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PubMedDate not supplied

Negative regulation of onconstatin M signaling by suppressor of cytokine signaling (SOCS-3).

Oncostatin M (OSM) is known to inhibit the growth of melanocytes and early-stage melanomas, but this ability is lost with melanoma progression. The biological effects of OSM involve the activation of Janus kinases (Jak) and signal transducer and activator of transcription (STAT) factors. Since SOCS (suppressor of cytokine signaling) a recently described family of regulatory proteins, has been shown to act through down-regulation of Jak-STAT signaling, we investigated their putative role in the inhibition of OSM signaling in the human melanoma cell line A375. We observed that, among the SOCS family members examined, only SOCS-3 mRNA was strongly and rapidly induced by OSM. SOCS-3 protein was present within 1h and rapidly declined thereafter. Constitutive expression of SOCS-3 protein completely abolished the activation of the Jak-STAT signaling pathway as well as the Ras-MAP kinase pathway. As a result, A375 cells acquired an OSM-resistant phenotype. Our findings demonstrate that SOCS-3 is a potent regulator of OSM response and suggest that dysregulation of SOCS-3 expression could provide a mechanism for OSM resistance acquisition during tumour progression.

Base Sequence↗

PubMed2004

Structure-switching signaling aptamers: transducing molecular recognition into fluorescence signaling.

The development of aptamer technology considerably broadens the utility of nucleic acids as molecular recognition elements, because it allows the creation of DNA or RNA molecules for binding a wide variety of analytes (targets) with high affinity and specificity. Several recent studies have focused on developing rational design strategies for transducing aptamer-target recognition events into easily detectable signals, so that aptamers can be widely exploited for detection directed applications. We have devised a generalizable strategy for designing nonfluorescent aptamers that can be turned into fluorescence-signaling reporters. The resultant signaling probes are denoted "structure-switching signaling aptamers" as they report target binding by switching structures from DNA/DNA duplex to DNA/target complex. The duplex is formed between a fluorophore-labeled DNA aptamer and an antisense DNA oligonucleotide modified with a quencher (denoted QDNA). In the absence of the target, the aptamer hybridizes with QDNA, bringing the fluorophore into close proximity of the quencher for efficient fluorescence quenching. When this system is exposed to the target, the aptamer switches its binding partner from QDNA to the target. This structure-switching event is coupled to the generation of a fluorescent signal through the departure of QDNA, permitting the real-time monitoring of the aptamer-target recognition. In this article, we discuss the conceptual framework of the structure-switching approach, the essential features of structure-switching signaling aptamers as well as remaining challenges and possible solutions associated with this new methodology.

Adenosine Triphosphate↗

PubMed1996

Correlated behavior of the EPR signal of cytochrome b-559 heme Fe(III) ligated by OH- and the multiline signal of the Mn cluster in PS-II membrane fragments.

EPR signals of Cyt b-559 heme Fe(III) ligated by OH- and the multiline signal of the Mn cluster in PS-II membrane fragments have been investigated. In 2,3-dicyano-5,6-dichloro-p-benzoquinone-oxidized PS-II membrane fragments the light-induced decrease of the EPR signal of the heme Fe(III)-OH- is accompanied by the appearance of the EPR multiline signal of the Mn cluster. Addition of F- ions, which act as a stronger ligand for heme Fe(III) than OH-, decreases to the same extent the dark- and light-induced signal of the heme Fe(III)-OH- and the light-induced multiline signal of the Mn cluster. These results are discussed in terms of the light-induced formation of a bound OH' radical shared between the Cyt b-559 heme Fe and the Mn cluster as a first step of water oxidation.

Benzoquinones↗

PubMed1988

Transmembrane signaling by bacterial chemoreceptors: E. coli transducers with locked signal output.

Methyl-accepting chemotaxis proteins (MCPs) function as transmembrane signalers in bacteria. We isolated and characterized mutants of the E. coli Tsr protein that produce output signals in the absence of overt stimuli and that are refractory to sensory adaptation. The properties of these "locked" transducers indicate that MCP molecules are capable of generating signals that actively augment clockwise and counter-clockwise rotation of the flagellar motors. Transitions between MCP signaling states can be influenced by amino acid replacements in many parts of the molecule, including the methylation sites, at least one of the two membrane-spanning segments, and a linker region connecting the receptor and signaling domains. These findings suggest that transmembrane signaling may involve direct propagation of conformational changes between the periplasmic and cytoplasmic portions of the MCP molecule.

Amino Acid Sequence↗

PubMed2004

Paradoxical parasellar high signals resembling shunt diseases on routine 3D time-of-flight MR angiography of the brain: mechanism for the signals and differential diagnosis from shunt diseases.

BACKGROUND AND PURPOSE: We occasionally encounter phenomena in which venous flow signals of the cavernous sinus (CS) and/or inferior petrosal sinus (IPS) are visualized paradoxically in patients without arteriovenous shunt in 3D time-of-flight magnetic resonance angiography (3D-TOF MRA) of the brain. The aims of this study are to examine the frequency and cause of this phenomenon ("pseudo-shunt" image) and to determine points of differentiation from definite arteriovenous shunt images ("real shunt"). METHODS: We retrospectively examined 85 maximum intensity projection images obtained by MRA in the absence of arteriovenous shunts to detect pseudo-shunt images, and evaluated source images of pseudo-shunt studies for venous structures. Four real-shunt MRA studies were compared with pseudo-shunt studies on three points: (1) extension of sinuses, (2) extension of cortical veins, and (3) signal intensity of sinuses as assessed by the scoring method (1 point when these findings exist, 0 when they do not). RESULTS: We detected five CS (3%) and six IPS (4%) signals in 9 (11%) of the 85 cases. In the source images of four pseudo-shunt images in the CS, we detected signals from the sphenoparietal sinus (SPS). The average score was significantly lower in the pseudo-shunt (0.22) than the real-shunt (2.75) images (P < .0001). CONCLUSION: In cerebral 3D-TOF MRA, pseudo-shunt images were seen in 11% (9/85) of the study population, with antegrade upward blood flow of the SPS considered as one of the causes. Real-shunt signals can be distinguished from pseudo-shunt signals by evaluation of source images.

Adolescent↗

PubMed1999

Differential signal detection system for improved analysis of overlapping signals in liquid chromatography.

We have developed a differential signal detection system for the analysis of liquid chromatographic signals using two or more detectors and a differential amplifier circuit. The proposed detection system is an improvement on conventional chromatography in which signals are detected by means of a single detector. The differential signal detection system eliminates difficulties of isolating minor components of the signal which are masked by the major component, as well as difficulties of separating two components of the signal having similar retention times.

Chromatography, Liquid↗

PubMed2004

Regulation of signal peptidase by phospholipids in membrane: characterization of phospholipid bilayer incorporated Escherichia coli signal peptidase.

Prokaryotic signal peptidases are membrane-bound enzymes. They cleave signal peptides from precursors of secretary proteins. To study the enzyme in its natural environment, which is phospholipid bilayers, we developed a method that allows us effectively to incorporate full-length Escherichia coli signal peptidase I into phospholipid vesicles. The membrane-bound signal peptidase showed high activity on a designed substrate. The autolysis site of the enzyme is separated from its catalytic site in vesicles by the lipid bilayer, resulting in a dramatic decrease of the autolysis rate. Phosphotidylethanolamine, which is the most abundant lipid in Escherichia coli inner membrane, is required to maintain activity of the membrane-incorporated signal peptidase. The maximal activity is achieved at about 55% phosphotidylethanolamine. Negatively charged lipids, which are also abundant in Escherichia coli inner membrane, enhances the activity of the enzyme too. Its mechanism, however, cannot be fully explained by its ability to increase the affinity of the substrate to the membrane. A reaction mechanism was developed based on the observation that cleavage only takes place when the enzyme and the substrate are bound to the same vesicle. Accordingly, a kinetic analysis is presented to explain some of the unique features of phospholipid vesicles incorporated signal peptidase, including the effect of lipid concentration and substrate-vesicle interaction.

Bacteriolysis↗

PubMed1994

Salicylic Acid Is Not the Translocated Signal Responsible for Inducing Systemic Acquired Resistance but Is Required in Signal Transduction.

Infection of plants by necrotizing pathogens can induce broad-spectrum resistance to subsequent pathogen infection. This systemic acquired resistance (SAR) is thought to be triggered by a vascular-mobile signal that moves throughout the plant from the infected leaves. A considerable amount of evidence suggests that salicylic acid (SA) is involved in the induction of SAR. Because SA is found in phloem exudate of infected cucumber and tobacco plants, it has been proposed as a candidate for the translocated signal. To determine if SA is the mobile signal, grafting experiments were performed using transgenic plants that express a bacterial SA-degrading enzyme. We show that transgenic tobacco root-stocks, although unable to accumulate SA, were fully capable of delivering a signal that renders nontransgenic scions resistant to further pathogen infection. This result indicated that the translocating, SAR-inducing signal is not SA. Reciprocal grafts demonstrated that the signal requires the presence of SA in tissues distant from the infection site to induce systemic resistance.

Journal Article↗

PubMed1976

Cancellation of rod signals by cones, and cone signals by rods in the cat retina.

1. The interaction of rod and cone signals at the level of cat retinal ganglion cells was studied by a method of light exchange. Two spectrally distinct lights were exchanged in such a manner that the rate of photon catch by rods increased in a stepwise manner at the same moment that the cone rate decreased in the same manner, and vice versa. 2. Under any conditions of adaptation, where both rods and cones contributed to the ganglion-cell discharge, it was always possible to adjust the ratio of the magnitudes of the rod and cone stimuli so that no change in ganglion-cell discharge could be detected by listening to the recorded activity via a loudspeaker. We term this condition a silent exchange. 3. On the face of it, the condition of silent exchange arises when rod and cone signals are able to cancel one another, when made opposite in phase by the exchange situation. But was this silence due to a true cancellation of the signals from one photoreceptor type by those of the other type, or was it due to our failure to stimulate the photoreceptors adequately? In order to test whether rod signals can cancel those of cones we bleached both visual pigments and set our exchange apparatus to stimulate the two photoreceptors in the antagonistic manner described above. At first no response could be heard on exchange, for the thresholds of both rods and cones lay above that of our apparatus. But the cones soon recovered and a strong response was heard on exchange. With no change in our stimulating situation, this response diminished with time and silence was again restored. This restoration of silence could not be due to the cones alone, for with time their sensitivity could only further increase. It could only be the increasing sensitivity of the rods that quietened the cone signals. In agreement with this conculsion, the dark-adaptation curve of the rods showed that they became sensitive to our stimulus at the time that the cones began to be silenced. 4. By means of coloured backgrounds we have also shown the converse, namely that rods signals can be cancelled by those of cones.

Animals↗

PubMed1998

Activation of the signal transducers and activators of transcription signaling pathway by growth hormone (GH) in skin fibroblasts from normal and GH binding protein-positive Laron Syndrome children.

We have previously described two families (H and M) with GH binding protein-positive Laron Syndrome (LS), proposed to have one or more post GHR signaling defects. In the present study, we have examined whether the signal transducers and activators of transcription (STAT) pathway is activated by GH in skin fibroblast cultures established from these LS children, to determine the level(s) at which GH insensitivity has occurred. On immunoblots, both normal and LS fibroblasts express JAK2 and STATs 1, 3, and 5. GH induced rapid tyrosine phosphorylation of a protein at approximately 93 kDa in normal fibroblasts, and Western blotting with STAT-specific antibodies revealed STAT5 activation (phosphorylation) by GH. To determine further the identity and the DNA binding characteristics of the STAT proteins that were activated by GH, EMSAs were performed using three DNA elements known to bind STAT proteins; m67, the high affinity c-sis-inducible element (SIE), the interferon response element (IRE), and the lactogenic hormone-responsive region (LHRR). GH failed to induce protein binding to the SIE or IRE in normal skin fibroblasts but did induce the formation of a specific complex with the LHRR. Induction by GH of this LHRR/protein complex, which could be supershifted partially by anti-STAT1 antisera and completely by anti-STAT5 antisera, was transient, maximal between 10 and 30 min and reduced by 60 min. GH also induced distinct LHRR/protein complexes in mouse 3T3-F442A fibroblasts and in human IM-9 lymphocytes, but supershift analysis revealed that these complexes contained STAT5 but not STAT1. Whereas no binding to the LHRR was observed in GH-treated H fibroblasts, GH induced binding to this element in M fibroblasts. These results demonstrate that 1) the JAK-STAT pathway is activated by GH in normal fibroblasts and that STATs 1 and 5 have a role in GH-dependent signaling in these cells; 2) GH activation of DNA/STAT binding is cell type- and species-specific; and 3) GH failed to activate the STAT pathway in H fibroblasts but induced STAT signaling in M fibroblasts, indicating that the site of GH resistance in the latter is likely to be located within another GH signaling pathway. These fibroblast cultures therefore provide unique models with which to further our understanding of the mechanisms of human GH signaling.

Carrier Proteins↗

PubMed2003

Boundary effect free and adaptive discrete signal sinc-interpolation algorithms for signal and image resampling.

The problem of digital signal and image resampling with discrete sinc interpolation is addressed. Discrete sine interpolation is theoretically the best one among the digital convolution-based signal resampling methods because it does not distort the signal as defined by its samples and is completely reversible. However, sinc interpolation is frequently not considered in applications because it suffers from boundary effects, tends to produce signal oscillations at the image edges, and has relatively high computational complexity when irregular signal resampling is required. A solution that enables the elimination of these limitations of the discrete sine interpolation is suggested. Two flexible and computationally efficient algorithms for boundary effects free and adaptive discrete sinc interpolation are presented: frame-wise (global) sine interpolation in the discrete cosine transform (DCT) domain and local adaptive sinc interpolation in the DCT domain of a sliding window. The latter offers options not available with other interpolation methods: interpolation with simultaneous signal restoration/enhancement and adaptive interpolation with super resolution.

Journal Article↗

PubMed2006

Imaging response inhibition in a stop-signal task: neural correlates independent of signal monitoring and post-response processing.

Execution of higher cortical functions requires inhibitory control to restrain habitual responses and meet changing task demands. We used functional magnetic resonance imaging to show the neural correlates of response inhibition during a stop-signal task. The task has a frequent "go" stimulus to set up a pre-potent response tendency and a less frequent "stop" signal for subjects to withhold their response. We contrasted brain activation between successful and failed inhibition for individual subjects and compared groups of subjects with short and long stop-signal reaction times. The two groups of subjects did not differ in their inhibition failure rates or the extent of signal monitoring, error monitoring, or task-associated frustration ratings. The results showed that short stop-signal reaction time or more efficient response inhibition was associated with greater activation in the superior medial and precentral frontal cortices. Moreover, activation of these inhibitory motor areas correlated negatively with stop-signal reaction time. These brain regions may represent the neural substrata of response inhibition independent of other cognitive and affective functions.

Adult↗

PubMed1986

Periventricular high signal lesions and signal void on magnetic resonance imaging in hydrocephalus. Diagnostic and prognostic significance.

The presence of periventricular high signal lesions and ventricular signal void was tabulated and compared in three groups: patients with unshunted hydrocephalus (n = 24), cerebral atrophy (n = 14), and a subgroup of treated hydrocephalus subjects studied both pre- and post-shunting (n = 6). We found that T2 high signal lesions and ventricular signal void are common in both hydrocephalus and atrophy and are of no value in distinguishing between the two. The pre-treatment presence or absence of periventricular high signal lesions and signal void were of no use in predicting the clinical outcome of shunting in hydrocephalus.

Adolescent↗

PubMed2001

Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signaling.

Thymic epithelial cells are specialized to play essential roles at multiple stages of T cell development in the thymus, yet the molecular basis of this specialization is largely unknown. Recently, the Notch family of transmembrane proteins has been implicated in thymocyte development. Such proteins interact with cell surface proteins of the Delta-like and Jagged families. It is known that Notch ligands are expressed intrathymically, and that Notch signaling is regulated by Notch ligands expressed on either the same or third-party cells. However, functional analysis of Notch ligand expression, and elucidation of the mechanism of Notch ligand signaling in thymocyte development, are unclear. Here, we find that Notch ligand expression in the thymus is compartmentalized, with MHC class II(+) thymic epithelium, but not thymocytes nor dendritic cells, expressing Jagged-1, Jagged-2 and Delta-like-1. We also provide evidence that contact with Notch ligands on thymic epithelium is necessary to activate and sustain Notch signaling in thymocytes, and that this can occur independently of positive selection induction. Our data suggest that Notch ligand expression by thymic epithelium may partly explain the specialization of these cells in supporting thymocyte development, by regulating Notch activation via an inductive signaling mechanism independently of signaling leading to positive selection.

Animals↗

PubMed1990

The methionine-rich domain of the 54 kd protein subunit of the signal recognition particle contains an RNA binding site and can be crosslinked to a signal sequence.

The 54 kd protein subunit of the signal recognition particle (SRP54) has been shown to bind signal sequences by UV crosslinking. Primary structure analysis and phylogenetic comparisons have suggested that SRP54 is composed of two domains: an amino-terminal domain that contains a putative GTP-binding site (G-domain) and a carboxy-terminal domain that contains a high abundance of methionine residues (M-domain). Partial proteolysis of SRP revealed that the two proposed domains of SRP54 indeed represent structurally discrete entities. Upon proteolysis the intact G-domain was released from SRP, whereas the M-domain remained attached to the core of the particle. Reconstitution experiments demonstrated that the isolated M-domain associates with 7SL RNA in the presence of SRP19. In addition, we observed a specific binding of the M-domain directly to 4.5S RNA of Escherichia coli, which contains a structural motif also present in 7SL RNA. This shows that the M-domain contains an RNA binding site, and suggests that SRP54 may be linked to the rest of SRP through this domain by a direct interaction with 7SL RNA. Using UV crosslinking, we found that in an in vitro translation system the preprolactin signal sequence contacts SRP through the M-domain of SRP54. These results imply that the M-domain contains the signal sequence binding site of SRP54, although we cannot exclude that the G-domain may also be in proximity to bound signal sequences.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed2001

Signal transduction driving technology driving signal transduction: factors in the design of targeted therapies.

A significant number of human diseases can be attributed to defects in cellular signal transduction pathways. Large-scale proteomics projects now in progress seek to better define critical components of signal transduction networks, to enable more intelligent design of therapeutic agents that can specifically correct disease-specific signaling alterations by targeting individual proteins. A complicating factor in this endeavor is the fact that intracellular signaling involves many diverse mechanisms that in sum finely modulate the activity of individual proteins in response to different biological inputs. Ability to develop reagents that selectively correct disease-associated signaling activities, while leaving intact benign or essential activities, encompassed within a single protein requires an intimate knowledge of pathway-specific control mechanisms. To illustrate these points, we provide examples of some of the complex control mechanisms regulating the Cas proteins, which contribute to integrin-dependent biological response. We then discuss issues involved in systematically incorporating information related to complex control mechanisms in proteomic databases. Finally, we describe some recent instances in which protein interaction technologies have been specifically adapted to identify small molecule agents that regulate protein response in physiologically desirable ways, and discuss issues relevant to future drug discovery efforts.

Adaptor Proteins, Signal Transducing↗

PubMed2007

PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways.

The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response.

Animals↗

PubMed1986

Internally transposed signal sequence of carp preproinsulin retains its functions with the signal recognition particle.

It is shown that the signal sequence of carp preproinsulin is functional with the dog pancreatic signal recognition particle (SRP) both when present at its normal location at the amino-terminus of the protein or when engineered to an internal location. Inhibition of translation by SRP in the absence of microsomal membranes, reconstitution by SRP of the translocation competence of high-salt inactivated microsomes and signal peptide cleavage all occur with the signal sequence being preceded by a highly charged peptide segment of 39 amino acid residues (the distance from the amino-terminus to the cleavage site of the signal peptidase is increased to 56 residues).

Amino Acid Sequence↗