to pre-injury levels. Animals showed recovery of normal reaching movements rather than compensation with abnormal movements. Transplants and NT-3 also improved right forelimb use during an unskilled vertical exploration, but not skilled right reaching. Intervention with fetal transplant tissue supported the growth of descending serotonergic, corticospinal, and rubrospinal fibers into the transplant at the lesion site. The addition of neurotrophins, however, did not significantly increase axonal growth at the lesion site. These studies suggest that the recovery of skilled and unskilled forelimb use is possible after a large cervical spinal cord injury following delayed intervention with fetal spinal cord and neurotrophins. Plasticity of both spared and axotomized descending pathways likely contributes to the functional recovery observed.

Animals↗
PubMed1993

Experimentally induced visual projections to the auditory thalamus in ferrets: evidence for a W cell pathway.

We have previously reported that following specific neonatal brain lesions in ferrets, a retinal projection is induced into the auditory thalamus (Sur et al., Science 242:1437, '88). In these "rewired" ferrets, a novel visual pathway is established through auditory thalamus [the medial geniculate nucleus (MGN)] and primary auditory cortex (A1); cells in both MGN and A1 are visually responsive and exhibit properties similar to those of visual cells in the normal visual pathway. In this paper, we use three approaches--physiological, anatomical, and developmental--to examine which of the retinal ganglion cells project to the MGN in these rewired ferrets. We find that: 1) physiological response properties of postsynaptic visual cells in the MGN are W-like; 2) retinal ganglion cells back-filled from the MGN are small and similar to soma sizes of subsets of the normal retinal W cell population; and 3) subpopulations of these small cells can be preferentially rerouted to the MGN in response to different surgical manipulations at birth, consistent with differential W cell projection patterns in normal animals. These data suggest that retinal W cells come to project to the MGN in rewired animals. These findings not only provide a basis on which to interpret functional properties of this novel visual pathway, but also provide important information about the developmental capabilities of specific retinal ganglion cell classes and the regulation of their projections by target structures in the brain during development.

Animals↗
PubMed2002

Some unresolved issues in motor unit research.

The intrinsic properties of motoneurones, muscle units, and synaptic inputs exhibit correlated variations that subserve a wide range of functional demands. In large limb muscles, these correlations suggest distinct "types" of motor units, while in smaller, distal muscles their distributions are more continuous. The CNS mechanisms that control recruitment patterns are still unclear, particularly the organization of spinal interneurone circuits. We need new approaches to identify segmental interneurones by their inputs and output targets. However, functional circuitry is changeable, depending on the "state" of the system. Shifting alliances of interneurone groups can in principle produce virtually unlimited permutations of motor unit coactivation and suppression. Although such state-dependence plasticity is a challenge, it can also be a useful tool in unraveling interneurone organization.

Animals↗