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Sample records for luminal signal target

  1. Cytosolic N-terminal arginine-based signals together with a luminal signal target a type II membrane protein to the plant ER

    PubMed Central

    2009-01-01

    Background In eukaryotic cells, the membrane compartments that constitute the exocytic pathway are traversed by a constant flow of lipids and proteins. This is particularly true for the endoplasmic reticulum (ER), the main "gateway of the secretory pathway", where biosynthesis of sterols, lipids, membrane-bound and soluble proteins, and glycoproteins occurs. Maintenance of the resident proteins in this compartment implies they have to be distinguished from the secretory cargo. To this end, they must possess specific ER localization determinants to prevent their exit from the ER, and/or to interact with receptors responsible for their retrieval from the Golgi apparatus. Very few information is available about the signal(s) involved in the retention of membrane type II protein in the ER but it is generally accepted that sorting of ER type II cargo membrane proteins depends on motifs mainly located in their cytosolic tails. Results Here, using Arabidopsis glucosidase I as a model, we have identified two types of signals sufficient for the location of a type II membrane protein in the ER. A first signal is located in the luminal domain, while a second signal corresponds to a short amino acid sequence located in the cytosolic tail of the membrane protein. The cytosolic tail contains at its N-terminal end four arginine residues constitutive of three di-arginine motifs (RR, RXR or RXXR) independently sufficient to confer ER localization. Interestingly, when only one di-arginine motif is present, fusion proteins are located both in the ER and in mobile punctate structures, distinct but close to Golgi bodies. Soluble and membrane ER protein markers are excluded from these punctate structures, which also do not colocalize with an ER-exit-site marker. It is hypothesized they correspond to sites involved in Golgi to ER retrotransport. Conclusion Altogether, these results clearly show that cytosolic and luminal signals responsible for ER retention could coexist in a same type

  2. Luminal-B breast cancer and novel therapeutic targets

    PubMed Central

    2011-01-01

    Gene expression profiling has led to a new molecular classification of breast cancer characterized by four intrinsic subtypes: basal-like, HER2-positive, luminal A, and luminal B. Despite expressing estrogen receptor, the luminal-B subtype confers increased risk of early relapse with endocrine therapy compared with the luminal-A subtype. Although luminal-B definitions vary, the hallmark appears to be increased expression of proliferation-related genes. Several biological pathways are identified as possible contributors to the poor outcomes, and novel agents targeting these pathways are being developed with aims to improve survival. We review the definition of luminal-B breast cancer, its pathological and clinical features, and potential targets for treatment. PMID:22217398

  3. Luminance and chromatic contributions to a hyperacuity task: isolation by contrast polarity and target separation.

    PubMed

    Sun, Hao; Cooper, Bonnie; Lee, Barry B

    2012-03-01

    Vernier thresholds are known to be elevated when a target pair has opposite contrast polarity. Polarity reversal is used to assess the role of luminance and chromatic pathways in hyperacuity performance. Psychophysical hyperacuity thresholds were measured for pairs of gratings of various combinations of luminance (Lum) and chromatic (Chr) contrast polarities, at different ratios of luminance to chromatic contrast. With two red-green gratings of matched luminance and chromatic polarity (+Lum+Chr), there was an elevation of threshold at isoluminance. When both luminance and chromatic polarity were mismatched (-Lum-Chr), thresholds were substantially elevated under all conditions. With the same luminance contrast polarity and opposite chromatic polarity (+Lum-Chr) thresholds were only elevated close to isoluminance; in the reverse condition (-Lum+Chr), thresholds were elevated as in the -Lum-Chr condition except close to equiluminance. Similar data were obtained for gratings isolating the short-wavelength cone mechanism. Further psychophysical measurements assessed the role of target separation with matched or mismatched contrast polarity; similar results were found for luminance and chromatic gratings. Comparison physiological data were collected from parafoveal ganglion cells of the macaque retina. Positional precision of ganglion cell signals was assessed under conditions related to the psychophysical measurements. On the basis of these combined observations, it is argued that both magnocellular, parvocellular, and koniocellular pathways have access to cortical positional mechanisms associated with vernier acuity. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Luminance and chromatic contributions to a hyperacuity task: isolation by contrast polarity and target separation

    PubMed Central

    Sun, Hao; Cooper, Bonnie; Lee, Barry B.

    2012-01-01

    Vernier thresholds are known to be elevated when a target pair has opposite contrast polarity. Polarity reversal is used to assess the role of luminance and chromatic pathways in hyperacuity performance. Psychophysical hyperacuity thresholds were measured for pairs of gratings of various combinations of luminance (Lum) and chromatic (Chr) contrast polarities, at different ratios of luminance to chromatic contrast. With two red-green gratings of matched luminance and chromatic polarity (+Lum+Chr), there was an elevation of threshold at isoluminance. When both luminance and chromatic polarity were mismatched (−Lum−Chr), thresholds were substantially elevated under all conditions. With the same luminance contrast polarity and opposite chromatic polarity (+Lum−Chr) thresholds were only elevated close to isoluminance; in the reverse condition (−Lum+Chr), thresholds were elevated as in the −Lum−Chr condition except close to equiluminance. Similar data were obtained for gratings isolating the short-wavelength cone mechanism. Further psychophysical measurements assessed the role of target separation with matched or mismatched contrast polarity; similar results were found for luminance and chromatic gratings. Comparison physiological data were collected from parafoveal ganglion cells of the macaque retina. Positional precision of ganglion cell signals was assessed under conditions related to the psychophysical measurements. On the basis of these combined observations, it is argued that both magnocellular, parvocellular, and koniocellular pathways have access to cortical positional mechanisms associated with vernier acuity. PMID:22306680

  5. Luminal Ca2+ dynamics during IP3R mediated signals

    NASA Astrophysics Data System (ADS)

    Lopez, Lucia F.; Ponce Dawson, Silvina

    2016-06-01

    The role of cytosolic Ca2+ on the kinetics of Inositol 1,4,5-triphosphate receptors (IP3Rs) and on the dynamics of IP3R-mediated Ca2+ signals has been studied at large both experimentally and by modeling. The role of luminal Ca2+ has not been investigated with that much detail although it has been found that it is relevant for signal termination in the case of Ca2+ release through ryanodine receptors. In this work we present the results of observing the dynamics of luminal and cytosolic Ca2+ simultaneously in Xenopus laevis oocytes. Combining observations and modeling we conclude that there is a rapid mechanism that guarantees the availability of free Ca2+ in the lumen even when a relatively large Ca2+ release is evoked. Comparing the dynamics of cytosolic and luminal Ca2+ during a release, we estimate that they are consistent with a 80% of luminal Ca2+ being buffered. The rapid availability of free luminal Ca2+ correlates with the observation that the lumen occupies a considerable volume in several regions across the images.

  6. Contour interaction for foveal acuity targets at different luminances.

    PubMed

    Bedell, Harold E; Siderov, John; Waugh, Sarah J; Zemanová, Romana; Pluháček, František; Musilová, Lenka

    2013-08-30

    Single-letter visual acuity is impaired by nearby flanking stimuli, a phenomenon known as contour interaction. We showed previously that when foveal acuity is degraded by a reduction of letter contrast, both the magnitude and angular spatial extent of foveal contour interaction remain unchanged. In this study, we asked whether contour interaction also remains unchanged when foveal visual acuity is degraded by a reduction of the target's background luminance. Percent correct letter identification was measured for isolated, near-threshold black Sloan letters and for letters surrounded by 4 flanking bars in 10 normal observers, 5 at Anglia Ruskin University, UK (ARU) and 5 at Palacky University, Czech Republic (PU). A stepwise reduction in the background luminance over 3 log units resulted in an approximately threefold increase in the near-threshold letter size. At each background luminance, black flanking bars with a width equal to 1 letter stroke were presented at separations between approximately 0.45 and 4.5 min arc (ARU) or 0.32 and 3.2 min arc (PU). The results indicate that the angular extent of contour interaction remains unchanged at approximately 4 min arc at all background luminances. On the other hand, the magnitude of contour interaction decreases systematically as luminance is reduced, from approximately a 50% reduction to a 30% reduction in percent correct. The constant angular extent and decreasing magnitude of contour interaction with a reduction of background luminance suggest foveal contour interaction is mediated by luminance-dependent lateral inhibition within a fixed angular region.

  7. The impact of target luminance and radiance on night vision device visual performance testing

    NASA Astrophysics Data System (ADS)

    Marasco, Peter L.; Task, H. Lee

    2003-09-01

    Visual performance through night-vision devices (NVDs) is a function of many parameters such as target contrast, objective and eyepiece lens focus, signal/noise of the image intensifier tube, quality of the image intensifier, night-vision goggle (NVG) gain, and NVG output luminance to the eye. The NVG output luminance depends on the NVG sensitive radiance emitted (or reflected) from the visual acuity target (usually a vision testing chart). The primary topic of this paper is the standardization (or lack thereof) of the radiance levels used for NVG visual acuity testing. The visual acuity chart light level might be determined in either photometric (luminance) units or radiometric (radiance) units. The light levels are often described as "starlight," "quarter moon," or "optimum" light levels and may not actually provide any quantitative photometric or radiometric information. While these terms may be useful to pilots and the users of night-vision devices, they are inadequate for accurate visual performance testing. This is because there is no widely accepted agreement in the night vision community as to the radiance or luminance level of the target that corresponds to the various named light levels. This paper examines the range of values for "starlight," "quarter moon," and "optimum" light commonly used by the night vision community and referenced in the literature. The impact on performance testing of variations in target luminance/radiance levels is also examined. Arguments for standardizing on NVG-weighted radiometric units for testing night-vision devices instead of photometric units are presented. In addition, the differences between theoretical weighted radiance and actual weighted radiance are also discussed.

  8. Luminal signalling links cell communication to tissue architecture during organogenesis.

    PubMed

    Durdu, Sevi; Iskar, Murat; Revenu, Celine; Schieber, Nicole; Kunze, Andreas; Bork, Peer; Schwab, Yannick; Gilmour, Darren

    2014-11-06

    Morphogenesis is the process whereby cell collectives are shaped into differentiated tissues and organs. The self-organizing nature of morphogenesis has been recently demonstrated by studies showing that stem cells in three-dimensional culture can generate complex organoids, such as mini-guts, optic-cups and even mini-brains. To achieve this, cell collectives must regulate the activity of secreted signalling molecules that control cell differentiation, presumably through the self-assembly of microenvironments or niches. However, mechanisms that allow changes in tissue architecture to feedback directly on the activity of extracellular signals have not been described. Here we investigate how the process of tissue assembly controls signalling activity during organogenesis in vivo, using the migrating zebrafish lateral line primordium. We show that fibroblast growth factor (FGF) activity within the tissue controls the frequency at which it deposits rosette-like mechanosensory organs. Live imaging reveals that FGF becomes specifically concentrated in microluminal structures that assemble at the centre of these organs and spatially constrain its signalling activity. Genetic inhibition of microlumen assembly and laser micropuncture experiments demonstrate that microlumina increase signalling responses in participating cells, thus allowing FGF to coordinate the migratory behaviour of cell groups at the tissue rear. As the formation of a central lumen is a self-organizing property of many cell types, such as epithelia and embryonic stem cells, luminal signalling provides a potentially general mechanism to locally restrict, coordinate and enhance cell communication within tissues.

  9. Measurement method for sun effects on target"s chromaticity and luminance

    NASA Astrophysics Data System (ADS)

    Yu, Hsueh-Ling; Hsiao, Chin-Chai

    2005-02-01

    The luminance and color of a traffic sign depend on the angle, illuminance, and spectrum of the illuminating sunlight. The general method for measuring the effects of sun on traffic signs is to use Xe source or Xe source with filters as a sun-simulator to simulate the CIE defined average sunlight spectrum, D65. The disadvantages of using the sun-simulator are the high cost and measurement error that arises from the difference between the spectrum of the sunlight and that of sun-simulator. Using Xe source as the sun-simulator may produce an error of around 3.5% due to the spectrum difference. To solve these problems, a measurement method has been applied to eliminate the need for sun-simulator in measuring the sun effect on traffic signs. Measuring the spectral reflectance of the target and calculating a luminance and illuminance translation factor allow us to calculate the luminance reflected from the target, regardless of the light source illuminating on it. For instance, the effects of other sunlight spectra, such as D55 or D75, on the targets can also be determined by this method without the use of any light source to simulate D55 or D75. The sunlight spectrum in the presented simulation equation is obtained directly from the CIE definition, eliminating the error associated with the difference between the sun simulator and sunlight spectra. The experimental results demonstrate that the calculated luminance is about 1% different from the measurement results. Low cost, good accuracy and high flexibility are the advantages of this method.

  10. Combining S-cone and luminance signals adversely affects discrimination of objects within backgrounds

    PubMed Central

    Jennings, Ben J.; Tsattalios, Konstantinos; Chakravarthi, Ramakrishna; Martinovic, Jasna

    2016-01-01

    The visual system processes objects embedded in complex scenes that vary in both luminance and colour. In such scenes, colour contributes to the segmentation of objects from backgrounds, but does it also affect perceptual organisation of object contours which are already defined by luminance signals, or are these processes unaffected by colour’s presence? We investigated if luminance and chromatic signals comparably sustain processing of objects embedded in backgrounds, by varying contrast along the luminance dimension and along the two cone-opponent colour directions. In the first experiment thresholds for object/non-object discrimination of Gaborised shapes were obtained in the presence and absence of background clutter. Contrast of the component Gabors was modulated along single colour/luminance dimensions or co-modulated along multiple dimensions simultaneously. Background clutter elevated discrimination thresholds only for combined S-(L + M) and L + M signals. The second experiment replicated and extended this finding by demonstrating that the effect was dependent on the presence of relatively high S-(L + M) contrast. These results indicate that S-(L + M) signals impair spatial vision when combined with luminance. Since S-(L + M) signals are characterised by relatively large receptive fields, this is likely to be due to an increase in the size of the integration field over which contour-defining information is summed. PMID:26856308

  11. The SDSS-IV Extended Baryon Oscillation Spectroscopic Survey: Luminous Red Galaxy Target Selection

    NASA Astrophysics Data System (ADS)

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; Ross, Ashley J.; Myers, Adam D.; Dawson, Kyle S.; Kneib, Jean-Paul; Percival, Will J.; Bautista, Julian E.; Comparat, Johan; Tinker, Jeremy L.; Schlegel, David J.; Tojeiro, Rita; Ho, Shirley; Lang, Dustin; Rao, Sandhya M.; McBride, Cameron K.; Ben Zhu, Guangtun; Brownstein, Joel R.; Bailey, Stephen; Bolton, Adam S.; Delubac, Timothée; Mariappan, Vivek; Blanton, Michael R.; Reid, Beth; Schneider, Donald P.; Seo, Hee-Jong; Carnero Rosell, Aurelio; Prada, Francisco

    2016-06-01

    We describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer. LRG targets are required to meet a set of color selection criteria and have z-band and i-band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71). We demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ˜89% of the target sample yields secure redshift measurements. We also present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.

  12. The SDSS-IV extended baryon oscillation spectroscopic survey: Luminous red galaxy target selection

    DOE PAGES

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; ...

    2016-06-08

    Here, we describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer. LRG targets are required to meet a set of color selection criteria and have z-band and i-band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71).more » We also demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ~89% of the target sample yields secure redshift measurements. Finally, we present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.« less

  13. The SDSS-IV extended baryon oscillation spectroscopic survey: Luminous red galaxy target selection

    SciTech Connect

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; Ross, Ashley J.; Myers, Adam D.; Dawson, Kyle S.; Kneib, Jean-Paul; Bautista, Julian E.; Comparat, Johan; Tinker, Jeremy L.; Schlegel, David J.; Tojeiro, Rita; Ho, Shirley; Lang, Dustin; Rao, Sandhya M.; McBride, Cameron K.; Zhu, Guangtun Ben; Brownstein, Joel R.; Bailey, Stephen; Bolton, Adam S.; Delubac, Timothée; Mariappan, Vivek; Blanton, Michael R.; Reid, Beth; Schneider, Donald P.; Seo, Hee-Jong; Rosell, Aurelio Carnero; Prada, Francisco

    2016-06-08

    Here, we describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer. LRG targets are required to meet a set of color selection criteria and have z-band and i-band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71). We also demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ~89% of the target sample yields secure redshift measurements. Finally, we present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.

  14. On the necessity of correcting peripheral target luminance for pupillary area

    SciTech Connect

    Bedell, H.E.; Katz, L.M.

    1982-10-01

    Despite the decrease in pupillary area for peripheral targets, retinal illuminance remains fairly constant to about 80 deg visual angle. Constant illuminance is maintained in the retinal periphery because the light that enters the pupil is concentrated into smaller retinal images. The correction of the peripheral target luminances for pupillary area is therefore unnecessary except under certain conditions.

  15. Paracrine Met signaling triggers epithelial–mesenchymal transition in mammary luminal progenitors, affecting their fate

    PubMed Central

    Di-Cicco, Amandine; Petit, Valérie; Chiche, Aurélie; Bresson, Laura; Romagnoli, Mathilde; Orian-Rousseau, Véronique; Vivanco, Maria dM; Medina, Daniel; Faraldo, Marisa M; Glukhova, Marina A; Deugnier, Marie-Ange

    2015-01-01

    HGF/Met signaling has recently been associated with basal-type breast cancers, which are thought to originate from progenitor cells residing in the luminal compartment of the mammary epithelium. We found that ICAM-1 efficiently marks mammary luminal progenitors comprising hormone receptor-positive and receptor-negative cells, presumably ductal and alveolar progenitors. Both cell populations strongly express Met, while HGF is produced by stromal and basal myoepithelial cells. We show that persistent HGF treatment stimulates the clonogenic activity of ICAM1-positive luminal progenitors, controlling their survival and proliferation, and leads to the expression of basal cell characteristics, including stem cell potential. This is accompanied by the induction of Snai1 and Snai2, two major transcription factors triggering epithelial–mesenchymal transition, the repression of the luminal-regulatory genes Elf5 and Hey1, and claudin down-regulation. Our data strongly indicate that paracrine Met signaling can control the function of luminal progenitors and modulate their fate during mammary development and tumorigenesis. DOI: http://dx.doi.org/10.7554/eLife.06104.001 PMID:26165517

  16. Luminance and chromatic signals interact differently with melanopsin activation to control the pupil light response.

    PubMed

    Barrionuevo, Pablo A; Cao, Dingcai

    2016-09-01

    Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin. These cells receive afferent inputs from rods and cones, which provide inputs to the postreceptoral visual pathways. It is unknown, however, how melanopsin activation is integrated with postreceptoral signals to control the pupillary light reflex. This study reports human flicker pupillary responses measured using stimuli generated with a five-primary photostimulator that selectively modulated melanopsin, rod, S-, M-, and L-cone excitations in isolation, or in combination to produce postreceptoral signals. We first analyzed the light adaptation behavior of melanopsin activation and rod and cones signals. Second, we determined how melanopsin is integrated with postreceptoral signals by testing with cone luminance, chromatic blue-yellow, and chromatic red-green stimuli that were processed by magnocellular (MC), koniocellular (KC), and parvocellular (PC) pathways, respectively. A combined rod and melanopsin response was also measured. The relative phase of the postreceptoral signals was varied with respect to the melanopsin phase. The results showed that light adaptation behavior for all conditions was weaker than typical Weber adaptation. Melanopsin activation combined linearly with luminance, S-cone, and rod inputs, suggesting the locus of integration with MC and KC signals was retinal. The melanopsin contribution to phasic pupil responses was lower than luminance contributions, but much higher than S-cone contributions. Chromatic red-green modulation interacted with melanopsin activation nonlinearly as described by a "winner-takes-all" process, suggesting the integration with PC signals might be mediated by a postretinal site.

  17. Motor preparation of manual aiming at a visual target manipulated in size, luminance contrast, and location.

    PubMed

    Ishihara, Masami; Imanaka, Kuniyasu

    2007-01-01

    We conducted two experiments to investigate whether the motor preparation of manual aiming to a visual target is affected by either the physical characteristics (size or luminance contrast) or spatial characteristics (location) of the target. Reaction time (RT) of both finger lifting (ie stimulus-detection time) and manual aiming (ie movement-triggering time) to the onset of the target was measured. The difference of RT (DRT) between two tasks (ie the difference of task complexity) was examined to clarify the temporal characteristics of manual aiming per se during visuomotor integration. Results show classical characteristics: RT decreased as either the target size or luminance contrast increased. Furthermore, the task-complexity and target-location factors significantly interacted with each other, where the aiming RT was longer than the finger-lifting RT and the effects of target location on RT differed for each task. However, the task factor did not interact with either the size or luminance-contrast factor, implying that the motor preparation of manual aiming is associated with the spatial characteristics rather than the physical characteristics of the target. Inspection of DRT revealed that the time needed for motor preparation for an ipsilateral target was significantly shorter than that for a contralateral target. This was the case both for the left and for the right hand. Foveal targets required longer processing time, implying a disadvantageous function of motor preparation for the gazed target. The left-hand superiority for the target appearing in the left visual field was also observed. Such lateralised effect and left-hand advantage to the left visual field in manual aiming suggest that visuospatial information processing is activated during the preparation of aiming action, with faster processing in the right hemisphere.

  18. Luminance and chromatic signals interact differently with melanopsin activation to control the pupil light response

    PubMed Central

    Barrionuevo, Pablo A.; Cao, Dingcai

    2016-01-01

    Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin. These cells receive afferent inputs from rods and cones, which provide inputs to the postreceptoral visual pathways. It is unknown, however, how melanopsin activation is integrated with postreceptoral signals to control the pupillary light reflex. This study reports human flicker pupillary responses measured using stimuli generated with a five-primary photostimulator that selectively modulated melanopsin, rod, S-, M-, and L-cone excitations in isolation, or in combination to produce postreceptoral signals. We first analyzed the light adaptation behavior of melanopsin activation and rod and cones signals. Second, we determined how melanopsin is integrated with postreceptoral signals by testing with cone luminance, chromatic blue-yellow, and chromatic red-green stimuli that were processed by magnocellular (MC), koniocellular (KC), and parvocellular (PC) pathways, respectively. A combined rod and melanopsin response was also measured. The relative phase of the postreceptoral signals was varied with respect to the melanopsin phase. The results showed that light adaptation behavior for all conditions was weaker than typical Weber adaptation. Melanopsin activation combined linearly with luminance, S-cone, and rod inputs, suggesting the locus of integration with MC and KC signals was retinal. The melanopsin contribution to phasic pupil responses was lower than luminance contributions, but much higher than S-cone contributions. Chromatic red-green modulation interacted with melanopsin activation nonlinearly as described by a “winner-takes-all” process, suggesting the integration with PC signals might be mediated by a postretinal site. PMID:27690169

  19. Luminal and systemic signals trigger intestinal adaptation in the juvenile python.

    PubMed

    Secor, S M; Whang, E E; Lane, J S; Ashley, S W; Diamond, J

    2000-12-01

    Juvenile pythons undergo large rapid upregulation of intestinal mass and intestinal transporter activities upon feeding. Because it is also easy to do surgery on pythons and to maintain them in the laboratory, we used a python model to examine signals and agents for intestinal adaptation. We surgically isolated the middle third of the small intestine from enteric continuity, leaving its mesenteric nerve and vascular supply intact. Intestinal continuity was restored by an end-to-end anastomosis between the proximal and distal thirds. Within 24 h of the snake's feeding, the reanastomosed proximal and distal segments (receiving luminal nutrients) had upregulated amino acid and glucose uptakes by up to 15-fold, had doubled intestinal mass, and thereby soon achieved total nutrient uptake capacities equal to those of the normal fed full-length intestine. At this time, however, the isolated middle segment, receiving no luminal nutrients, experienced no changes from the fasted state in either nutrient uptakes or in morphology. By 3 days postfeeding, the isolated middle segment had upregulated nutrient uptakes to the same levels as the reanastomosed proximal and distal segments, but it still lacked any appreciable morphological response. These contrasting results for the reanastomosed intestine and for the isolated middle segment suggest that luminal nutrients and/or pancreatic biliary secretions are the agents triggering rapid upregulation of transporters and of intestinal mass and that systemic nerve or hormonal signals later trigger transporter regulation but no trophic response.

  20. "Pop-out" of targets modulated in luminance or colour: the effect of intrinsic and extrinsic uncertainty.

    PubMed

    Baldassi, Stefano; Burr, David C

    2004-06-01

    Targets defined by attributes such as colour or brightness are said to "pop-out" from a cluttered scene, with little or no dependency on the size of the set to be searched, while search for other attributes can depend strongly on set-size. We measured contrast thresholds for increments and decrements in luminance or colour and show that they increase strongly with set-size (as previously observed for orientation). However, in some conditions, where the potential distractors were not salient visual targets, there was no dependency of set-size at all ("pop-out"). All the data can be modelled by assuming two main sources of uncertainty: the intrinsic uncertainty due to the number of detectors monitored during a specific task and the extrinsic uncertainty introduced by increasing the number of items displayed. The strength of the effect is well explained by a simple signal detection theory "signed-max" model suited for two-tailed tasks [Journal of Vision 2 (8), 559]. The results suggest that "pop-out" is not peculiar to luminance or colour, but may occur in conditions when the intrinsic uncertainty is so high as to saturate the effects of further uncertainty sources.

  1. Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling.

    PubMed

    Carrara, Marta; Prischi, Filippo; Nowak, Piotr R; Ali, Maruf Mu

    2015-06-03

    Stress caused by accumulation of misfolded proteins within the endoplasmic reticulum (ER) elicits a cellular unfolded protein response (UPR) aimed at maintaining protein-folding capacity. PERK, a key upstream component, recognizes ER stress via its luminal sensor/transducer domain, but the molecular events that lead to UPR activation remain unclear. Here, we describe the crystal structures of mammalian PERK luminal domains captured in dimeric state as well as in a novel tetrameric state. Small angle X-ray scattering analysis (SAXS) supports the existence of both crystal structures also in solution. The salient feature of the tetramer interface, a helix swapped between dimers, implies transient association. Moreover, interface mutations that disrupt tetramer formation in vitro reduce phosphorylation of PERK and its target eIF2α in cells. These results suggest that transient conversion from dimeric to tetrameric state may be a key regulatory step in UPR activation.

  2. Faster target selection in preview visual search depends on luminance onsets: behavioral and electrophysiological evidence.

    PubMed

    Kiss, Monika; Eimer, Martin

    2011-08-01

    To investigate how target detection in visual search is modulated when a subset of distractors is presented in advance (preview search), we measured search performance and the N2pc component as an electrophysiological marker of attentional target selection. Targets defined by a color/shape conjunction were detected faster and the N2pc emerged earlier in preview search relative to a condition in which all items were presented simultaneously. Behavioral and electrophysiological preview benefits disappeared when stimuli were equiluminant with their background, in spite of the fact that targets were feature singletons among the new items in preview search. The results demonstrate that previewing distractors expedites the spatial selection of targets at early sensory-perceptual stages, and that these preview benefits depend on rapid attentional capture by luminance onsets.

  3. The Visibility of Point Sources as a Function of Background Luminance, Target Luminance, Eccentricity, Wavelength, and Flicker Rate

    DTIC Science & Technology

    2005-10-01

    the German scientist, Ernst Heinrich Weber (1795-1878), states that the increase in stimulus which is necessary to produce a just noticeable...thresholds at 60° eccentricity. 3 predict thresholds in the Weber range. Its threshold predictions as a function of eccentricity are based on...such as VIDEM that assume a constant Weber fraction tend to underestimate visual thresholds at low ambient luminances and overestimate them at

  4. Parafoveal Target Detectability Reversal Predicted by Local Luminance and Contrast Gain Control

    NASA Technical Reports Server (NTRS)

    Ahumada, Albert J., Jr.; Beard, Bettina L.; Null, Cynthia H. (Technical Monitor)

    1996-01-01

    This project is part of a program to develop image discrimination models for the prediction of the detectability of objects in a range of backgrounds. We wanted to see if the models could predict parafoveal object detection as well as they predict detection in foveal vision. We also wanted to make our simplified models more general by local computation of luminance and contrast gain control. A signal image (0.78 x 0.17 deg) was made by subtracting a simulated airport runway scene background image (2.7 deg square) from the same scene containing an obstructing aircraft. Signal visibility contrast thresholds were measured in a fully crossed factorial design with three factors: eccentricity (0 deg or 4 deg), background (uniform or runway scene background), and fixed-pattern white noise contrast (0%, 5%, or 10%). Three experienced observers responded to three repetitions of 60 2IFC trials in each condition and thresholds were estimated by maximum likelihood probit analysis. In the fovea the average detection contrast threshold was 4 dB lower for the runway background than for the uniform background, but in the parafovea, the average threshold was 6 dB higher for the runway background than for the uniform background. This interaction was similar across the different noise levels and for all three observers. A likely reason for the runway background giving a lower threshold in the fovea is the low luminance near the signal in that scene. In our model, the local luminance computation is controlled by a spatial spread parameter. When this parameter and a corresponding parameter for the spatial spread of contrast gain were increased for the parafoveal predictions, the model predicts the interaction of background with eccentricity.

  5. Perseveration in congenitally blind children: effects of luminous and acoustic targets on a modified A-not-B task.

    PubMed

    da Rocha Diz, Maria Caroline; Mauerberg-deCastro, Eliane; Romani, Maria Fernanda

    2012-12-01

    The purpose of this study was to determine whether or not blind children perseverate during a modified Piagetian A-not-B reaching task, with conditions that employ luminous AB targets and acoustic AB targets. Ten congenitally blind children, ages 1-4 years, with residual vision for light, took part in this study. Behavioral and kinematic data were computed for participants' reaches, performed in six A trials and in two B trials, in both stimulus conditions. All of the children perseverated in the luminous condition, and none of them perseverated in the condition using acoustic targets. The children tilted their heads in the direction of the target as they reached towards it. However, this coupling action (head-reaching) occurred predominantly in the A trials in the acoustic condition. In the luminous condition, in contrast to the acoustic condition, the children took longer times to initiate the reaching movement. Also, in the luminous condition, the children explored the target surroundings, unlike the acoustic condition, in which they reached straight ahead. For these blind children, sound was more relevant to reaching than was the luminous stimulus. The luminous input caused perseveration in congenitally blind children in a similar way that has been reported in the literature for typically-developing, sighted infants, ages 8-12 months, performing A-not-B tasks with visual inputs. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Influence of the luminance signal and red-green and yellow-blue opponent chromatic signals in figural-stimuli stereograms.

    PubMed

    Jiménez, J R; Rubiño, M; Díaz, J A; Jiménez del Barco, L

    1995-09-01

    The influence of color signals on stereopsis has been studied using figural-stimuli stereograms with variations introduced according to the opponent chromatic channels (red-green and yellow-blue), derived from Boynton's color-vision model. We used wallpaper stereograms, which enable the rank-order disparity ranges of the chromatic and luminance signals to be compared with the rank-order disparity range of proximity, a particular spatial configuration of the stereogram in which there are no variations in chromaticity and/or luminance. The results indicate that both chromatic signals contribute to stereopsis as does the luminance signal, contradicting the model of Hubel and Livingstone. The results also show there are no clear dependencies upon the kind of signal processed, as luminance and chromatic variations are processed with the same efficiency.

  7. Common profiles of Notch signaling differentiate disease-free survival in luminal type A and triple negative breast cancer

    PubMed Central

    Orzechowska, Magdalena; Jędroszka, Dorota; Bednarek, Andrzej K

    2017-01-01

    Breast cancer (BC) is characterized by high heterogeneity regarding its biology and clinical characteristics. The Notch pathway regulates such processes as organ modeling and epithelial-to-mesenchymal transition (EMT). The aim of the study was to determine the effect of differential expression of Notch members on disease-free survival (DFS) in luminal type A (lumA) and triple negative (TN) BC. The differential expression of 19 Notch members was examined in a TCGA BC cohort. DFS analysis was performed using the log-rank test (p<0.05). Biological differences between DFS groups were determined with Gene Set Enrichment Analysis (GSEA) (tTest, FDR<0.25). Common expression profiles according to Notch signaling were examined using ExpressCluster (K-means, mean centered, Euclidean distance metric). The overexpression of HES1, LFNG and PSEN1 was found to be favorable for DFS in lumA, and lowered expression favorable for DFS in TN. GSEA analysis showed that differential Notch signaling is associated with cell cycle, tissue architecture and remodeling. Particularly, targets of E2F, early stage S phase transcription factor, were upregulated in the lumA unfavorable group and the TN favorable group differentiated on a basis of HES1 and PSEN1 expression. Summarizing, our analysis show significance of Notch signaling in BRCA progression through triggering EMT. Moreover, identification of numerous genes which overexpression is associated with disease recurrence may serve as a source of potential targets for a new anticancer therapy. PMID:27888801

  8. Targeting FGFR Signaling in Cancer.

    PubMed

    Touat, Mehdi; Ileana, Ecaterina; Postel-Vinay, Sophie; André, Fabrice; Soria, Jean-Charles

    2015-06-15

    The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents.

  9. Luminance, but not chromatic visual pathways mediate amplification of conditioned danger signals in human visual cortex

    PubMed Central

    Keil, Andreas; Miskovic, Vladimir; Gray, Michael J.; Martinovic, Jasna

    2013-01-01

    Complex organisms rely on experience to optimize the function of perceptual and motor systems in situations relevant to survival. It is well established that visual cues reliably paired with danger are processed more efficiently than neutral cues and that such facilitated sensory processing extends to low levels of the visual system. The neurophysiological mechanisms mediating biased sensory processing however are not well understood. Here we used grating stimuli specifically designed to engage luminance or chromatic pathways of the human visual system in a differential classical conditioning paradigm. Behavioral ratings and visual electroencephalographic steady-state potentials were recorded in healthy human participants. Our findings indicate that the visuo-cortical response to high spatial frequency, isoluminant (red-green) grating stimuli was not modulated by fear conditioning, but low-contrast, low spatial frequency reversal of grayscale gratings resulted in pronounced conditioning effects. We conclude that sensory input conducted via the chromatic pathways into retinotopic visual cortex has limited access to the bi-directional connectivity with brain networks mediating the acquisition and expression of fear, such as the amygdaloid complex. Conversely, luminance information is necessary to establish amplification of learned danger signals in hierarchically early regions of the visual system. PMID:23889165

  10. miR-221/222 control luminal breast cancer tumor progression by regulating different targets.

    PubMed

    Dentelli, Patrizia; Traversa, Matteo; Rosso, Arturo; Togliatto, Gabriele; Olgasi, Cristina; Marchiò, Caterina; Provero, Paolo; Lembo, Antonio; Bon, Giulia; Annaratone, Laura; Sapino, Anna; Falcioni, Rita; Brizzi, Maria Felice

    2014-01-01

    α6β4 integrin is an adhesion molecule for laminin receptors involved in tumor progression. We present a link between β4 integrin expression and miR-221/222 in the most prevalent human mammary tumor: luminal invasive carcinomas (Lum-ICs). Using human primary tumors that display different β4 integrin expression and grade, we show that miR-221/222 expression inversely correlates with tumor proliferating index, Ki67. Interestingly, most high-grade tumors express β4 integrin and low miR-221/222 levels. We ectopically transfected miR-221/222 into a human-derived mammary tumor cell line that recapitulates the luminal subtype to investigate whether miR-221/222 regulates β4 expression. We demonstrate that miR-221/222 overexpression results in β4 expression downregulation, breast cancer cell proliferation, and invasion inhibition. The role of miR-221/222 in driving β4 integrin expression is also confirmed via mutating the miR-221/222 seed sequence for β4 integrin 3'UTR. Furthermore, we show that these 2 miRNAs are also key breast cancer cell proliferation and invasion regulators, via the post-transcriptional regulation of signal transducer and activator of transcription 5A (STAT5A) and of a disintegrin and metalloprotease-17 (ADAM-17). We further confirm these data by silencing ADAM-17, using a dominant-negative or an activated STAT5A form. miR-221/222-driven β4 integrin, STAT5A, and ADAM-17 did not occur in MCF-10A cells, denoted "normal" breast epithelial cells, indicating that the mechanism is cancer cell-specific.   These results provide the first evidence of a post-transcriptional mechanism that regulates β4 integrin, STAT5A, and ADAM-17 expression, thus controlling breast cancer cell proliferation and invasion. Pre-miR-221/222 use in the aggressive luminal subtype may be a powerful therapeutic anti-cancer strategy.

  11. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    SciTech Connect

    Hua, Wei; Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing; Yang, An-Gang; Zhang, Rui; Fan, Jing; Bian, Ka

    2015-08-07

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells.

  12. Mixing of Chromatic and Luminance Retinal Signals in Primate Area V1

    PubMed Central

    Li, Xiaobing; Chen, Yao; Lashgari, Reza; Bereshpolova, Yulia; Swadlow, Harvey A.; Lee, Barry B.; Alonso, Jose Manuel

    2015-01-01

    Vision emerges from activation of chromatic and achromatic retinal channels whose interaction in visual cortex is still poorly understood. To investigate this interaction, we recorded neuronal activity from retinal ganglion cells and V1 cortical cells in macaques and measured their visual responses to grating stimuli that had either luminance contrast (luminance grating), chromatic contrast (chromatic grating), or a combination of the two (compound grating). As with parvocellular or koniocellular retinal ganglion cells, some V1 cells responded mostly to the chromatic contrast of the compound grating. As with magnocellular retinal ganglion cells, other V1 cells responded mostly to the luminance contrast and generated a frequency-doubled response to equiluminant chromatic gratings. Unlike magnocellular and parvocellular retinal ganglion cells, V1 cells formed a unimodal distribution for luminance/color preference with a 2- to 4-fold bias toward luminance. V1 cells associated with positive local field potentials in deep layers showed the strongest combined responses to color and luminance and, as a population, V1 cells encoded a diverse combination of luminance/color edges that matched edge distributions of natural scenes. Taken together, these results suggest that the primary visual cortex combines magnocellular and parvocellular retinal inputs to increase cortical receptive field diversity and to optimize visual processing of our natural environment. PMID:24464943

  13. Mixing of Chromatic and Luminance Retinal Signals in Primate Area V1.

    PubMed

    Li, Xiaobing; Chen, Yao; Lashgari, Reza; Bereshpolova, Yulia; Swadlow, Harvey A; Lee, Barry B; Alonso, Jose Manuel

    2015-07-01

    Vision emerges from activation of chromatic and achromatic retinal channels whose interaction in visual cortex is still poorly understood. To investigate this interaction, we recorded neuronal activity from retinal ganglion cells and V1 cortical cells in macaques and measured their visual responses to grating stimuli that had either luminance contrast (luminance grating), chromatic contrast (chromatic grating), or a combination of the two (compound grating). As with parvocellular or koniocellular retinal ganglion cells, some V1 cells responded mostly to the chromatic contrast of the compound grating. As with magnocellular retinal ganglion cells, other V1 cells responded mostly to the luminance contrast and generated a frequency-doubled response to equiluminant chromatic gratings. Unlike magnocellular and parvocellular retinal ganglion cells, V1 cells formed a unimodal distribution for luminance/color preference with a 2- to 4-fold bias toward luminance. V1 cells associated with positive local field potentials in deep layers showed the strongest combined responses to color and luminance and, as a population, V1 cells encoded a diverse combination of luminance/color edges that matched edge distributions of natural scenes. Taken together, these results suggest that the primary visual cortex combines magnocellular and parvocellular retinal inputs to increase cortical receptive field diversity and to optimize visual processing of our natural environment. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  14. Intestinal serotonin acts as a paracrine substance to mediate vagal signal transmission evoked by luminal factors in the rat

    PubMed Central

    Zhu, J X; Wu, X Y; Owyang, C; Li, Y

    2001-01-01

    The vagus nerve conveys primary afferent information produced by a meal to the brainstem. Serotonin (5-HT), which abounds in intestinal enterochromaffin cells, is released in response to various stimuli. We have recently demonstrated that 5-HT released from intestinal enterochromaffin cells activates 5-HT3 receptors on vagal afferent fibres to mediate luminal non-cholecystokinin-stimulated pancreatic secretion. The present study was designed to evaluate the responses of vagal sensory neurons to intraluminal osmotic stimulation and luminal infusion of maltose, glucose or 5-HT. We investigated the role of endogenous 5-HT in signal transmission evoked by luminal stimuli to activate vagal sensory neurons. The discharges of vagal primary afferent neurons innervating the intestine were recorded from rat nodose ganglia. Luminal factors such as intestinal osmotic stimuli and perfusion of carbohydrates elicited powerful vagal nodose responses. Electrical subdiaphragmatic vagal stimulation activated 364 single units; 40 of these responded to intestinal mucosal stimuli. Of these 40, 30 responded to intraduodenal perfusion of hyperosmolar NaCl (500 mosmol l−1), 27 responded to tap water (5 mosmol l−1) and 20 and 19 responded to maltose (300 mM) and glucose (277.5 mM), respectively. The 5-HT3/4 antagonist tropisetron (ICS 205-930) or 5-HT3 antagonist granisetron abolished luminal stimuli-evoked nodose neuronal responses. Intraluminal infusion of 10−5 and 10−4 M 5-HT elicited increases in vagal afferent discharge in 25 and 31 units, respectively, by activating the 5-HT3 receptors. Acute subdiaphragmatic vagotomy, intestinal mucosal application of the local anaesthetic lidocaine (lignocaine) or administration of 5-HT3 antagonist each abolished the luminal 5-HT-induced nodose neuronal responses. In contrast, distension-sensitive neurons did not respond to duodenal infusion of 5-HT. Pharmacological depletion of 5-HT stores using p-chlorophenylalanine (PCPA), a 5-HT

  15. The effects of time, luminance, and high contrast targets: revisiting grating acuity in the domestic cat.

    PubMed

    Clark, Daria L; Clark, Robert A

    2013-11-01

    Based on optical clarity and retinal cone density, the cat has a potential acuity of 20-30 cycles per degree (cpd), yet most behavioral studies estimate feline acuity between 3 and 9 cpd. Those studies, however, were limited by restrictive experimental conditions that may have inadvertently lowered the estimated grating acuity. Two domestic cats previously trained on a two-choice visual discrimination task were retrained on a grating detection/discrimination task with unlimited time, high luminance, high contrast targets, and adequate space to prevent poor accommodation from affecting the results. Initially, vertical gratings of increasing cpd were tested until failure. Then, horizontal gratings of increasing cpd were tested until failure. Finally, the finest horizontal grating resolved was confirmed with a third test requiring 24 correct out of 36 consecutive trials, yielding a binomial probability less than 0.02 of non-random occurrence. M1, a 7-year-old male gray tabby with +2.00 OU refraction, tested for a grating detection acuity of 15 cpd for both vertical and horizontal gratings (binomial probability = 0.009). F1, a 2-year-old female gray tabby with +0.25 OU refraction, tested for a grating orientation discrimination acuity of 20 cpd for both vertical and horizontal gratings (binomial probability = 0.004). These results demonstrate that a young cat with good focus is capable of discriminating 20 cpd, in close agreement with the physiologic maximum. Uncorrected focusing errors appear to degrade visual performance. Optimum experimental conditions resulted in better grating acuity measurements than previously reported, emphasizing the importance of environmental factors in feline behavioral testing.

  16. Micro RNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR

    PubMed Central

    He, Yuan; Fu, Xing; Fu, Liya; Zhu, Zhengmao; Fu, Li; Dong, Jin-Tang

    2016-01-01

    Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment. PMID:26744318

  17. MicroRNA 100 sensitizes luminal A breast cancer cells to paclitaxel treatment in part by targeting mTOR.

    PubMed

    Zhang, Baotong; Zhao, Ranran; He, Yuan; Fu, Xing; Fu, Liya; Zhu, Zhengmao; Fu, Li; Dong, Jin-Tang

    2016-02-02

    Luminal A breast cancer usually responds to hormonal therapies but does not benefit from chemotherapies, including microtubule-targeted paclitaxel. MicroRNAs could play a role in mediating this differential response. In this study, we examined the role of micro RNA 100 (miR-100) in the sensitivity of breast cancer to paclitaxel treatment. We found that while miR-100 was downregulated in both human breast cancer primary tumors and cell lines, the degree of downregulation was greater in the luminal A subtype than in other subtypes. The IC50 of paclitaxel was much higher in luminal A than in basal-like breast cancer cell lines. Ectopic miR-100 expression in the MCF-7 luminal A cell line enhanced the effect of paclitaxel on cell cycle arrest, multinucleation, and apoptosis, while knockdown of miR-100 in the MDA-MB-231 basal-like line compromised these effects. Similarly, overexpression of miR-100 enhanced the effects of paclitaxel on tumorigenesis in MCF-7 cells. Rapamycin-mediated inhibition of the mammalian target of rapamycin (mTOR), a target of miR-100, also sensitized MCF-7 cells to paclitaxel. Gene set enrichment analysis showed that genes that are part of the known paclitaxel-sensitive signature had a significant expression correlation with miR-100 in breast cancer samples. In addition, patients with lower levels of miR-100 expression had worse overall survival. These results suggest that miR-100 plays a causal role in determining the sensitivity of breast cancers to paclitaxel treatment.

  18. Duodenal luminal nutrient sensing

    PubMed Central

    Rønnestad, Ivar; Akiba, Yasutada; Kaji, Izumi; Kaunitz, Jonathan D

    2016-01-01

    The gastrointestinal mucosa is exposed to numerous chemical substances and microorganisms, including macronutrients, micronutrients, bacteria, endogenous ions, and proteins. The regulation of mucosal protection, digestion, absorption and motility is signaled in part by luminal solutes. Therefore, luminal chemosensing is an important mechanism enabling the mucosa to monitor luminal conditions, such as pH, ion concentrations, nutrient quantity, and microflora. The duodenal mucosa shares luminal nutrient receptors with lingual taste receptors in order to detect the five basic tastes, in addition to essential nutrients, and unwanted chemicals. The recent ‘de-orphanization’ of nutrient sensing G protein-coupled receptors provides an essential component of the mechanism by which the mucosa senses luminal nutrients. In this review, we will update the mechanisms of and underlying physiological and pathological roles in luminal nutrient sensing, with a main focus on the duodenal mucosa. PMID:25113991

  19. Advances in Targeting Signal Transduction Pathways

    PubMed Central

    McCubrey, James A.; Steelman, Linda S.; Chappell, William H.; Sun, Lin; Davis, Nicole M.; Abrams, Stephen L.; Franklin, Richard A.; Cocco, Lucio; Evangelisti, Camilla; Chiarini, Francesca; Martelli, Alberto M.; Libra, Massimo; Candido, Saverio; Ligresti, Giovanni; Malaponte, Grazia; Mazzarino, Maria C.; Fagone, Paolo; Donia, Marco; Nicoletti, Ferdinando; Polesel, Jerry; Talamini, Renato; Bäsecke, Jörg; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Milella, Michele; Tafuri, Agostino; Dulińska-Litewka, Joanna; Laidler, Piotr; D'Assoro, Antonio B.; Drobot, Lyudmyla; Umezawa, Kazuo; Montalto, Giuseppe; Cervello, Melchiorre; Demidenko, Zoya N.

    2012-01-01

    Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies. PMID:23455493

  20. A MAP OF THE INTEGRATED SACHS-WOLFE SIGNAL FROM LUMINOUS RED GALAXIES

    SciTech Connect

    Granett, Benjamin R.; Neyrinck, Mark C.; Szapudi, Istvan

    2009-08-10

    We construct a map of the time derivative of the gravitational potential traced by Sloan Digital Sky Survey luminous red galaxies (LRGs). The potential decays on large scales due to cosmic acceleration, leaving an imprint on cosmic microwave background (CMB) radiation through the integrated Sachs-Wolfe (ISW) effect. With a template fit, we directly measure this signature on the CMB at a 2{sigma} confidence level. The measurement is consistent with the cross-correlation statistic, strengthening the claim that dark energy is indeed the cause of the correlation. This new approach potentially simplifies the cosmological interpretation. Our constructed linear ISW map shows no evidence for degree-scale cold and hot spots associated with supervoid and supercluster structures. This suggests that the linear ISW effect in a concordance {lambda}CDM cosmology is insufficient to explain the strong CMB imprints from these structures that we previously reported.

  1. Notch signaling functions as a binary switch for the determination of glandular and luminal fates of endodermal epithelium during chicken stomach development.

    PubMed

    Matsuda, Yoshimasa; Wakamatsu, Yoshio; Kohyama, Jun; Okano, Hideyuki; Fukuda, Kimiko; Yasugi, Sadao

    2005-06-01

    During development of the chicken proventriculus (glandular stomach), gut endoderm differentiates into glandular and luminal epithelium. We found that Delta1-expressing cells, undifferentiated cells and Notch-activated cells colocalize within the endodermal epithelium during early gland formation. Inhibition of Notch signaling using Numb or dominant-negative form of Su(H) resulted in a luminal differentiation, while forced activation of Notch signaling promoted the specification of immature glandular cells, but prevented the subsequent differentiation and the invagination of the glands. These results suggest that Delta1-mediated Notch signaling among endodermal cells functions as a binary switch for determination of glandular and luminal fates, and regulates patterned differentiation of glands in the chicken proventriculus.

  2. Inhibitors targeting two-component signal transduction.

    PubMed

    Watanabe, Takafumi; Okada, Ario; Gotoh, Yasuhiro; Utsumi, Ryutaro

    2008-01-01

    A two-component signal transduction system (TCS) is an attractive target for antibacterial agents. In this chapter, we review the TCS inhibitors developed during the past decade and introduce novel drug discovery systems to isolate the inhibitors of the YycG/YycF system, an essential TCS for bacterial growth, in an effort to develop a new class of antibacterial agents.

  3. Optimal snake-based segmentation of a random luminance target on a spatially disjoint background

    NASA Astrophysics Data System (ADS)

    Germain, Olivier; Réfrégier, Philippe

    1996-11-01

    We describe a segmentation processor that is optimal for tracking the shape of a target with random white Gaussian intensity appearing on a random white Gaussian spatially disjoint background. This algorithm, based on an active contours model (snakes), consists of correlations of binary references with preprocessed versions of the scene image. This result can provide a practical method to adapt the reference image to correlation techniques.

  4. Targeting the TGFβ signalling pathway in disease

    PubMed Central

    Akhurst, Rosemary J.; Hata, Akiko

    2012-01-01

    Many drugs that target transforming growth factor-β (TGFβ) signalling have disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens. PMID:23000686

  5. Targeting calcium signaling in cancer therapy.

    PubMed

    Cui, Chaochu; Merritt, Robert; Fu, Liwu; Pan, Zui

    2017-01-01

    The intracellular calcium ions (Ca(2+)) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca(2+) homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca(2+) signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca(2+) channels, transporters and Ca(2+)-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca(2+) channels/transporters or Ca(2+)-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca(2+) signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca(2+) channels or transporters.

  6. Aequorin targeted to the endoplasmic reticulum reveals heterogeneity in luminal Ca++ concentration and reports agonist- or IP3-induced release of Ca++.

    PubMed Central

    Button, D; Eidsath, A

    1996-01-01

    A chimeric protein (ERaeq) comprised of the invariant chain (Ii) of class II major histocompatability complex (MHC-II) and aequorin was localized in the endoplasmic reticulum (ER) of transfected human embryonal kidney 293 cells. The targeted aequorin resided in the lumen of the ER membrane system, including the nuclear cistern, and following addition of the chromophore coelenterazine underwent Ca(++)-activated chemiluminescence. The majority of chemiluminescence produced by coelenterazine treatment of ERaeq-expressing 293 cells was consumed rapidly (within 2-4 min) upon re-addition of Ca++ to coelenterazine-loaded cells, a finding consistent with very high Ca++ concentrations (approximately 10(-5)-10(-3) M Ca++ ion) inside the ER. However, following the initial rapid consumption of ERaeq chemiluminescence, the activity that remained (10-30% of total sample luminescence of permeabilized cells or 50-70% of total sample luminescence of intact cells) was found to produce a stable baseline corresponding to a Ca++ ion concentration < or = 1-2 microM. The stable baseline of luminescence observed following rapid consumption of the majority of the sample's activity was not derived from re-binding of fresh chromophore to spent photoprotein, suggesting that a minority fraction of the ER membrane system within which the ERaeq chimera was distributed contained a relatively low Ca++ concentration. Addition of IP3 to digitonin-permeabilized cells, or agonist treatment of intact cells decreased this residual signal. Luminescence recordings from cells expressing an ER-targeted aequorin with relatively high affinity for Ca++ thus reveal heterogeneity in luminal ER Ca++ concentration and permit observation of receptor- and IP3-activated release of Ca++ from the ER membrane system. Images PMID:8868470

  7. Vision-targeted health related quality of life in older adults: patient-reported visibility problems in low luminance activities are more likely to decline than daytime activities.

    PubMed

    Owsley, Cynthia; McGwin, Gerald

    2016-07-07

    Commonly used vision-targeted health-related quality of life questionnaires almost exclusively focus items on vision under daytime conditions. Older adults even when in good eye health frequently report experiencing vision problems at night and under low environmental light levels, and psychophysical studies also document these visibility problems. Here we compare the progression of self-reported low luminance visibility problems and self-reported visibility problems under daytime conditions in older adults. Trained interviewers administered two questionnaires to older adults in normal eye health: the National Eye Institute Visual Function Questionnaire - 25 (NEI VFQ-25) where items are almost entirely focused on difficulties in daytime activities, and the Low Luminance Questionnaire (LLQ) where items are focused on difficulties seeing at night and under low luminance conditions. The following visual functions were also measured: visual acuity, low luminance visual acuity, low luminance deficit, contrast sensitivity, light sensitivity in the macula, and rod-mediated dark adaptation. The protocol was repeated 3 years later. Scores on the NEI VFQ-25 composite and its subscales were unchanged between baseline and 3-year follow-up, whereas scores on the LLQ composite and 5 of 6 subscales significantly decreased (corresponding to less functionality) at the 3-year follow-up. Participants were more likely to display a ≥ 5 point decrease on the LLQ composite than on the NEI VFQ-25 over 3 years. Visual functional tests were largely unrelated to changes in NEI VFQ-25 and LLQ scores from baseline to follow-up. Older adults' vision-targeted quality of life as measured by questionnaire is more likely to exhibit a practically significant decrease over 3 years using a questionnaire that focused on low luminance activities (LLQ) than one focused on daytime activities (NEI VFQ-25). That the results of visual functional testing did not correspond to older adults' decline in

  8. Luminous supernovae.

    PubMed

    Gal-Yam, Avishay

    2012-08-24

    Supernovae, the luminous explosions of stars, have been observed since antiquity. However, various examples of superluminous supernovae (SLSNe; luminosities >7 × 10(43) ergs per second) have only recently been documented. From the accumulated evidence, SLSNe can be classified as radioactively powered (SLSN-R), hydrogen-rich (SLSN-II), and hydrogen-poor (SLSN-I, the most luminous class). The SLSN-II and SLSN-I classes are more common, whereas the SLSN-R class is better understood. The physical origins of the extreme luminosity emitted by SLSNe are a focus of current research.

  9. Targeting TGF-β signaling in cancer

    PubMed Central

    Katz, Lior H; Li, Ying; Chen, Jiun-Sheng; Muñoz, Nina M; Majumdar, Avijit; Chen, Jian; Mishra, Lopa

    2013-01-01

    Introduction The transforming growth factor-β (TGF-β) signaling pathway has a pivotal role in tumor suppression and yet, paradoxically, in tumor promotion. Functional context dependent insights into the TGF-β pathway are crucial in developing TGF-β-based therapeutics for cancer. Areas covered This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression by TGF-β. It is then explained how tumors can evade these effects and how TGF-β contributes to further growing and spreading of some of the tumors. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. This review focuses on anti-TGF-β based treatment and other options targeting activated pathways in tumors where the TGF-β tumor suppressor pathway is lost. Pre-clinical as well up to date results of the most recent clinical trials are given. Expert opinion Targeting the TGF-β pathway can be a promising direction in cancer treatment. However, several challenges still exist, the most important are differentiating between the carcinogenic effects of TGF-β and its other physiological roles, and delineating the tumor suppressive versus the tumor promoting roles of TGF-β in each specific tumor. Future studies are needed in order to find safer and more effective TGF-β-based drugs. PMID:23651053

  10. Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca2+-dependent Cl− and K+ channels

    PubMed Central

    Hollenhorst, Monika I; Lips, Katrin S; Wolff, Miriam; Wess, Jürgen; Gerbig, Stefanie; Takats, Zoltan; Kummer, Wolfgang; Fronius, Martin

    2012-01-01

    BACKGROUND AND PURPOSE Recent studies detected the expression of proteins involved in cholinergic metabolism in airway epithelial cells, although the function of this non-neuronal cholinergic system is not known in detail. Thus, this study focused on the effect of luminal ACh as a regulator of transepithelial ion transport in epithelial cells. EXPERIMENTAL APPROACH RT-PCR experiments were performed using mouse tracheal epithelial cells for ChAT and organic cation transporter (OCT) transcripts. Components of tracheal airway lining fluid were analysed with desorption electrospray ionization (DESI) MS. Effects of nicotine on mouse tracheal epithelial ion transport were examined with Ussing-chamber experiments. KEY RESULTS Transcripts encoding ChAT and OCT1–3 were detected in mouse tracheal epithelial cells. The DESI experiments identified ACh in the airway lining fluid. Luminal ACh induced an immediate, dose-dependent increase in the transepithelial ion current (EC50: 23.3 µM), characterized by a transient peak and sustained plateau current. This response was not affected by the Na+-channel inhibitor amiloride. The Cl−-channel inhibitor niflumic acid or the K+-channel blocker Ba2+ attenuated the ACh effect. The calcium ionophore A23187 mimicked the ACh effect. Luminal nicotine or muscarine increased the ion current. Experiments with receptor gene-deficient animals revealed the participation of muscarinic receptor subtypes M1 and M3. CONCLUSIONS AND IMPLICATIONS The presence of luminal ACh and activation of transepithelial ion currents by luminal ACh receptors identifies a novel non-neuronal cholinergic pathway in the airway lining fluid. This pathway could represent a novel drug target in the airways. PMID:22300281

  11. Targets of light signalling in Trichoderma reesei

    PubMed Central

    2013-01-01

    Background The tropical ascomycete Trichoderma reesei (Hypocrea jecorina) represents one of the most efficient plant cell wall degraders. Regulation of the enzymes required for this process is affected by nutritional signals as well as other environmental signals including light. Results Our transcriptome analysis of strains lacking the photoreceptors BLR1 and BLR2 as well as ENV1 revealed a considerable increase in the number of genes showing significantly different transcript levels in light and darkness compared to wild-type. We show that members of all glycoside hydrolase families can be subject to light dependent regulation, hence confirming nutrient utilization including plant cell wall degradation as a major output pathway of light signalling. In contrast to N. crassa, photoreceptor mediated regulation of carbon metabolism in T. reesei occurs primarily by BLR1 and BLR2 via their positive effect on induction of env1 transcription, rather than by a presumed negative effect of ENV1 on the function of the BLR complex. Nevertheless, genes consistently regulated by photoreceptors in N. crassa and T. reesei are significantly enriched in carbon metabolic functions. Hence, different regulatory mechanisms are operative in these two fungi, while the light dependent regulation of plant cell wall degradation appears to be conserved. Analysis of growth on different carbon sources revealed that the oxidoreductive D-galactose and pentose catabolism is influenced by light and ENV1. Transcriptional regulation of the target enzymes in these pathways is enhanced by light and influenced by ENV1, BLR1 and/or BLR2. Additionally we detected an ENV1-regulated genomic cluster of 9 genes including the D-mannitol dehydrogenase gene lxr1, with two genes of this cluster showing consistent regulation in N. crassa. Conclusions We show that one major output pathway of light signalling in Trichoderma reesei is regulation of glycoside hydrolase genes and the degradation of hemicellulose

  12. Targeting RTK Signaling Pathways in Cancer

    PubMed Central

    Regad, Tarik

    2015-01-01

    The RAS/MAP kinase and the RAS/PI3K/AKT pathways play a key role in the regulation of proliferation, differentiation and survival. The induction of these pathways depends on Receptor Tyrosine Kinases (RTKs) that are activated upon ligand binding. In cancer, constitutive and aberrant activations of components of those pathways result in increased proliferation, survival and metastasis. For instance, mutations affecting RTKs, Ras, B-Raf, PI3K and AKT are common in perpetuating the malignancy of several types of cancers and from different tissue origins. Therefore, these signaling pathways became prime targets for cancer therapy. This review aims to provide an overview about the most frequently encountered mutations, the pathogenesis that results from such mutations and the known therapeutic strategies developed to counteract their aberrant functions. PMID:26404379

  13. Targeting NRF2 signaling for cancer chemoprevention

    SciTech Connect

    Kwak, Mi-Kyoung; Kensler, Thomas W.

    2010-04-01

    Modulation of the metabolism and disposition of carcinogens through induction of cytoprotective enzymes is one of several promising strategies to prevent cancer. Chemopreventive efficacies of inducers such as dithiolethiones and sulforaphane have been extensively studied in animals as well as in humans. The KEAP1-NRF2 system is a key, but not unilateral, molecular target for these chemopreventive agents. The transcription factor NRF2 (NF-E2-related factor 2) is a master regulator of the expression of a subset of genes, which produce proteins responsible for the detoxication of electrophiles and reactive oxygen species as well as the removal or repair of some of their damage products. It is believed that chemopreventive enzyme inducers affect the interaction between KEAP1 and NRF2 through either mediating conformational changes of the KEAP1 protein or activating phosphorylation cascades targeting the KEAP1-NRF2 complex. These events in turn affect NRF2 stability and trafficking. Recent advances elucidating the underlying structural biology of KEAP1-NRF2 signaling and identification of the gene clusters under the transcriptional control of NRF2 are facilitating understanding of the potential pleiotropic effects of NRF2 activators and discovery of novel classes of potent chemopreventive agents such as the triterpenoids. Although there is appropriately a concern regarding a deleterious role of the KEAP1-NRF2 system in cancer cell biology, especially as the pathway affects cell survival and drug resistance, the development and the use of NRF2 activators as chemopreventive agents still holds a great promise for protection of normal cells from a diversity of environmental stresses that contribute to the burden of cancer and other chronic, degenerative diseases.

  14. Luminous presence

    NASA Astrophysics Data System (ADS)

    Dawson, Paula

    2008-02-01

    The Luminous Presence project examines the use of standard film language in the framing, angle and of points of view of holographic subjects though eight digital holographic stereograms; seven 25 x 25 cm, Hail, Water, Rain, Snow, Sun, Text, Imprint and 1.5 x 1 m, Luminous Presences i. However, before embarking on a discussion of how filmic language can be used in digital holograms it is first important to explain why this line of investigation could be fruitful. Undoubtedly several of the compositional practices which sprung up and evolved throughout the development of the diverse forms of the holographic medium have contributed to a unique hologram pictorial language, however it is well known that the reading of visual imagery of any type relies a great deal on the viewer's knowledge of and experience of other images .The lens-recorded imagery of film is a far more familiar language than that of holograms and the correlation between certain filmic pictorial conventions and emotional responses are well documented and understood. ii . In short the language of film contains a highly nuanced vocabulary of shot types and lens types (which may be criticised as being formulaic) yet are effective in lending emotion to figures.

  15. Automatic target recognition employing signal compression.

    PubMed

    Ragothaman, Pradeep; Mikhael, Wasfy B; Muise, Robert R; Mahalanobis, Abhijit

    2007-07-20

    Quadratic correlation filters (QCFs) have been used successfully to detect and recognize targets embedded in background clutter. Recently, a QCF called the Rayleigh quotient quadratic correlation filter (RQQCF) was formulated for automatic target recognition (ATR) in IR imagery. Using training images from target and clutter classes, the RQQCF explicitly maximized a class separation metric. What we believe to be a novel approach is presented for ATR that synthesizes the RQQCF using compressed images. The proposed approach considerably reduces the computational complexity and storage requirements while retaining the high recognition accuracy of the original RQQCF technique. The advantages of the proposed scheme are illustrated using sample results obtained from experiments on IR imagery.

  16. Nhe1 is a luminal Na+/H+ exchanger in mouse choroid plexus and is targeted to the basolateral membrane in Ncbe/Nbcn2-null mice.

    PubMed

    Damkier, Helle Hasager; Prasad, Vikram; Hübner, Christian Andreas; Praetorius, Jeppe

    2009-06-01

    The choroid plexus epithelium (CPE) secretes the major fraction of the cerebrospinal fluid (CSF). The Na(+)-HCO(3)(-) transporter Ncbe/Nbcn2 in the basolateral membrane of CPE cells is important for Na(+)-dependent pH(i) increases and probably for CSF secretion. In the current study, the anion transport inhibitor DIDS had no effect on the residual pH(i) recovery in acidified CPE from Ncbe/Nbcn2 knockout mouse by 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-fluorescence microscopy in the presence of CO(2)/HCO(3)(-) (Ncbe/Nbcn2-ko+DIDS 109% of control, P = 0.76, n = 5). Thus Ncbe/Nbcn2 mediates the DIDS-sensitive Na(+)-dependent pH(i) recovery in the CPE. The Na(+)/H(+) exchanger-1 Nhe1 is proposed to mediate similar functions as Ncbe/Nbcn2 in CPE. Here, we immunolocalize the Nhe1 protein to the luminal membrane domain in mouse and human CPE. The Na(+)-dependent pH(i) recovery of Nhe1 wild-type (Nhe1-wt) mice in the absence of CO(2)/HCO(3)(-) was abolished in the Nhe1 knockout CPE (Nhe1-ko 0.37% of Nhe1-wt, P = 0.0007, n = 5). In Ncbe/Nbcn2-ko mice, Nhe1 was targeted to the basolateral membrane. Nevertheless, the luminal Na(+)-dependent pH(i) recovery was increased in Ncbe/Nbcn2-ko compared with wild-type littermates (Nhe1-ko 146% of Nhe1-wt, P = 0.007, n = 5). Whereas the luminal Nhe activity was inhibited by the Nhe blocker EIPA (10 microM) in the Ncbe/Nbcn2-wt, it was insensitive to the inhibitor in Ncbe/Nbcn2-ko (Ncbe/Nbcn2-ko+EIPA 100% of control, P = 0.98, n = 5). This indicates that a luminal EIPA-insensitive Nhe was induced in Ncbe/Nbcn2-ko CPE and that EIPA-sensitive Nhe activity was basolateral. The Nhe1 translocation in Ncbe/Nbcn2-ko CPE may reflect a compensatory response, which provides the cells with better means of regulating pH(i) or transporting Na(+) after Ncbe/Nbcn2 disruption.

  17. Echo signal modeling of imaging LADAR target simulator

    NASA Astrophysics Data System (ADS)

    Xu, Rui; Shi, Rui; Wang, Xin; Li, Zhuo

    2014-11-01

    LADAR guidance technology is one of the most promising precision guidance technologies. In the aim of simulating the return waveform of the target, a 3D geometrical model of a target is built and mathematical model of target echo signal for imaging LADAR target simulator is established by using the coordinate transformation, radar equation and ranging equation. First, the 3D geometrical data of the object model is obtained by 3D geometrical modeling. Then, target coordinate system and viewpoint coordinate system are created respectively. 3D geometrical model is built in the target coordinate system. The 3D geometrical model is transformed to the viewpoint coordinate system based on the derived relationship between the two coordinate systems. Furthermore, the range information of the target could be obtained under viewpoint coordinate system. Thus, the data of the target echo signal can be obtained by using radar equation and ranging equation. Finally, the echo signal can be exported through corresponding data interface. In order to validate the method proposed in this paper, the echo signal generated by a typical target is computed and compared with the theory solutions. The signals can be applied to drive target simulator to generate a physical target LADAR image.

  18. Targeting sonic hedgehog signaling in neurological disorders.

    PubMed

    Patel, Sita Sharan; Tomar, Sunil; Sharma, Diksha; Mahindroo, Neeraj; Udayabanu, Malairaman

    2017-03-01

    Sonic hedgehog (Shh) signaling influences neurogenesis and neural patterning during the development of central nervous system. Dysregulation of Shh signaling in brain leads to neurological disorders like autism spectrum disorder, depression, dementia, stroke, Parkinson's diseases, Huntington's disease, locomotor deficit, epilepsy, demyelinating disease, neuropathies as well as brain tumors. The synthesis, processing and transport of Shh ligand as well as the localization of its receptors and signal transduction in the central nervous system has been carefully reviewed. Further, we summarize the regulation of small molecule modulators of Shh pathway with potential in neurological disorders. In conclusion, further studies are warranted to demonstrate the potential of positive and negative regulators of the Shh pathway in neurological disorders.

  19. CD49f and CD61 identify Her2/neu-induced mammary tumor initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFβ signaling

    PubMed Central

    Lo, Pang-Kuo; Kanojia, Deepak; Liu, Xinfeng; Singh, Udai P.; Berger, Franklin G.; Wang, Qian; Chen, Hexin

    2011-01-01

    HER2/Neu is overexpressed in 20-30% of breast cancers and associated with aggressive phenotypes and poor prognosis. For deciphering the role of HER2/Neu in breast cancer, mouse mammary tumor virus (MMTV)-Her2/neu transgenic mice that develop mammary tumors resembling human HER2-subtype breast cancer have been established. Several recent studies have revealed that HER2/Neu is overexpressed in and regulates self renewal of breast tumor initiating cells (TICs). However, in the MMTV-Her2/neu transgenic mouse model, the identity of TICs remains elusive, despite previous studies showing supportive evidence for existence of TICs in Her2/neu-induced mammary tumors. Through systematic screening and characterization, we identified surface markers CD49f, CD61 and ESA were aberrantly overexpressed in Her2-overexpressing mammary tumor cells. Analysis of these markers as well as CD24 detected anomalous expansion of the luminal progenitor population in preneoplastic mammary glands of Her2/neu-transgenic mice, indicating that aberrant luminal progenitors originated Her2-induced mammary tumors. The combined markers, CD49f and CD61, further delineated the CD49fhighCD61high-sorted fraction as a TIC-enriched population, which displayed increased tumorsphere formation ability, enhanced tumorigenicity both in vitro and in vivo and drug resistance to pacitaxel and doxorubicin. Moreover, the TIC-enriched population manifested increased TGFβ signaling and exhibited gene expression signatures of stemness, TGFβ signaling and Epithelial-to-Mesenchymal Transition. Our findings that self-renewal and clonogenicity of TICs were suppressed by pharmacologically inhibiting the TGFβ signaling further indicate that the TGFβ pathway is vital for maintenance of the TIC population. Finally, we showed that the integrin β3 (CD61) signaling pathway was required for sustaining active TGFβ signaling and self-renewal of TICs. We for the first time developed a technique to highly enrich TICs from mammary

  20. Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention.

    PubMed

    Parsons, J Thomas; Slack-Davis, Jill; Tilghman, Robert; Roberts, W Gregory

    2008-02-01

    The tumor microenvironment plays a central role in cancer progression and metastasis. Within this environment, cancer cells respond to a host of signals including growth factors and chemotactic factors, as well as signals from adjacent cells, cells in the surrounding stroma, and signals from the extracellular matrix. Targeting the pathways that mediate many of these signals has been a major goal in the effort to develop therapeutics.

  1. Development of anticancer agents targeting the Hedgehog signaling.

    PubMed

    Zhang, Xiangqian; Tian, Ye; Yang, Yanling; Hao, Jijun

    2017-03-17

    Hedgehog signaling is an evolutionarily conserved pathway which is essential in embryonic and postnatal development as well as adult organ homeostasis. Abnormal regulation of Hedgehog signaling is implicated in many diseases including cancer. Consequently, substantial efforts have made in the past to develop potential therapeutic agents that specifically target the Hedgehog signaling for cancer treatment. Here, we review the therapeutic agents for inhibition of the Hedgehog signaling and their clinical advances in cancer treatment.

  2. Targeting extracellular ROS signaling of tumor cells.

    PubMed

    Bauer, Georg

    2014-04-01

    Expression of membrane-associated NADPH oxidase (NOX1) represents a characteristic feature of malignant cells. NOX1-derived extracellular superoxide anions are the basis for autocrine stimulation of proliferation, but also drive the HOCl and the NO/peroxynitrite signaling pathways. This may cause the elimination of transformed cells. Tumor cells express membrane-associated catalase that efficiently protects the cells against apoptosis-inducing reactive oxygen species (ROS) signaling. Membrane-associated superoxide dismutase (SOD) plays a co-modulatory protective role that is functionally interrelated with the protective effect mediated by catalase. Due to the co-localization of NOX1, catalase and SOD on the outer membrane of tumor cells, specific inhibition of membrane-associated SOD causes superoxide anion-dependent inhibition of catalase. This establishes a strong apoptotic signaling through the NO/peroxynitrite pathway. In parallel, it causes a drastic decrease in the concentration of proliferation-stimulating H2O2. Knowledge of the biochemical network on the surface of tumor cells should, therefore, allow development of specific novel strategies for tumor therapy, based on the specific features of tumor cell-specific extracellular ROS interactions.

  3. Circumferential targeted renal sympathetic nerve denervation with preservation of the renal arterial wall using intra-luminal ultrasound

    NASA Astrophysics Data System (ADS)

    Roth, Austin; Coleman, Leslie; Sakakura, Kenichi; Ladich, Elena; Virmani, Renu

    2015-03-01

    An intra-luminal ultrasound catheter system (ReCor Medical's Paradise System) has been developed to provide circumferential denervation of the renal sympathetic nerves, while preserving the renal arterial intimal and medial layers, in order to treat hypertension. The Paradise System features a cylindrical non-focused ultrasound transducer centered within a balloon that circulates cooling fluid and that outputs a uniform circumferential energy pattern designed to ablate tissues located 1-6 mm from the arterial wall and protect tissues within 1 mm. RF power and cooling flow rate are controlled by the Paradise Generator which can energize transducers in the 8.5-9.5 MHz frequency range. Computer simulations and tissue-mimicking phantom models were used to develop the proper power, cooling flow rate and sonication duration settings to provide consistent tissue ablation for renal arteries ranging from 5-8 mm in diameter. The modulation of these three parameters allows for control over the near-field (border of lesion closest to arterial wall) and far-field (border of lesion farthest from arterial wall, consisting of the adventitial and peri-adventitial spaces) depths of the tissue lesion formed by the absorption of ultrasonic energy and conduction of heat. Porcine studies have confirmed the safety (protected intimal and medial layers) and effectiveness (ablation of 1-6 mm region) of the system and provided near-field and far-field depth data to correlate with bench and computer simulation models. The safety and effectiveness of the Paradise System, developed through computer model, bench and in vivo studies, has been demonstrated in human clinical studies.

  4. Advances and challenges in targeting FGFR signalling in cancer.

    PubMed

    Babina, Irina S; Turner, Nicholas C

    2017-05-01

    Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Deregulation of FGFR signalling is observed in a subset of many cancers, making activated FGFRs a highly promising potential therapeutic target supported by multiple preclinical studies. However, early-phase clinical trials have produced mixed results with FGFR-targeted cancer therapies, revealing substantial complexity to targeting aberrant FGFR signalling. In this Review, we discuss the increasing understanding of the differences between diverse mechanisms of oncogenic activation of FGFR, and the factors that determine response and resistance to FGFR targeting.

  5. Target of rapamycin signaling mediates vacuolar fragmentation.

    PubMed

    Stauffer, Bobbiejane; Powers, Ted

    2017-02-01

    In eukaryotic cells, cellular homeostasis requires that different organelles respond to intracellular as well as environmental signals and modulate their behavior as conditions demand. Understanding the molecular mechanisms required for these changes remains an outstanding goal. One such organelle is the lysosome/vacuole, which undergoes alterations in size and number in response to environmental and physiological stimuli. Changes in the morphology of this organelle are mediated in part by the equilibrium between fusion and fission processes. While the fusion of the yeast vacuole has been studied intensively, the regulation of vacuolar fission remains poorly characterized by comparison. In recent years, a number of studies have incorporated genome-wide visual screens and high-throughput microscopy to identify factors required for vacuolar fission in response to diverse cellular insults, including hyperosmotic and endoplasmic reticulum stress. Available evidence now demonstrates that the rapamycin-sensitive TOR network, a master regulator of cell growth, is required for vacuolar fragmentation in response to stress. Importantly, many of the genes identified in these studies provide new insights into potential links between the vacuolar fission machinery and TOR signaling. Together these advances both extend our understanding of the regulation of vacuolar fragmentation in yeast as well as underscore the role of analogous events in mammalian cells.

  6. Role of signal peptides in targeting of proteins in cyanobacteria.

    PubMed Central

    Mackle, M M; Zilinskas, B A

    1994-01-01

    Proteins of cyanobacteria may be transported across one of two membrane systems: the typical eubacterial cell envelope (consisting of an inner membrane, periplasmic space, and an outer membrane) and the photosynthetic thylakoids. To investigate the role of signal peptides in targeting in cyanobacteria, Synechococcus sp. strain PCC 7942 was transformed with vectors carrying the chloramphenicol acetyltransferase reporter gene fused to coding sequences for one of four different signal peptides. These included signal peptides of two proteins of periplasmic space origin (one from Escherichia coli and the other from Synechococcus sp. strain PCC 7942) and two other signal peptides of proteins located in the thylakoid lumen (one from a cyanobacterium and the other from a higher plant). The location of the gene fusion products expressed in Synechococcus sp. strain PCC 7942 was determined by a chloramphenicol acetyltransferase enzyme-linked immunosorbent assay of subcellular fractions. The distribution pattern for gene fusions with periplasmic signal peptides was different from that of gene fusions with thylakoid lumen signal peptides. Primary sequence analysis revealed conserved features in the thylakoid lumen signal peptides that were absent from the periplasmic signal peptides. These results suggest the importance of the signal peptide in protein targeting in cyanobacteria and point to the presence of signal peptide features conserved between chloroplasts and cyanobacteria for targeting of proteins to the thylakoid lumen. Images PMID:8144451

  7. Mammalian circadian signaling networks and therapeutic targets.

    PubMed

    Liu, Andrew C; Lewis, Warren G; Kay, Steve A

    2007-10-01

    Virtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, with the suprachiasmatic nuclei (SCN) acting as the central pacemaker. The SCN synchronizes to daily light-dark cycles and coordinates rhythmic physiology and behavior. Synchronization in the SCN and at the organismal level is a key feature of the circadian clock system. In particular, intercellular coupling in the SCN synchronizes neuron oscillators and confers robustness against perturbations. Recent advances in our knowledge of and ability to manipulate circadian rhythms make available cell-based clock models, which lack strong coupling and are ideal for target discovery and chemical biology.

  8. Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened.

    PubMed

    Gonnissen, Annelies; Isebaert, Sofie; Haustermans, Karin

    2015-06-10

    An essential role for Hedgehog (Hh) signaling in human cancer has been established beyond doubt. At present, targeting Hh signaling has mainly been investigated with SMO inhibitors. Unfortunately, resistance against currently used SMO inhibitors has already been observed in basal cell carcinoma (BCC) patients. Therefore, the use of Hh inhibitors targeting the signaling cascade more downstream of SMO could represent a more promising strategy. Furthermore, besides the classical canonical way of Hh signaling activation, non-canonical activation of the GLI transcription factors by multiple important signaling pathways (e.g. MAPK, PI3K, TGFβ) has also been described, pinpointing the importance of targeting the transcription factors GLI1/2. The most promising agent in this context is probably the GLI1/2 inhibitor GANT61 which has been investigated preclinically in numerous tumor types in the last few years. In this review, the emerging role of Hh signaling in cancer is critically evaluated focusing on the potential of targeting Hh signaling more downstream of SMO, i.e. at the level of the GLI transcription factors. Furthermore, the working mechanism and therapeutic potential of the most extensively studied GLI inhibitor in human cancer, i.e. GANT61, is discussed in detail. In conclusion, GANT61 appears to be highly effective against human cancer cells and in xenograft mouse models, targeting almost all of the classical hallmarks of cancer and could hence represent a promising treatment option for human cancer.

  9. Lidar Luminance Quantizer

    NASA Technical Reports Server (NTRS)

    Quilligan, Gerard; DeMonthier, Jeffrey; Suarez, George

    2011-01-01

    This innovation addresses challenges in lidar imaging, particularly with the detection scheme and the shapes of the detected signals. Ideally, the echoed pulse widths should be extremely narrow to resolve fine detail at high event rates. However, narrow pulses require wideband detection circuitry with increased power dissipation to minimize thermal noise. Filtering is also required to shape each received signal into a form suitable for processing by a constant fraction discriminator (CFD) followed by a time-to-digital converter (TDC). As the intervals between the echoes decrease, the finite bandwidth of the shaping circuits blends the pulses into an analog signal (luminance) with multiple modes, reducing the ability of the CFD to discriminate individual events

  10. Target image search using fMRI signals

    NASA Astrophysics Data System (ADS)

    Xiong, Shi; Song, Sutao; Zhan, Yu; Zhang, Jiacai

    2014-03-01

    Recent neural signal decoding studies based on functional magnetic resonance imaging (fMRI) have identified the specific image presenting to the subject from a set of potential images, and some studies extend neural decoding into image reconstruction, i.e. image contents that the subject perceived were decoded from the fMRI signals recorded during the subject looking at images. In this paper, we decoded the target images using fMRI signals and described a target image searching method based on the relationship between target image stimuli and fMRI activity. We recorded fMRI data during a serial visual stimuli image presentation task, some of the stimuli images were target images and the rest images were non-target ones. Our fMRI data analysis results showed that in the serial visual presentation task, target images elicited a stereotypical response in the fMRI, which can be detected by multi-voxel pattern analysis (MVPA). Classifiers designed with support vector machine (SVM) used this response to decipher target images from non-target images. The leave-one-run-out cross-validation showed that we can pick out the target images with a possibility far above the chance level, which indicate that there's a neural signatures correlated with the target image recognition process in the human systems.

  11. Targeting the Notch signaling pathway in cancer therapeutics.

    PubMed

    Guo, Huajiao; Lu, Yi; Wang, Jianhua; Liu, Xia; Keller, Evan T; Liu, Qian; Zhou, Qinghua; Zhang, Jian

    2014-11-01

    Despite advances in surgery, imaging, chemotherapy, and radiotherapy, the poor overall cancer-related death rate remains unacceptable. Novel therapeutic strategies are desperately needed. Nowadays, targeted therapy has become the most promising therapy and a welcome asset to the cancer therapeutic arena. There is a large body of evidence demonstrating that the Notch signaling pathway is critically involved in the pathobiology of a variety of malignancies. In this review, we provide an overview of emerging data, highlight the mechanism of the Notch signaling pathway in the development of a wide range of cancers, and summarize recent progress in therapeutic targeting of the Notch signaling pathway.

  12. Nonlinear photoacoustic signal amplification from single targets in absorption background☆

    PubMed Central

    Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Menyaev, Yulian A.; Juratli, Mazen A.; Zharov, Vladimir P.

    2013-01-01

    Photoacoustic (PA) detection of single absorbing targets such as nanoparticles or cells can be limited by absorption background. We show here that this problem can be overcome by using the nonlinear photoacoustics based on the differences in PA signal dependences on the laser energy from targets and background. Among different nonlinear phenomena, we focused on laser generation of nanobubbles as more efficient PA signal amplifiers from strongly absorbing, highly localized targets in the presence of spatially homogenous absorption background generating linear signals only. This approach was demonstrated by using nonlinear PA flow cytometry platform for label-free detection of circulating melanoma cells in blood background in vitro and in vivo. Nonlinearly amplified PA signals from overheated melanin nanoclusters in melanoma cells became detectable above still linear blood background. Nonlinear nanobubble-based photoacoustics provide new opportunities to significantly (5–20-fold) increase PA contrast of single nanoparticles, cells, viruses and bacteria in complex biological environments. PMID:24921062

  13. Targeting the Hedgehog signaling pathway for cancer therapy.

    PubMed

    Li, Yiwei; Maitah, Ma'in Y; Ahmad, Aamir; Kong, Dejuan; Bao, Bin; Sarkar, Fazlul H

    2012-01-01

    Hedgehog (Hh) signaling pathway plays key roles in embryonic development, formation and maintenance of cancer stem cells (CSCs) and acquisition of epithelial-to-mesenchymal transition (EMT). Since CSCs and EMT are important biological factors responsible for cancer cell invasion, metastasis, drug resistance and tumor recurrence, the Hh signaling pathway is believed to be an important target for cancer therapy. In recent years, small-molecule inhibitors of Hh signaling have been synthesized for cancer treatment. Clinical trials using these inhibitors are being conducted to determine their toxicity profiles and efficacies. In addition, nutraceuticals (such as isoflavones, curcumin, vitamin D, etc) have been shown to inhibit cancer growth through downregulation of Hh signaling. Inhibition of Hh signaling is important for suppression of cancer growth, invasion, metastasis and recurrence in cancer therapy. However, targeting only one molecule in Hh signaling may not be sufficient to kill cancer cells because cancers show deregulation of multiple signals. Therefore, utilizing new technologies to determine alterations in Hh and other signals for individuals and designing combination strategies with small-molecule Hh inhibitors, nutraceuticals and other chemotherapeutics in targeted personalized therapy could have a significant effect on improving the overall survival of patients with cancers.

  14. Feature long axis size and local luminance contrast determine ship target acquisition performance: strong evidence for the TOD case

    NASA Astrophysics Data System (ADS)

    Bijl, Piet; Toet, Alexander; Kooi, Frank L.

    2016-10-01

    Visual images of a civilian target ship on a sea background were produced using a CAD model. The total set consisted of 264 images and included 3 different color schemes, 2 ship viewing aspects, 5 sun illumination conditions, 2 sea reflection values, 2 ship positions with respect to the horizon and 3 values of atmospheric contrast reduction. In a perception experiment, the images were presented on a display in a long darkened corridor. Observers were asked to indicate the range at which they were able to detect the ship and classify the following 5 ship elements: accommodation, funnel, hull, mast, and hat above the bridge. This resulted in a total of 1584 Target Acquisition (TA) range estimates for two observers. Next, the ship contour, ship elements and corresponding TA ranges were analyzed applying several feature size and contrast measures. Most data coincide on a contrast versus angular size plot using (1) the long axis as characteristic ship/ship feature size and (2) local Weber contrast as characteristic ship/ship feature contrast. Finally, the data were compared with a variety of visual performance functions assumed to be representative for Target Acquisition: the TOD (Triangle Orientation Discrimination), MRC (Minimum Resolvable Contrast), CTF (Contrast Threshold Function), TTP (Targeting Task Performance) metric and circular disc detection data for the unaided eye (Blackwell). The results provide strong evidence for the TOD case: both position and slope of the TOD curve match the ship detection and classification data without any free parameter. In contrast, the MRC and CTF are too steep, the TTP and disc detection curves are too shallow and all these curves need an overall scaling factor in order to coincide with the ship and ship feature recognition data.

  15. Multiple Distinct Targeting Signals in Integral Peroxisomal Membrane Proteins

    PubMed Central

    Jones, Jacob M.; Morrell, James C.; Gould, Stephen J.

    2001-01-01

    Peroxisomal proteins are synthesized on free polysomes and then transported from the cytoplasm to peroxisomes. This process is mediated by two short well-defined targeting signals in peroxisomal matrix proteins, but a well-defined targeting signal has not yet been described for peroxisomal membrane proteins (PMPs). One assumption in virtually all prior studies of PMP targeting is that a given protein contains one, and only one, distinct targeting signal. Here, we show that the metabolite transporter PMP34, an integral PMP, contains at least two nonoverlapping sets of targeting information, either of which is sufficient for insertion into the peroxisome membrane. We also show that another integral PMP, the peroxin PEX13, also contains two independent sets of peroxisomal targeting information. These results challenge a major assumption of most PMP targeting studies. In addition, we demonstrate that PEX19, a factor required for peroxisomal membrane biogenesis, interacts with the two minimal targeting regions of PMP34. Together, these results raise the interesting possibility that PMP import may require novel mechanisms to ensure the solubility of integral PMPs before their insertion in the peroxisome membrane, and that PEX19 may play a central role in this process. PMID:11402059

  16. Therapeutics Targeting FGF Signaling Network in Human Diseases.

    PubMed

    Katoh, Masaru

    2016-12-01

    Fibroblast growth factor (FGF) signaling through its receptors, FGFR1, FGFR2, FGFR3, or FGFR4, regulates cell fate, angiogenesis, immunity, and metabolism. Dysregulated FGF signaling causes human diseases, such as breast cancer, chondrodysplasia, gastric cancer, lung cancer, and X-linked hypophosphatemic rickets. Recombinant FGFs are pro-FGF signaling therapeutics for tissue and/or wound repair, whereas FGF analogs and gene therapy are under development for the treatment of cardiovascular disease, diabetes, and osteoarthritis. FGF traps, anti-FGF/FGFR monoclonal antibodies (mAbs), and small-molecule FGFR inhibitors are anti-FGF signaling therapeutics under development for the treatment of cancer, chondrodysplasia, and rickets. Here, I discuss the benefit-risk and cost-effectiveness issues of precision medicine targeting FGFRs, ALK, EGFR, and FLT3. FGFR-targeted therapy should be optimized for cancer treatment, focusing on genomic tests and recurrence.

  17. Notch Signaling Proteins: Legitimate Targets for Cancer Therapy

    PubMed Central

    Wang, Zhiwei; Li, Yiwei; Sarkar, Fazlul H.

    2011-01-01

    Proteins and small peptides (growth factors and hormones) are key molecules in maintaining cellular homeostasis. To that end, Notch signaling pathway proteins are known to play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis, and thus it has been suggested that Notch may be responsible for the development and progression of human malignancies. Therefore, the Notch signaling pathway proteins may present novel therapeutic targets, which could have promising therapeutic impact on eradicating human malignancies. This review describes the role of Notch signaling pathway proteins in cancer and how its deregulation is involved in tumor development and progression leading to metastasis and the ultimate demise of patients diagnosed with cancer. Further, we summarize the role of several Notch inhibitors especially “natural agents” that could represent novel therapeutic strategies targeting Notch signaling toward better treatment outcome of patients diagnosed with cancer. PMID:20491628

  18. The eukaryotic signal sequence, YGRL, targets the chlamydial inclusion

    PubMed Central

    Kabeiseman, Emily J.; Cichos, Kyle H.; Moore, Elizabeth R.

    2014-01-01

    Understanding how host proteins are targeted to pathogen-specified organelles, like the chlamydial inclusion, is fundamentally important to understanding the biogenesis of these unique subcellular compartments and how they maintain autonomy within the cell. Syntaxin 6, which localizes to the chlamydial inclusion, contains an YGRL signal sequence. The YGRL functions to return syntaxin 6 to the trans-Golgi from the plasma membrane, and deletion of the YGRL signal sequence from syntaxin 6 also prevents the protein from localizing to the chlamydial inclusion. YGRL is one of three YXXL (YGRL, YQRL, and YKGL) signal sequences which target proteins to the trans-Golgi. We designed various constructs of eukaryotic proteins to test the specificity and propensity of YXXL sequences to target the inclusion. The YGRL signal sequence redirects proteins (e.g., Tgn38, furin, syntaxin 4) that normally do not localize to the chlamydial inclusion. Further, the requirement of the YGRL signal sequence for syntaxin 6 localization to inclusions formed by different species of Chlamydia is conserved. These data indicate that there is an inherent property of the chlamydial inclusion, which allows it to recognize the YGRL signal sequence. To examine whether this “inherent property” was protein or lipid in nature, we asked if deletion of the YGRL signal sequence from syntaxin 6 altered the ability of the protein to interact with proteins or lipids. Deletion or alteration of the YGRL from syntaxin 6 does not appreciably impact syntaxin 6-protein interactions, but does decrease syntaxin 6-lipid interactions. Intriguingly, data also demonstrate that YKGL or YQRL can successfully substitute for YGRL in localization of syntaxin 6 to the chlamydial inclusion. Importantly and for the first time, we are establishing that a eukaryotic signal sequence targets the chlamydial inclusion. PMID:25309881

  19. Controversies in cancer stem cells: targeting embryonic signaling pathways.

    PubMed

    Takebe, Naoko; Ivy, S Percy

    2010-06-15

    Selectively targeting cancer stem cells (CSC) or tumor-initiating cells (TIC; from this point onward referred to as CSCs) with novel agents is a rapidly emerging field of oncology. Our knowledge of CSCs and their niche microenvironments remains a nascent field. CSC's critical dependence upon self-renewal makes these regulatory signaling pathways ripe for the development of experimental therapeutic agents. Investigational agents targeting the Notch, Hedgehog, and Wnt pathways are currently in late preclinical development stages, with some early phase 1-2 testing in human subjects. This series of articles will provide an overview and summary of the current state of knowledge of CSCs, their interactive microenvironment, and how they may serve as important targets for antitumor therapies. We also examine the scope and stage of development of early experimental agents that specifically target these highly conserved embryonic signaling pathways.

  20. Autofluorescence-Free Targeted Tumor Imaging Based on Luminous Nanoparticles with Composition-Dependent Size and Persistent Luminescence.

    PubMed

    Wang, Jie; Ma, Qinqin; Hu, Xiao-Xiao; Liu, Haoyang; Zheng, Wei; Chen, Xueyuan; Yuan, Quan; Tan, Weihong

    2017-08-22

    Optical bioimaging is an indispensable tool in modern biology and medicine, but the technique is susceptible to autofluorescence interference. Persistent nanophosphors provide an easy-to-perform and highly efficient means to eliminate tissue autofluorescence. However, direct synthesis of persistent nanophosphors with tunable properties to meet different bioimaging requirements remains largely unexplored. In this work, zinc gallogermanate (Zn1+xGa2-2xGexO4:Cr, 0 ≤ x ≤ 0.5, ZGGO:Cr) persistent luminescence nanoparticles with composition-dependent size and persistent luminescence are reported. The size of the ZGGO:Cr nanoparticles gradually increases with the increase of x in the chemical formula. Moreover, the intensity and decay time of persistent luminescence in ZGGO:Cr nanoparticles can also be fine-tuned by simply changing x in the formula. In vivo bioimaging tests demonstrate that ZGGO:Cr nanoparticles can efficiently eliminate tissue autofluorescence, and the nanoparticles also show good promise in long-term bioimaging as they can be easily reactivated in vivo. Furthermore, an aptamer-guided ZGGO:Cr bioprobe is constructed, and it displays excellent tumor-specific accumulation. The ZGGO:Cr nanoparticles are ideal for autofluorescence-free targeted bioimaging, indicating their great potential in monitoring cellular networks and construction of guiding systems for surgery.

  1. Perception of chromatic motion requires luminance interaction.

    PubMed

    Baraas, Rigmor C

    2005-01-01

    There is an ongoing debate related to whether chromatic motion perception arises as a consequence of a chromatic signal only (eg Wandell et al 1999 Neuron 24 901-909) or a signal that is essentially based on luminance processes (luminance artifacts) (Mullen et al 2003 Vision Research 43 1235-1247). These two views conform to the idea that colour and luminance processes are physiologically independent (Livingstone and Hubel 1988 Science 240 740-749), but according to other reports many primary cortical 'V1' cells respond to both colour and luminance contrast (eg Vidyasagar et al 2002 European Journal of Neuroscience 16 945-956). A psychophysical task was designed to test whether possible interaction between luminance and chromatic contrast could account for perception of chromatic motion. It is shown that subjects respond in a manner that reflects involvement of both processes.

  2. Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

    PubMed Central

    Ahmed, Wesam; Van Etten, Richard A.

    2013-01-01

    The chronic leukemias, including chronic myeloid leukemia (CML), the Philadelphia-negative myeloproliferative neoplasms (MPNs), and chronic lymphocytic leukemia (CLL), have been characterized extensively for abnormalities of cellular signaling pathways. This effort has led to the elucidation of the central role of dysregulated tyrosine kinase signaling in the chronic myeloid neoplasms and of constitutive B-cell receptor signaling in CLL. This, in turn, has stimulated the development of small molecule inhibitors of these signaling pathways for therapy of chronic leukemia. Although the field is still in its infancy, the clinical results with these agents have ranged from encouraging (CLL) to spectacular (CML). In this review, we summarize recent studies that have helped to define the signaling pathways critical to the pathogenesis of the chronic leukemias. We also discuss correlative studies emerging from clinical trials of drugs targeting these pathways. PMID:23307472

  3. OLED lightings with optical feedback for luminance difference compensation

    NASA Astrophysics Data System (ADS)

    Shin, D. K.; Park, J. W.

    2013-12-01

    We have employed an optical feedback circuit in an organic light-emitting diode (OLED) lighting system to ensure uniform light output across large-area OLED lighting tiles. In a lighting system with several large-area OLED lighting tiles involved, the panel aging (luminance decrease) may appear differently in each, resulting in a falling-off in lighting quality. To tackle this, light output from each OLED tile is monitored by the optical feedback circuit that consists of a photodetector, I-V converter, 10-bit analogue-digital converter (ADC), and comparator. A photodetector mounted on a glass side generates a feedback signal (current) by detecting side-emitting OLED light. To monitor bottom-emitting output light by detecting side-emitting OLED light, a mapping table between the ADC value and the luminance of bottom emission has been established. If the ADC value is lower or higher than the reference one corresponding to the target luminance of OLED tiles, a micro controller unit adjusts the pulse width modulation used for the control of the power supplied to OLED tiles in such a way that the ADC value obtained from optical feedback is the same as the reference one. As a result, the target luminance of each individual OLED tile is kept unchanged. With the optical feedback circuit included in the lighting system, we have observed less than 2% difference in relative intensity of neighboring OLED tiles.

  4. Assessing the effects of dynamic luminance contrast noise masking on a color discrimination task.

    PubMed

    Linhares, João M M; João, Catarina A R; Silva, Eva D G; de Almeida, Vasco M N; Santos, Jorge L A; Álvaro, Leticia; Nascimento, Sérgio M C

    2016-03-01

    The aim of this work was to assess the influence of dynamic luminance contrast noise masking (LCNM) on color discrimination for color normal and anomalous trichromats. The stimulus was a colored target on a background presented on a calibrated CRT display. In the static LCNM condition, the background and target consisted of packed circles with variable size and static random luminance. In the dynamic LCNM condition, a 10 Hz square luminance signal was added to each circle. The phase of this signal was randomized across circles. Discrimination thresholds were estimated along 20 hue directions concurrent at the color of the background. Six observers with normal color vision, six deuteranomalous observers, and three protanomalous observers performed the test in both conditions. With dynamic LCNM, thresholds were significantly lower for anomalous observers but not for normal observers, suggesting a facilitation effect of the masking for anomalous trichromats.

  5. Rigid and elastic acoustic scattering signal separation for underwater target.

    PubMed

    Jia, Hongjian; Li, Xiukun; Meng, Xiangxia

    2017-08-01

    Underwater target elastic acoustic scattering and other acoustic scattering components are aliasing together in the time and frequency domains, and the existing signal processing methods cannot recognize the elastic scattering features under the aliasing condition because of the resolution limitation. To address this problem, this study, which is based on the target echo highlight model, analyzes the characteristics of target acoustic scattering components when the transmitted signal is a linear frequency modulation pulse. The target acoustic scattering structure in the fractional Fourier transform (FRFT) domain is deduced theoretically. Then, filtering is used in the FRFT domain to separate the target elastic acoustic scattering components. In addition, noise suppression performance and filter resolution are discussed. The target rigid and elastic acoustic scattering components are separated. Experimental results show that filtering in the FRFT domain can separate the elastic scattering components from the target echoes. Moreover, separated elastic acoustic scattering components have consistent theoretical features, which lay the foundation for studying the elastic scattering characteristics further.

  6. Cotranslational signal independent SRP preloading during membrane targeting

    PubMed Central

    Chartron, Justin W.; Hunt, Katherine C. L.; Frydman, Judith

    2016-01-01

    Ribosome-associated factors must faithfully decode the limited information available in nascent polypeptides to direct them to their correct cellular fate1. It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site2,3. Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum (ER), involving recognition of linear hydrophobic Signal Sequences (SS) or Transmembrane Domains (TMD) by the Signal Recognition Particle (SRP)4,5. Intriguingly, SRP is in low abundance relative to the large number of ribosome nascent chain complexes (RNCs), yet it accurately selects those destined to the ER6. Despite their overlapping specificities, SRP and the cotranslational Hsp70 SSB display exquisite mutually exclusive selectivity in vivo for their cognate RNCs7,8. To understand cotranslational nascent chain recognition in vivo, we interrogated the cotranslational membrane targeting cycle using ribosome profiling (herein Ribo-seq)9 coupled with biochemical fractionation of ribosome populations. Unexpectedly, SRP preferentially binds secretory RNCs before targeting signals are translated. We show non-coding mRNA elements can promote this signal-independent SRP pre-recruitment. Our study defines the complex kinetic interplay between elongation and determinants in the polypeptide and mRNA modulating SRP-substrate selection and membrane targeting. PMID:27487213

  7. Key cancer cell signal transduction pathways as therapeutic targets.

    PubMed

    Bianco, Roberto; Melisi, Davide; Ciardiello, Fortunato; Tortora, Giampaolo

    2006-02-01

    Growth factor signals are propagated from the cell surface, through the action of transmembrane receptors, to intracellular effectors that control critical functions in human cancer cells, such as differentiation, growth, angiogenesis, and inhibition of cell death and apoptosis. Several kinases are involved in transduction pathways via sequential signalling activation. These kinases include transmembrane receptor kinases (e.g., epidermal growth factor receptor EGFR); or cytoplasmic kinases (e.g., PI3 kinase). In cancer cells, these signalling pathways are often altered and results in a phenotype characterized by uncontrolled growth and increased capability to invade surrounding tissue. Therefore, these crucial transduction molecules represent attractive targets for cancer therapy. This review will summarize current knowledge of key signal transduction pathways, that are altered in cancer cells, as therapeutic targets for novel selective inhibitors. The most advanced targeted agents currently under development interfere with function and expression of several signalling molecules, including the EGFR family; the vascular endothelial growth factor and its receptors; and cytoplasmic kinases such as Ras, PI3K and mTOR.

  8. Progress in Small Molecule and Biologic Therapeutics Targeting Ghrelin Signaling.

    PubMed

    McGovern, Kayleigh R; Darling, Joseph E; Hougland, James L

    2016-01-01

    Ghrelin is a circulating peptide hormone involved in regulation of a wide array of physiological processes. As an endogenous ligand for growth hormone secretagogue receptor (GHSR1a), ghrelin is responsible for signaling involved in energy homeostasis, including appetite stimulation, glucose metabolism, insulin signaling, and adiposity. Ghrelin has also been implicated in modulation of several neurological processes. Dysregulation of ghrelin signaling is implicated in diseases related to these pathways, including obesity, type II diabetes, and regulation of appetite and body weight in patients with Prader-Willi syndrome. Multiple steps in the ghrelin signaling pathway are available for targeting in the development of therapeutics for these diseases. Agonists and antagonists of GHS-R1a have been widely studied and have shown varying levels of effectiveness within ghrelin-related physiological pathways. Agents targeting ghrelin directly, either through depletion of ghrelin levels in circulation or inhibitors of ghrelin O-acyltransferase whose action is required for ghrelin to become biologically active, are receiving increasing attention as potential therapeutic options. We discuss the approaches utilized to target ghrelin signaling and highlight the current challenges toward developing small-molecule agents as potential therapeutics for ghrelin-related diseases.

  9. TNFα reverse signaling promotes sympathetic axon growth and target innervation

    PubMed Central

    Kisiswa, Lilian; Osório, Catarina; Erice, Clara; Vizard, Thomas; Wyatt, Sean; Davies, Alun M

    2013-01-01

    Reverse signaling via members of the tumor necrosis factor (TNF) superfamily is increasingly recognized among cells of the immune system where it controls multiple aspects of immune function. Here we document TNFα reverse signaling in the nervous system for the first time and show that it plays a crucial role in establishing sympathetic innervation. During postnatal development, sympathetic axons express TNFα as they grow and branch in their target tissues which in turn express TNFR1. In culture, soluble forms of TNFR1 act directly on postnatal sympathetic axons to promote growth and branching by a mechanism that depends on membrane integrated TNFα and downstream MEK/ERK activation. Sympathetic innervation density is significantly reduced in several tissues in postnatal and adult mice lacking either TNFα or TNFR1. These findings reveal that target-derived TNFR1 acts as a reverse signaling ligand for membrane-integrated TNFα to promote sympathetic axon growth and branching. PMID:23749144

  10. An effect of contrast and luminance on visual representational momentum for location.

    PubMed

    Hubbard, Timothy L; Ruppel, Susan E

    2014-01-01

    Effects of the contrast of target luminance and background luminance, and of the absolute level of target luminance, on representational momentum for the remembered final location of a previously viewed moving target were examined. Targets were high in contrast or luminance, decreasing in contrast or luminance, increasing in contrast or luminance, or low in contrast or luminance; the background was black or white. Representational momentum for target location was larger if targets were high or increasing in contrast or luminance and smaller if targets were low or decreasing in contrast or luminance. Representational momentum for target location was larger if targets were presented on a white background than on a black background. Implications for theories of localization and for theories of representational momentum are discussed.

  11. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway.

    PubMed

    Deng, Chao; Pan, Bo; Engel, Martin; Huang, Xu-Feng

    2013-03-01

    Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.

  12. Targeting kinase signaling pathways with constrained peptide scaffolds.

    PubMed

    Hanold, Laura E; Fulton, Melody D; Kennedy, Eileen J

    2017-02-07

    Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles. Constrained peptide inhibitors have emerged as an alternative strategy for kinase inhibition. Distinct from small molecule inhibitors, peptides can provide a large binding surface area that allows them to bind shallow protein surfaces rather than defined pockets within the target protein structure. By including chemical constraints within the peptide sequence, additional benefits can be bestowed onto the peptide scaffold such as improved target affinity and target selectivity, cell permeability and proteolytic resistance. In this review, we highlight examples of diverse chemistries that are being employed to constrain kinase-targeting peptide scaffolds and highlight their application to modulate kinase signaling as well as their potential clinical implications.

  13. Hedgehog signaling pathway as a therapeutic target for ovarian cancer.

    PubMed

    Li, Haixia; Li, Jinghua; Feng, Limin

    2016-02-01

    Ovarian cancer is the most lethal cause of death among gynecological malignancies. Despite advancements in surgery and chemotherapy treatment strategies, the prognosis of ovarian cancer patients remains poor; a majority of patients relapse and eventually succumb to this disease. Therefore, novel therapeutic approaches to improve patient outcome are urgently needed. The hedgehog signaling pathway is vital for embryonic development and tissue homeostasis, and its deregulation is implicated in cancer cell growth, survival, differentiation, and metastasis. The critical role of hedgehog signaling in multiple biologic processes raises concerns about its potential therapeutic use in cancer. Consequently, many studies are focusing on hedgehog signaling as an attractive target in cancer treatment. In this review, we present an overview of the hedgehog pathway and its pathological aberrations in ovarian cancer. We also discuss inhibitors of the hedgehog signaling pathway that are currently being investigated in the laboratory and in early clinical trials; as well as the clinical challenges these inhibitors face.

  14. The 2XMMi/SDSS Galaxy Cluster Survey. III. Clusters associated with spectroscopically targeted luminous red galaxies in SDSS-DR10

    NASA Astrophysics Data System (ADS)

    Takey, A.; Schwope, A.; Lamer, G.

    2014-04-01

    We present a sample of 383 X-ray selected galaxy groups and clusters with spectroscopic redshift measurements (up to z ~ 0.79) from the 2XMMi/SDSS Galaxy Cluster Survey. The X-ray cluster candidates were selected as serendipitously detected sources from the 2XMMi-DR3 catalogue that were located in the footprint of the Sloan Digital Sky Survey (SDSS-DR7). The cluster galaxies with available spectroscopic redshifts were selected from the SDSS-DR10. We developed an algorithm for identifying the cluster candidates that are associated with spectroscopically targeted luminous red galaxies and for constraining the cluster spectroscopic redshift. A cross-correlation of the constructed cluster sample with published optically selected cluster catalogues yielded 264 systems with available redshifts. The present redshift measurements are consistent with the published values. The current cluster sample extends the optically confirmed cluster sample from our cluster survey by 67 objects. Moreover, it provides spectroscopic confirmation for 78 clusters among our published cluster sample, which previously had only photometric redshifts. Of the new cluster sample that comprises 67 systems, 55 objects are newly X-ray discovered clusters and 52 systems are sources newly discovered as galaxy clusters in optical and X-ray wavelengths. Based on the measured redshifts and the fluxes given in the 2XMMi-DR3 catalogue, we estimated the X-ray luminosities and masses of the cluster sample. The cluster catalog is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/564/A54

  15. Pharmacological strategies to target oncogenic KRAS signaling in pancreatic cancer.

    PubMed

    Chuang, Hsiao-Ching; Huang, Po-Hsien; Kulp, Samuel K; Chen, Ching-Shih

    2017-03-01

    The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.

  16. Intracellular signaling by phospholipase D as a therapeutic target.

    PubMed

    Steed, P M; Chow, A H

    2001-09-01

    The pharmaceutical industry has recently focused on intracellular signaling as a means to integrate the multiple facets of complex disease states, such as inflammation, because these pathways respond to numerous extracellular signals and coordinate a collection of cell responses contributing to pathology. One critical aspect of intracellular signaling is regulation of key cell functions by lipid mediators, in particular the generation of a key mediator, phosphatidic acid (PA) via the hydrolysis of phosphatidylcholine by phospholipase D (PLD). Research in this field has intensified, due in part to the recent cloning and partial characterization of the two PLD isoforms in mammalian cells, and this work has contributed significantly to our understanding of events downstream of PA generation. It is these effector functions of PLD activity that make this pathway attractive as a therapeutic target while the biochemical properties of the PLD isozymes make them amenable to small molecule intervention. Recent studies indicate that PA, and its immediate metabolites diacylglycerol and lyso-PA, affect numerous cellular pathways including ligand-mediated secretion, cytoskeletal reorganisations, respiratory burst, prostaglandin release, cell migration, cytokine release, and mitogenesis. This review summarises the data implicating signaling via PLD in these cell functions, obtained from: (i) molecular analyses of PLD/effector interactions, (ii) correlation between PA production and cell responses, (iii) experimental manipulation of PA levels, (iv) inhibition of PLD regulators, and (v) direct inhibition of PA production. The utility of targeting PLD signaling for the treatment of acute/chronic inflammation and other indications is discussed in light of these data.

  17. Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control

    PubMed Central

    Loewith, Robbie; Hall, Michael N.

    2011-01-01

    TOR (Target Of Rapamycin) is a highly conserved protein kinase that is important in both fundamental and clinical biology. In fundamental biology, TOR is a nutrient-sensitive, central controller of cell growth and aging. In clinical biology, TOR is implicated in many diseases and is the target of the drug rapamycin used in three different therapeutic areas. The yeast Saccharomyces cerevisiae has played a prominent role in both the discovery of TOR and the elucidation of its function. Here we review the TOR signaling network in S. cerevisiae. PMID:22174183

  18. Adaptive stress signaling in targeted therapy resistance in cancer

    PubMed Central

    Pazarentzos, Evangelos; Bivona, Trever G.

    2015-01-01

    The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. While substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumor cell survival during treatment and the development of resistance. Here, we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize or eliminate targeted therapy resistance, thereby unleashing the full potential of targeted therapies to transform many cancers from lethal to chronic or curable conditions. PMID:25703329

  19. Some new luminance-gradient effects.

    PubMed

    Zavagno, D

    1999-01-01

    Three compelling luminance-gradient effects are described. The first effect concerns a brightness enhancement and a luminous mist spreading out from a central area having the same luminance as the white background and surrounded by four rectangular inducers shaded with a linear luminance gradient. The second effect is perceived with a photographically reversed configuration, and concerns what may be considered a brightness reduction or the enhancement of a darkness quality of a target area of the visual scene. The third effect concerns the perception of a self-luminous disk inside a somewhat foggy medium. The effects are worthy of further examination because they challenge current theories of luminosity perception and brightness perception in general.

  20. Signaling Pathways in Schizophrenia: emerging targets and therapeutic strategies

    PubMed Central

    Karam, Caline S; Ballon, Jacob S; Bivens, Nancy M; Freyberg, Zachary; Girgis, Ragy R; Lizardi-Ortiz, Jose E; Markx, Sander; Lieberman, Jeffrey A; Javitch, Jonathan A

    2013-01-01

    Dopamine D2 receptor antagonism is a unifying property of all antipsychotic drugs in clinical use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe a number of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, neuregulin/ERB4, and components of the Akt/GSK-3 pathway. PMID:20579747

  1. Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

    PubMed Central

    Ahmad, Faiyaz; Murata, Taku; Simizu, Kasumi; Degerman, Eva; Maurice, Donald; Manganiello, Vincent

    2014-01-01

    By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners. PMID:25056711

  2. Adiponectin signaling and function in insulin target tissues

    PubMed Central

    Ruan, Hong; Dong, Lily Q.

    2016-01-01

    Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide, posing a major threat on human health, productivity, and quality of life. Despite great progress made towards a better understanding of the molecular basis of diabetes, the available clinical counter-measures against insulin resistance, a defect that is central to obesity-linked type 2 diabetes, remain inadequate. Adiponectin, an abundant adipocyte-secreted factor with a wide-range of biological activities, improves insulin sensitivity in major insulin target tissues, modulates inflammatory responses, and plays a crucial role in the regulation of energy metabolism. However, adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention, and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation, and reveal therapeutic targets. Here, we discuss tissue- and cell-specific functions of adiponectin, with an emphasis on the regulation of adiponectin signaling pathways, and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation. Understanding better just why and how adiponectin and its downstream effector molecules work will be essential, together with empirical trials, to guide us to therapies that target the root cause(s) of type 2 diabetes and insulin resistance. PMID:26993044

  3. NF-κB Signaling: Multiple angles to target OA

    PubMed Central

    Marcu, Kenneth B.; Otero, Miguel; Olivotto, Eleonora; Borzi, Rosa Maria; Goldring, Mary B.

    2011-01-01

    In the context of OA disease, NF-κB transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-κB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-κB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including β-catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a “loss of maturational arrest” that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-κB signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-κB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-κB activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-κB kinases IKKα or IKKβ or specific activating canonical NF-κB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-κB inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects. PMID:20199390

  4. Apparent speed increases at low luminance

    PubMed Central

    Vaziri-Pashkam, Maryam; Cavanagh, Patrick

    2009-01-01

    To investigate the effect of luminance on apparent speed, subjects adjusted the speed of a low-luminance rotating grating (0.31 cd/m2) to match that of a high-luminance one (1260 cd/m2). Above 4 Hz, subjects overestimated the speed of the low-luminance grating. This overestimation increased as a function of temporal rate and reached 30% around 10 Hz temporal rates. The speed overestimation became significant once the lower luminance was 2.4 log units lower than the high luminance comparison. Next the role of motion smear in speed overestimation was examined. First it was shown that the length of the perceived motion smear increased at low luminances. Second, the length of the visible smear was manipulated by changing the presentation time of the stimuli. Speed overestimation was reduced at shorter presentation times. Third the speed of a blurred stimulus was compared to a stimulus with sharp edges and the blurred stimulus was judged to move faster. These results indicate that the length of motion smear following a target contributes to its perceived speed and that this leads to speed overestimation at low luminance where motion traces lengthen because of increased persistence. PMID:19146275

  5. Targeting fibroblast growth factor receptor signaling in hepatocellular carcinoma.

    PubMed

    Cheng, Ann-Lii; Shen, Ying-Chun; Zhu, Andrew X

    2011-01-01

    Hepatocellular carcinoma (HCC) is the primary type of liver cancer, and both the age-adjusted incidence and mortality of HCC have steadily increased in recent years. Advanced HCC is associated with a very poor survival rate. Despite accumulating data regarding the risk factors for HCC, the mechanisms that contribute to HCC tumorigenesis remain poorly understood. Signaling through the fibroblast growth factor (FGF) family is involved in fibrosis and its progression to cirrhosis of the liver, which is a risk factor for the development of HCC. Furthermore, several alterations in FGF/FGF receptor (FGFR) signaling correlate with the outcomes of HCC patients, suggesting that signaling through this family of proteins contributes to the development or progression of HCC tumors. Currently, there are no established systemic treatments for patients with advanced HCC in whom sorafenib treatment has failed or who were unable to tolerate it. Recently, several multikinase inhibitors that target FGFRs have demonstrated some early evidence of antitumor activity in phase I/II trials. Therefore, this review discusses the molecular implications of FGFR-mediated signaling in HCC and summarizes the clinical evidence for novel FGFR-targeted therapies for HCC currently being studied in clinical trials.

  6. Targeting TRAF3 Downstream Signaling Pathways in B cell Neoplasms

    PubMed Central

    Moore, Carissa R; Edwards, Shanique KE; Xie, Ping

    2015-01-01

    B cell neoplasms comprise >50% of blood cancers. However, many types of B cell malignancies remain incurable. Identification and validation of novel genetic risk factors and oncogenic signaling pathways are imperative for the development of new therapeutic strategies. We and others recently identified TRAF3, a cytoplasmic adaptor protein, as a novel tumor suppressor in B lymphocytes. We found that TRAF3 inactivation results in prolonged survival of mature B cells, which eventually leads to spontaneous development of B lymphomas in mice. Corroborating our findings, TRAF3 deletions and inactivating mutations frequently occur in human B cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma, multiple myeloma, Waldenström’s macroglobulinemia, and Hodgkin lymphoma. In this context, we have been investigating TRAF3 signaling mechanisms in B cells, and are developing new therapeutic strategies to target TRAF3 downstream signaling pathways in B cell neoplasms. Here we discuss our new translational data that demonstrate the therapeutic potential of targeting TRAF3 downstream signaling pathways in B lymphoma and multiple myeloma. PMID:25960828

  7. Labor inhibits placental mechanistic target of rapamycin complex 1 signaling.

    PubMed

    Lager, S; Aye, I L M H; Gaccioli, F; Ramirez, V I; Jansson, T; Powell, T L

    2014-12-01

    Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Placental tissue was collected from healthy, term pregnancies (n = 15 no-labor; n = 12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFĸB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFĸB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

    PubMed Central

    LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

    2014-01-01

    Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

  9. Advanced UXO discrimination: resolving multiple targets and overlapping EMI signals

    NASA Astrophysics Data System (ADS)

    Shubitidze, Fridon; Barrowes, Benjamin E.; Shamatava, Irma; Fernandez, Juan Pablo; Bijamov, Alex; O'Neill, Kevin

    2011-06-01

    In this paper we employ advanced electromagnetic induction models to resolve multiple targets with overlapping EMI signals-i.e. to discriminate objects of interest, such as unexploded ordnance (UXO), from innocuous items. The models include a) a joint diagonalization (JD) technique that takes data from next-generation EMI sensors and uses the eigenvalues of the multistatic response matrix to estimate the number of potential targets, and b) the orthonormalized volume magnetic source (ONVMS) model, a physically complete, fast, and accurate forward model whose representation of a target's intrinsic EMI response is used to extract classification parameters. In the given approach the overall EMI inversion and classification problem proceeds as follows: first, the JD is applied to the data and the number of targets is estimated; once this is known, the ONVMS is combined with an optimization technique to yield the location and orientation of each buried object, as well as the amplitude of its ONVMS. Finally, a total ONVMS is calculated for each object and used as a discriminant to distinguish between UXO and non-UXO items and between different kinds of UXO. We illustrate the applicability of our multi-target analysis technique by using it on several teststand and live-site datasets collected with the TEMTADS sensor array. We end by demonstrating the superior performance of the ONVMS by applying it to multi-target blind-test data compiled at the Aberdeen Proving Ground test-stand facility.

  10. Protein kinase A signaling as an anti-aging target.

    PubMed

    Enns, Linda C; Ladiges, Warren

    2010-07-01

    Protein kinase A (PKA) is a multi-unit protein kinase that mediates signal transduction of G-protein-coupled receptors through its activation by adenyl cyclase (AC)-mediated cAMP. The vital importance of PKA signaling to cellular function is reflected in the widespread expression of PKA subunit genes. As one of its many functions, PKA plays a key role in the regulation of metabolism and triglyceride storage. The PKA pathway has become of great interest to the study of aging, since mutations that cause a reduction in PKA signaling have been shown to extend lifespan in yeast, and to both delay the incidence and severity of age-related disease, and to promote leanness and longevity, in mice. There is increasing interest in the potential for the inhibition or redistribution of adiposity to attenuate aging, since obesity is associated with impaired function of most organ systems, and is a strong risk factor for shortened life span. Its association with coronary heart disease, hypertension, type 2 diabetes, cancer, sleep apnea and osteoarthritis is leading to its accession as a major cause of global ill health. Therefore, gene signaling pathways such as PKA that promote adiposity are potential inhibitory targets for aging intervention. Since numerous plant compounds have been found that both prevent adipogenesis and inhibit PKA signaling, a focused investigation into their effects on biological systems and the corresponding molecular mechanisms would be of high relevance to the discovery of novel and non-toxic compounds that promote healthy aging.

  11. Oct4 was a novel target of Wnt signaling pathway.

    PubMed

    Li, Jun; Li, Jingyi; Chen, Bingbo

    2012-03-01

    The specific expression of Oct4 during early mouse development is required for the correct maintenance of pluripotent cells, and the regulatory control of the Oct4 expression is important. Wnt signaling could have multiple and/or complex effects on embryonic stem (ES) cells characteristics. Elucidation of the molecular mechanisms affecting Wnt signaling in ES cells could provide a better understanding of how these effects occur. The purpose of this study was to determine whether Oct4 was regulated by Wnt signaling in undifferentiated ES cells. Here, we report Oct4 as a novel target of β-catenin-mediated transcription. First, we observe that Wnt signaling pathway is activated in undifferentiated mouse ES cells. In 239T cells, Oct4 promoter was regulated by β-catenin. Through promoter mapping and chromatin immuno-precipitation assays, we found that Oct4 is a direct target of β-catenin/TCF-mediated transcription and the binding site at -875/-881 of Oct4 promoter is critical for b-catenin/TCF-dependent expression regulation. We further detect the expression of Oct4 in treatment with glycogen syntheses kinase (GSK)-3-specific inhibitor in mouse ES cells and HepG2 cells. We found that GSK-3-specific inhibitor can maintain the expression of Oct4 in ES cells and can enhance the expression of Oct4 in HepG2 cells. Our results suggest that Oct4 might be a novel target of β-catenin/TCF-mediated downstream gene in Wnt-activated cells.

  12. Involvement and targeted intervention of dysregulated Hedgehog signaling in osteosarcoma.

    PubMed

    Lo, Winnie W; Wunder, Jay S; Dickson, Brendan C; Campbell, Veronica; McGovern, Karen; Alman, Benjamin A; Andrulis, Irene L

    2014-02-15

    During development, the Hedgehog pathway plays important roles regulating the proliferation and differentiation of chondrocytes, providing a template for growing bone. In this study, the authors investigated the components of dysregulated Hedgehog signaling as potential therapeutic targets for osteosarcoma. Small-molecule agonists and antagonists that modulate the Hedgehog pathway at different levels were used to investigate the mechanisms of dysregulation and the efficacy of Hedgehog blockade in osteosarcoma cell lines. The inhibitory effect of a small-molecule Smoothened (SMO) antagonist, IPI-926 (saridegib), also was examined in patient-derived xenograft models. An inverse correlation was identified in osteosarcoma cell lines between endogenous glioma-associated oncogene 2 (GLI2) levels and Hedgehog pathway induction levels. Cells with high levels of GLI2 were sensitive to GLI inhibition, but not SMO inhibition, suggesting that GLI2 overexpression may be a mechanism of ligand-independent activation. In contrast, cells that expressed high levels of the Hedgehog ligand gene Indian hedgehog (IHH) and the target genes patched 1 (PTCH1) and GLI1 were sensitive to modulation of both SMO and GLI, suggesting ligand-dependent activation. In 2 xenograft models, active autocrine and paracrine, ligand-dependent Hedgehog signaling was identified. IPI-926 inhibited the Hedgehog signaling interactions between the tumor and the stroma and demonstrated antitumor efficacy in 1 of 2 ligand-dependent models. The current results indicate that both ligand-dependent and ligand-independent Hedgehog dysregulation may be involved in osteosarcoma. It is the first report to demonstrate Hedgehog signaling crosstalk between the tumor and the stroma in osteosarcoma. The inhibitory effect of IPI-926 warrants additional research and raises the possibility of using Hedgehog pathway inhibitors as targeted therapeutics to improve treatment for osteosarcoma. © 2013 American Cancer Society.

  13. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression

    PubMed Central

    Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

    2015-01-01

    Purpose Extensive correlative studies in human prostate cancer (PCa) as well as studies in vitro and in mouse models indicate that FGF receptor (FGFR) signaling plays an important role in PCa progression. In this study, we employed a probe compound for an FGFR inhibitor which potently inhibits FGFR1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine if targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Experimental Design Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in PCa cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. Results AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nM, which is an achievable in vivo concentration. These results in marked inhibition of ERK phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all PCa cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Conclusions Targeting FGFR signaling is a promising new approach to treating aggressive PCa. PMID:22573348

  14. The Most Luminous Galaxies Found by WISE

    NASA Astrophysics Data System (ADS)

    Eisenhardt, Peter

    2012-08-01

    We have used photometry from NASA's Wide-field Infrared Survey Explorer (WISE) to select an all-sky sample of objects which are extremely luminous. Herschel far-IR follow-up observations of these sources are underway. We find most are brighter than 10 trillion solar luminosities, and about 10% exceed 100 trillion solar luminosities. We request one night with LRIS-ADC to obtain redshifts for 20 candidate WISE Ultra-Luminous IR Galaxies which are targets of the Herschel program. The redshifts are essential to one of the two primary science objectives for WISE: to identify the most luminous galaxies in the Universe.

  15. Targeting signals and subunit interactions in coated vesicle adaptor complexes

    PubMed Central

    1995-01-01

    There are two clathrin-coated vesicle adaptor complexes in the cell, one associated with the plasma membrane and one associated with the TGN. The subunit composition of the plasma membrane adaptor complex is alpha-adaptin, beta-adaptin, AP50, and AP17; while that of the TGN adaptor complex is gamma-adaptin, beta'-adaptin, AP47, and AP19. To search for adaptor targeting signals, we have constructed chimeras between alpha-adaptin and gamma-adaptin within their NH2-terminal domains. We have identified stretches of sequence in the two proteins between amino acids approximately 130 and 330-350 that are essential for targeting. Immunoprecipitation reveals that this region determines whether a construct coassemblies with AP50 and AP17, or with AP47 and AP19. These observations suggest that these other subunits may play an important role in targeting. In contrast, beta- and beta'-adaptins are clearly not involved in this event. Chimeras between the alpha- and gamma-adaptin COOH-terminal domains reveal the presence of a second targeting signal. We have further investigated the interactions between the adaptor subunits using the yeast two-hybrid system. Interactions can be detected between the beta/beta'-adaptins and the alpha/gamma- adaptins, between the beta/beta'-adaptins and the AP50/AP47 subunits, between alpha-adaptin and AP17, and between gamma-adaptin and AP19. These results indicate that the adaptor subunits act in concert to target the complex to the appropriate membrane. PMID:7593184

  16. Monoubiquitination joins polyubiquitination as an esteemed proteasomal targeting signal.

    PubMed

    Livneh, Ido; Kravtsova-Ivantsiv, Yelena; Braten, Ori; Kwon, Yong Tae; Ciechanover, Aaron

    2017-06-01

    A polyubiquitin chain attached covalently to the target substrate has been recognized for long as the "canonical" proteasomal degradation signal. However, several proteins have been shown to be targeted for degradation following monoubiquitination, indicating that the proteasome can recognize signals other than a ubiquitin polymer. A comprehensive screen aiming at determining the extent of this mode of recognition revealed that ∼40% of mammalian and ∼20% of yeast proteins are degraded following monoubiquitination. Characterization of these proteins showed that on average, the monoubiquitinated proteins are smaller than the polyubiquitinated ones, and in humans, are less disordered. Further, proteins degraded by the two different modes belong to distinct functional groups. These findings along with detailed structural analysis of the proteasome, its ubiquitin receptors and deubiquitinating enzymes, suggest that the ubiquitin signal - its formation, recognition, editing, and removal - is far more complex and diverse than originally assumed. Also see the video abstract here: https://youtu.be/QKpN9c6Rg20. © 2017 WILEY Periodicals, Inc.

  17. Bacterial type I signal peptidases as antibiotic targets.

    PubMed

    Smitha Rao, C V; Anné, Jozef

    2011-11-01

    Despite an alarming increase in morbidity and mortality caused by multidrug-resistant bacteria, the number of antibiotics available to efficiently combat them is dwindling. Consequently, there is a pressing need for new drugs, preferably with novel modes of action to avert the problem of cross-resistance. Several new targets have been proposed, including proteins essential in the protein secretion pathway such as the type I signal peptidase (SPase), indispensable for the release of the signal peptide during secretion of Sec- and Tat-dependent proteins. The type I SPase is considered to be an attractive target because it is essential, substantially different from the eukaryotic counterpart, and its active site is located at the outer leaflet of the cytoplasmic membrane, permitting relatively easy access to potential inhibitors. A few SPase inhibitors have already been identified, but their suitability as drugs is yet to be confirmed. An overview is given on the currently known SPase inhibitors, how they can give valuable information on the structural, biochemical and target validation aspects of the SPases, the approaches to identify them, and their future potential as drugs.

  18. Intracellular signals of lung cancer cells as possible therapeutic targets

    PubMed Central

    Tanaka, Kiyomichi; Kumano, Keiki; Ueno, Hiroo

    2015-01-01

    In recent years, several molecularly targeted therapies have been developed as part of lung cancer treatment; they have produced dramatically good results. However, among the many oncogenes that have been identified to be involved in the development of lung cancers, a number of oncogenes are not covered by these advanced therapies. For the treatment of lung cancers, which is a group of heterogeneous diseases, persistent effort in developing individual therapies based on the respective causal genes is important. In addition, for the development of a novel therapy, identification of the lung epithelial stem cells and the origin cells of lung cancer, and understanding about candidate cancer stem cells in lung cancer tissues, their intracellular signaling pathways, and the mechanism of dysregulation of the pathways in cancer cells are extremely important. However, the development of drug resistance by cancer cells, despite the use of molecularly targeted drugs for the causal genes, thus obstructing treatment, is a well-known phenomenon. In this article, we discuss major causal genes of lung cancers and intracellular signaling pathways involving those genes, and review studies on origin and stem cells of lung cancers, as well as the possibility of developing molecularly targeted therapies based on these studies. PMID:25707772

  19. Transsynaptic Teneurin Signaling in Neuromuscular Synapse Organization and Target Choice

    PubMed Central

    Mosca, Timothy J.; Hong, Weizhe; Dani, Vardhan S.; Favaloro, Vincenzo; Luo, Liqun

    2012-01-01

    Synapse assembly requires transsynaptic signals between the pre- and postsynapse1, but the understanding of essential organizational molecules remains incomplete2. Teneurins are conserved, EGF-repeat containing transmembrane proteins with large extracellular domains3. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic while Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization transsynaptically and cell-autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with α-spectrin. Genetic analyses of teneurin and neuroligin reveal their differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates specific motoneuron-muscle target selection. Our study identifies the Teneurins as a key bi-directional transsynaptic signal in general synapse organization, and demonstrates that such a molecule can also regulate target selection. PMID:22426000

  20. SIFTER: Signal inversion for target extraction and registration

    NASA Astrophysics Data System (ADS)

    Fridman, Sergey V.; Nickisch, L. J.

    2004-02-01

    Signal inversion for target extraction and registration (SIFTER) is a technique for enhanced radar target detection and coordinate registration (CR). The technique is currently being developed for over-the-horizon radar (OTHR). The power received by a radar as a function of radar coordinates and Doppler shift may be expressed as an integral operator applied to the field of backscatter cross section (FBC) per unit area of the illuminated region. The FBC is a function of the geographic position and the velocity vector of the scattering point. The kernel of the integral operator is treated as a known function that is determined by the model of the propagation channel, antenna patterns, and the radar signal processing parameters. The relationship between the FBC and the received power is treated as an integral equation to be resolved with respect to the FBC. This inversion is accomplished using techniques for ill-posed problems. The obtained FBC is subsequently analyzed for peaks. The location of a peak provides an estimate for actual ground coordinates and velocity vector of the target. Gain in sensitivity and CR is achieved by introducing a continuity equation, which evolves the FBC between radar revisit cycles. The evolved FBC is corrected using data from each subsequent revisit. Two versions of the SIFTER algorithm are presented. One is based on Tikhonov's method, and the other is based on the Kalman filter method. SIFTER concepts and performance are demonstrated using modeled data.

  1. Small molecules from natural sources, targeting signaling pathways in diabetes.

    PubMed

    Liu, Qiong; Chen, Lili; Hu, Lihong; Guo, Yuewei; Shen, Xu

    2010-01-01

    Diabetes mellitus (DM) is a metabolic disease caused by genetic or environmental factors. It has rendered a severe menace to the middle-aged and elderly, while there is still lack of efficient drugs against this disease. The pathogenic mechanism for DM is complex, and the complicated networks related to this disease involve distinct signaling pathways. Currently, discovery of potential modulators targeting these pathways has become a potent approach for anti-diabetic drug lead compound development. Compared with synthetic compounds, natural products provide inherent larger-scale structural diversity and have been the major resource of bioactive agents for new drug discovery. To date, more and more active components from plants or marine organisms have been reported to regulate diabetic pathophysiological signaling pathways and exhibit anti-diabetic activity. This review will summarize the regulation of natural small molecules on some key signaling pathways involved in DM. These pathways include insulin signaling pathway, carbohydrate metabolism pathway, the pathways involving insulin secretion and PPAR regulation, endoplasmic reticulum (ER) stress and inflammation related pathways and chromatin modification pathways. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. Targeting MAPK Signaling in Age-Related Macular Degeneration

    PubMed Central

    Kyosseva, Svetlana V.

    2016-01-01

    Age-related macular degeneration (AMD) is a major cause of irreversible blindness affecting elderly people in the world. AMD is a complex multifactorial disease associated with demographic, genetics, and environmental risk factors. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in the pathogenesis of AMD. The mitogen-activated protein kinase (MAPK) signaling pathways are activated by diverse extracellular stimuli, including growth factors, mitogens, hormones, cytokines, and different cellular stressors such as oxidative stress. They regulate cell proliferation, differentiation, survival, and apoptosis. This review addresses the novel findings from human and animal studies on the relationship of MAPK signaling with AMD. The use of specific MAPK inhibitors may represent a potential therapeutic target for the treatment of this debilitating eye disease. PMID:27385915

  3. FGFR Signaling as a Target for Lung Cancer Therapy.

    PubMed

    Desai, Arpita; Adjei, Alex A

    2016-01-01

    Lung cancer is the leading cause of cancer-related death in developed countries. Recently, molecular targeted therapies have shown promising results in the management of lung cancer. These therapies require a clear understanding of the relevant pathways that drive carcinogenesis and maintenance of the malignant phenotype. The fibroblast growth factor receptor (FGFR) signaling axis is one such pathway that plays a central role in normal cellular function. Alterations in this pathway have been found in many cancers. In this review article, we focus on the role of this pathway in lung cancer. We present the molecular structure of FGFR, the interaction of the receptor with its ligands (the fibroblast growth factors), its downstream signaling, and aberrations in the FGFR pathway. We also discuss clinical trials involving selective and multikinase FGFR inhibitors in lung cancer treatment.

  4. Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals.

    PubMed

    Bagalkot, Vaishali; Badgeley, Marcus A; Kampfrath, Thomas; Deiuliis, Jeffrey A; Rajagopalan, Sanjay; Maiseyeu, Andrei

    2015-11-10

    Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid-latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100nm nanoparticles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and "eat-me" phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable Li

  5. Hybrid nanoparticles improve targeting to inflammatory macrophages through phagocytic signals

    PubMed Central

    Bagalkot, Vaishali; Badgeley, Marcus A.; Kampfrath, Thomas; Deiuliis, Jeffrey A.; Rajagopalan, Sanjay; Maiseyeu, Andrei

    2016-01-01

    Macrophages are innate immune cells with great phenotypic plasticity, which allows them to regulate an array of physiological processes such as host defense, tissue repair, and lipid/lipoprotein metabolism. In this proof-of-principle study, we report that macrophages of the M1 inflammatory phenotype can be selectively targeted by model hybrid lipid–latex (LiLa) nanoparticles bearing phagocytic signals. We demonstrate a simple and robust route to fabricate nanoparticles and then show their efficacy through imaging and drug delivery in inflammatory disease models of atherosclerosis and obesity. Self-assembled LiLa nanoparticles can be modified with a variety of hydrophobic entities such as drug cargos, signaling lipids, and imaging reporters resulting in sub-100 nm nano-particles with low polydispersities. The optimized theranostic LiLa formulation with gadolinium, fluorescein and “eat-me” phagocytic signals (Gd-FITC-LiLa) a) demonstrates high relaxivity that improves magnetic resonance imaging (MRI) sensitivity, b) encapsulates hydrophobic drugs at up to 60% by weight, and c) selectively targets inflammatory M1 macrophages concomitant with controlled release of the payload of anti-inflammatory drug. The mechanism and kinetics of the payload discharge appeared to be phospholipase A2 activity-dependent, as determined by means of intracellular Förster resonance energy transfer (FRET). In vivo, LiLa targets M1 macrophages in a mouse model of atherosclerosis, allowing noninvasive imaging of atherosclerotic plaque by MRI. In the context of obesity, LiLa particles were selectively deposited to M1 macrophages within inflamed adipose tissue, as demonstrated by single-photon intravital imaging in mice. Collectively, our results suggest that phagocytic signals can preferentially target inflammatory macrophages in experimental models of atherosclerosis and obesity, thus opening the possibility of future clinical applications that diagnose/treat these conditions. Tunable

  6. Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment

    PubMed Central

    Zhong, Li

    2017-01-01

    The Wnt, Hedgehog, and Notch pathways are inherent signaling pathways in normal embryogenesis, development, and hemostasis. However, dysfunctions of these pathways are evident in multiple tumor types and malignancies. Specifically, aberrant activation of these pathways is implicated in modulation of cancer stem cells (CSCs), a small subset of cancer cells capable of self-renewal and differentiation into heterogeneous tumor cells. The CSCs are accountable for tumor initiation, growth, and recurrence. In this review, we focus on roles of Wnt, Hedgehog, and Notch pathways in CSCs' stemness and functions and summarize therapeutic studies targeting these pathways to eliminate CSCs and improve overall cancer treatment outcomes. PMID:28356914

  7. Advances in targeting cell surface signalling molecules for immune modulation

    PubMed Central

    Yao, Sheng; Zhu, Yuwen; Chen, Lieping

    2013-01-01

    The past decade has witnessed a surge in the development of immunomodulatory approaches to combat a broad range of human diseases, including cancer, viral infections, autoimmunity and inflammation as well as in the prevention of transplant rejection. Immunomodulatory approaches mostly involve the use of monoclonal antibodies or recombinant fusion proteins that target cell surface signalling molecules on immune cells to drive immune responses towards the desired direction. Advances in our understanding of the human immune system, along with valuable lessons learned from the first generation of therapeutic biologics, are aiding the design of the next generation of immunomodulatory biologics with better therapeutic efficacy, minimized adverse effects and long-lasting clinical benefit. The recent encouraging results from antibodies targeting programmed cell death protein 1 (PD1) and B7 homolog 1 (B7H1; also known as PDL1) for the treatment of various advanced human cancers show that immunomodulatory therapy has come of age. PMID:23370250

  8. Therapeutic Implications of Targeting AKT Signaling in Melanoma

    PubMed Central

    Madhunapantula, SubbaRao V.; Robertson, Gavin P.

    2011-01-01

    Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted. PMID:21461351

  9. Targeting cancer by binding iron: Dissecting cellular signaling pathways

    PubMed Central

    Lui, Goldie Y.L.; Kovacevic, Zaklina; Richardson, Vera; Merlot, Angelica M.; Kalinowski, Danuta S.; Richardson, Des R.

    2015-01-01

    Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti-proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-β, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer. PMID:26125440

  10. How different are luminal A and basal breast cancers?

    PubMed

    Bertucci, François; Finetti, Pascal; Cervera, Nathalie; Charafe-Jauffret, Emmanuelle; Buttarelli, Max; Jacquemier, Jocelyne; Chaffanet, Max; Maraninchi, Dominique; Viens, Patrice; Birnbaum, Daniel

    2009-03-15

    Heterogeneity of breast cancer makes its evolution difficult to predict, and its treatment far from being optimal. At least 5 main molecular subtypes exist. Two major subtypes are luminal A and basal subtypes, which have opposite features, notably survival. To characterize these 2 subtypes better, with the hope of better understanding their different biology and clinical outcome, we have profiled a series of 138 tumours (80 luminal A and 58 basal) using Affymetrix whole-genome DNA microarrays. We have identified 5,621 probe sets as differentially expressed between the 2 subtypes in our series. These differences were validated in 6 independent public series (more than 600 tumours) profiled using different DNA microarrays platforms. Analysis of functions and pathways related to these probe sets, and the extent of the observed differences, confirmed that the 2 subtypes represent very distinct entities. Genes associated with proliferation, cell cycle, cell motility, angiogenesis, and NFkB signalling were overexpressed in basal tumours. Genes involved in fatty acid metabolism, TGFB signalling, and oestrogen receptor (ER) signalling were overexpressed in luminal A samples. Half of the genes overexpressed in luminal tumours contained ER-binding sites. The number of differentially expressed genes was as high as the set of genes discriminating 2 cancers of different anatomical origin (breast and colon) or discriminating acute myeloid and lymphoid leukaemia. We provide a comprehensive list of genes/pathways that define potential diagnostic, prognostic and therapeutic targets for these 2 subtypes, which should be treated differently given the profound differences observed at the molecular level.

  11. Establishment of a Three-dimensional Floating Cell Culture System for Screening Drugs Targeting KRAS-mediated Signaling Molecules.

    PubMed

    Tsunoda, Toshiyuki; Ishikura, Shuhei; Doi, Keiko; Iwaihara, Yuri; Hidesima, Hiromasa; Luo, Hao; Hirose, Yumiko; Shirasawa, Senji

    2015-08-01

    Oncogenic mutations in the KRAS gene are critically involved in many human tumors but drugs targeting oncogenic KRAS have not yet been clinically developed. Herein, we established a three-dimensional floating (3DF) culture system for screening drugs that target KRAS-mediated signaling molecules. HKe3 cells, derived from colorectal cancer HCT116 cells and disrupted at mutated (mt) KRAS gene, were infected with a retrovirus expressing wild-type (wt) KRAS or mtKRAS to establish HKe3-derived cells expressing wtKRAS or mtKRAS. Established cells were cultured in 96-well plates with an ultra-low attachment surface and round bottom for 3DF culture. HKe3-wtKRAS and HKe3-mtKRAS cells in 3DF culture rapidly assembled into respective single spherical structures (spheroids). Furthermore, mtKRAS but not wtKRAS expression inhibited luminal apoptosis in spheroids indicating that the 3DF culture was compatible with the 3D matrigel culture. This 3DF culture system could be useful for screening drugs that target KRAS-mediated signaling molecules. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  12. Targeting the Mitotic Catastrophe Signaling Pathway in Cancer

    PubMed Central

    Mc Gee, Margaret M.

    2015-01-01

    Mitotic catastrophe, as defined in 2012 by the International Nomenclature Committee on Cell Death, is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. Thus, failed mitotic catastrophe can promote the unrestrained growth of defective cells, thereby representing a major gateway to tumour development. Furthermore, the activation of mitotic catastrophe offers significant therapeutic advantage which has been exploited in the action of conventional and targeted anticancer agents. Yet, despite its importance in tumour prevention and treatment, the molecular mechanism of mitotic catastrophe is not well understood. A better understanding of the signals that determine cell fate following failed or defective mitosis will reveal new opportunities to selectively target and enhance the programme for therapeutic benefit and reveal biomarkers to predict patient response. This review is focused on the molecular mechanism of mitotic catastrophe induction and signalling and highlights current strategies to exploit the process in cancer therapy. PMID:26491220

  13. Glycation & the RAGE axis: targeting signal transduction through DIAPH1.

    PubMed

    Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie

    2017-02-01

    The consequences of chronic disease are vast and unremitting; hence, understanding the pathogenic mechanisms mediating such disorders holds promise to identify therapeutics and diminish the consequences. The ligands of the receptor for advanced glycation end products (RAGE) accumulate in chronic diseases, particularly those characterized by inflammation and metabolic dysfunction. Although first discovered and reported as a receptor for advanced glycation end products (AGEs), the expansion of the repertoire of RAGE ligands implicates the receptor in diverse milieus, such as autoimmunity, chronic inflammation, obesity, diabetes, and neurodegeneration. Areas covered: This review summarizes current knowledge regarding the ligand families of RAGE and data from human subjects and animal models on the role of the RAGE axis in chronic diseases. The recent discovery that the cytoplasmic domain of RAGE binds to the formin homology 1 (FH1) domain, DIAPH1, and that this interaction is essential for RAGE ligand-stimulated signal transduction, is discussed. Finally, we review therapeutic opportunities targeting the RAGE axis as a means to mitigate chronic diseases. Expert commentary: With the aging of the population and the epidemic of cardiometabolic disease, therapeutic strategies to target molecular pathways that contribute to the sequelae of these chronic diseases are urgently needed. In this review, we propose that the ligand/RAGE axis and its signaling nexus is a key factor in the pathogenesis of chronic disease and that therapeutic interruption of this pathway may improve quality and duration of life.

  14. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer.

    PubMed

    Masuda, Mari; Sawa, Masaaki; Yamada, Tesshi

    2015-12-01

    The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development.

  15. Oleuropein Mediated Targeting of Signaling Network in Cancer.

    PubMed

    Fayyaz, Sundas; Aydin, Tuba; Cakir, Ahmet; Gasparri, Maria Luisa; Panici, Pierluigi Benedetti; Farooqi, Ammad Ahmad

    2016-01-01

    Cancer is a multifaceted and genomically complex disease. Rapidly accumulating preclinical and clinical studies are emphasizing on wide ranging molecular mechanisms that underpin cancer development, progression and metastasis. Intratumor heterogeneity, loss of apoptosis, rapidly developing resistance against molecular therapeutics and off-target effects are some of the deeply studied resistance mechanisms. Data obtained through high-throughput technologies has considerably enhanced our understanding of the intracellular signaling cascades frequently dysregulated spatio-temporally. There is an ever-expanding list of synthetic and natural agents reported to activate tumor suppressor genes and inhibit oncogenes in cancer cells. Markedly reduced tumor growth has also been documented in xenografted mice administered with phytochemicals. Oleuropein is a bioactive ingredient isolated from various sources and there is evidence of complete regression of tumors in 9- 12 days in mice orally administered with Oleuropein. In this review we summarize recent developments in use of Oleuropein as an anticancer agent. Extraction and isolation of Oleuropein and how it modulates intracellular signaling network to induce apoptosis in cancer cells. Human epidermal growth factor receptor 2 (HER2) frequently overexpressed in breast cancer cells is inhibited by Oleuropein. Interestingly, trastuzumab efficacy was notably enhanced in Oleuropein treated breast cancer cells. There is still insufficient information related to Oleuropein mediated microRNA regulation in cancer cells. We still do not have information about regulation of different signaling cascades by Oleuropein which are deregulated in cancer. Future studies must converge on a deeper analysis of target molecular network of Oleuropein and its efficacy as a tumor growth inhibitor in xenografted mice.

  16. Fisetin regulates obesity by targeting mTORC1 signaling.

    PubMed

    Jung, Chang Hwa; Kim, Heemun; Ahn, Jiyun; Jeon, Tae-Il; Lee, Dae-Hee; Ha, Tae-Youl

    2013-08-01

    Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties. In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis. To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes. Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells. The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner. Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity. Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR. The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling. Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue. We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue. Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice. Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Mammalian target of rapamycin signaling in diabetic cardiovascular disease.

    PubMed

    Chong, Zhao Zhong; Maiese, Kenneth

    2012-07-16

    Diabetes mellitus currently affects more than 170 million individuals worldwide and is expected to afflict another 200 million individuals in the next 30 years. Complications of diabetes as a result of oxidant stress affect multiple systems throughout the body, but involvement of the cardiovascular system may be one of the most severe in light of the impact upon cardiac and vascular function that can result in rapid morbidity and mortality for individuals. Given these concerns, the signaling pathways of the mammalian target of rapamycin (mTOR) offer exciting prospects for the development of novel therapies for the cardiovascular complications of diabetes. In the cardiovascular and metabolic systems, mTOR and its multi-protein complexes of TORC1 and TORC2 regulate insulin release and signaling, endothelial cell survival and growth, cardiomyocyte proliferation, resistance to β-cell injury, and cell longevity. Yet, mTOR can, at times, alter insulin signaling and lead to insulin resistance in the cardiovascular system during diabetes mellitus. It is therefore vital to understand the complex relationship mTOR and its downstream pathways hold during metabolic disease in order to develop novel strategies for the complications of diabetes mellitus in the cardiovascular system.

  18. Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling

    PubMed Central

    Touré, Fatouma; Chitayat, Seth; Pei, Renjun; Song, Fei; Li, Qing; Zhang, Jinghua; Rosario, Rosa; Ramasamy, Ravichandran; Chazin, Walter J.

    2012-01-01

    The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA–RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA. PMID:23209312

  19. Honokiol inhibits melanoma stem cells by targeting notch signaling.

    PubMed

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A; Anant, Shrikant; Mammen, Joshua M V

    2015-12-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling.

  20. Honokiol Inhibits Melanoma Stem Cells by Targeting Notch Signaling

    PubMed Central

    Kaushik, Gaurav; Venugopal, Anand; Ramamoorthy, Prabhu; Standing, David; Subramaniam, Dharmalingam; Umar, Shahid; Jensen, Roy A.; Anant, Shrikant; Mammen, Joshua M.V.

    2016-01-01

    Melanoma is an aggressive disease with limited therapeutic options. Here, we determined the effects of honokiol (HNK), a biphenolic natural compound on melanoma cells and stemness. HNK significantly inhibited melanoma cell proliferation, viability, clonogenicity and induced autophagy. In addition, HNK significantly inhibited melanosphere formation in a dose dependent manner. Western blot analyses also demonstrated reduction in stem cell markers CD271, CD166, Jarid1b, and ABCB5. We next examined the effect of HNK on Notch signaling, a pathway involved in stem cell self-renewal. Four different Notch receptors exist in cells, which when cleaved by a series of enzymatic reactions catalyzed by Tumor Necrosis Factor-α-Converting Enzyme (TACE) and γ-secretase protein complex, results in the release of the Notch intracellular domain (NICD), which then translocates to the nucleus and induces target gene expression. Western blot analyses demonstrated that in HNK treated cells there is a significant reduction in the expression of cleaved Notch-2. In addition, there was a reduction in the expression of downstream target proteins, Hes-1 and cyclin D1. Moreover, HNK treatment suppressed the expression of TACE and γ-secretase complex proteins in melanoma cells. To confirm that suppression of Notch-2 activation is critical for HNK activity, we overexpressed NICD1, NICD2, and performed HNK treatment. NICD2, but not NICD1, partially restored the expression of Hes-1 and cyclin D1, and increased melanosphere formation. Taken together, these data suggest that HNK is a potent inhibitor of melanoma cells, in part, through the targeting of melanoma stem cells by suppressing Notch-2 signaling. PMID:25491779

  1. FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells.

    PubMed

    Katoh, Yuriko; Katoh, Masaru

    2006-03-01

    WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine.

  2. Targeted inhibition of Src kinase signaling attenuates pancreatic tumorigenesis

    PubMed Central

    Nagaraj, Nagathihalli S.; Smith, J. Joshua; Revetta, Frank; Washington, M. Kay; Merchant, Nipun B.

    2012-01-01

    Elevated Src expression correlates with malignant potential and metastatic disease in many tumors including pancreas cancer. We sought to characterize the molecular effects of Src kinase inhibition with dasatinib (BMS-354825) a novel, multi-targeted kinase inhibitor that targets Src family kinases, in pancreas ductal adenocarcinoma (PDA). We identified sensitive and resistant PDA cell lines to dasatinib treatment and tested the molecular effects of Src inhibition in vitro and in vivo. We show for the first time that cellular localization of Src expression impacts survival in patients with PDA. Pancreas tumors with increased membranous expression of Src result in decreased survival compared with tumors that have increased cytoplasmic Src expression. Src kinase inhibition with dasatinib markedly inhibits cell proliferation, migration, invasion, cell cycle progression and anchorage independent growth and stimulates apoptosis. This is accompanied by decreased phosphorylation of Src, FAK, paxillin, AKT, STAT3, ERK, JNK and MAPK, as well as decreased cyclinD1 expression in a time and concentration-dependent manner. Furthermore, siRNA to Src results in significant decrease in cell proliferation, invasion and migration of pancreas cancer cells. Dasatinib treatment also inhibits in vivo pancreas tumor growth. Mechanisms of resistance to Src inhibition appear to be related to a lack of inhibition of STAT3 and MAPK signaling. These results establish a mechanistic rationale for Src inhibition with dasatinib as a therapeutic target in the treatment of pancreas cancer and identify potential biomarkers of resistance to Src inhibition. PMID:20682659

  3. Structure, Regulation, Signaling, and Targeting of Abl Kinases in Cancer

    PubMed Central

    2012-01-01

    Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumorigenesis. Over the past decades, biochemical and functional studies on the molecular mechanisms of Abl regulation have gone hand in hand with progression of our structural understanding of autoinhibited and active Abl conformations. In parallel, Abl oncoproteins have become prime molecular targets for cancer therapy, using adenosine triphosphate (ATP)–competitive kinase inhibitors, such as imatinib. Abl-targeting drugs serve as a paradigm for our understanding of kinase inhibitor action, specificity, and resistance development. In this review article, I will review the molecular mechanisms that are responsible for the regulation of Abl kinase activity and how oncogenic Abl fusions signal. Furthermore, past and ongoing efforts to target Abl oncoproteins using ATP-competitive and allosteric inhibitors, as well as future possibilities using combination therapy, will be discussed. PMID:23226581

  4. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia

    PubMed Central

    McCarthy, Cathal; Kenny, Louise C.

    2016-01-01

    Aberrant placentation generating placental oxidative stress is proposed to play a critical role in the pathophysiology of preeclampsia. Unfortunately, therapeutic trials of antioxidants have been uniformly disappointing. There is provisional evidence implicating mitochondrial dysfunction as a source of oxidative stress in preeclampsia. Here we provide evidence that mitochondrial reactive oxygen species mediates endothelial dysfunction and establish that directly targeting mitochondrial scavenging may provide a protective role. Human umbilical vein endothelial cells exposed to 3% plasma from women with pregnancies complicated by preeclampsia resulted in a significant decrease in mitochondrial function with a subsequent significant increase in mitochondrial superoxide generation compared to cells exposed to plasma from women with uncomplicated pregnancies. Real-time PCR analysis showed increased expression of inflammatory markers TNF-α, TLR-9 and ICAM-1 respectively in endothelial cells treated with preeclampsia plasma. MitoTempo is a mitochondrial-targeted antioxidant, pre-treatment of cells with MitoTempo protected against hydrogen peroxide-induced cell death. Furthermore MitoTempo significantly reduced mitochondrial superoxide production in cells exposed to preeclampsia plasma by normalising mitochondrial metabolism. MitoTempo significantly altered the inflammatory profile of plasma treated cells. These novel data support a functional role for mitochondrial redox signaling in modulating the pathogenesis of preeclampsia and identifies mitochondrial-targeted antioxidants as potential therapeutic candidates. PMID:27604418

  5. Regulation of neuronal PKA signaling through AKAP targeting dynamics.

    PubMed

    Dell'Acqua, Mark L; Smith, Karen E; Gorski, Jessica A; Horne, Eric A; Gibson, Emily S; Gomez, Lisa L

    2006-07-01

    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

  6. Transcription factors and target genes of pre-TCR signaling.

    PubMed

    López-Rodríguez, Cristina; Aramburu, Jose; Berga-Bolaños, Rosa

    2015-06-01

    Almost 30 years ago pioneering work by the laboratories of Harald von Boehmer and Susumo Tonegawa provided the first indications that developing thymocytes could assemble a functional TCRβ chain-containing receptor complex, the pre-TCR, before TCRα expression. The discovery and study of the pre-TCR complex revealed paradigms of signaling pathways in control of cell survival and proliferation, and culminated in the recognition of the multifunctional nature of this receptor. As a receptor integrated in a dynamic developmental process, the pre-TCR must be viewed not only in the light of the biological outcomes it promotes, but also in context with those molecular processes that drive its expression in thymocytes. This review article focuses on transcription factors and target genes activated by the pre-TCR to drive its different outcomes.

  7. Endocannabinoid signaling and energy metabolism: a target for dietary intervention.

    PubMed

    Kim, Jeffrey; Li, Yong; Watkins, Bruce A

    2011-06-01

    The endocannabinoid (EC) signaling (ECS) system involves the activation of receptors targeted by endogenously produced ligands called endocannabinoids that trigger specific physiologic events in various organs and tissues throughout the body. ECs are lipid mediators that bind to specific receptors and elicit cell signaling. The focus of this review is to discuss the responses that direct pathways of systemic energy metabolism. Recent findings have indicated that an imbalance of the ECS contributes to visceral fat accumulation and disrupts energy homeostasis, which are characteristics of the metabolic syndrome. Constant activation of ECS has been linked to metabolic processes that are associated with the hypothalamus and peripheral tissues of obese patients. In contrast, inhibition of ECS results in weight loss in animal and human subjects. Despite these findings, the mechanism involved in the dysregulation of ECS is unclear. Interestingly, the level of endogenous ligands, derived from arachidonic acid, can be directly manipulated by nutrient intervention, in that a diet rich in long-chain ω-3 polyunsaturated fatty acids will decrease the production of ligands to modulate the activation of target receptors. In contrast, a diet that is high in ω-6 polyunsaturated fatty acids will cause an increase in ECS activation and stimulate tissue specific activities that decrease insulin sensitivity in muscle and promote fat accumulation in the adipose tissue. The purpose of this review is to explain the components of ECS, its role in adipose and muscle energy metabolism, and how nutritional approaches with dietary ω-3 polyunsaturated fatty acids may reverse the dysregulation of this system to improve insulin sensitivity and control body fat.

  8. ATP-independent luminal oscillations and release of Ca2+ and H+ from mast cell secretory granules: implications for signal transduction.

    PubMed

    Quesada, Ivan; Chin, Wei-Chun; Verdugo, Pedro

    2003-08-01

    InsP(3) is an important link in the intracellular information network. Previous observations show that activation of InsP(3)-receptor channels on the granular membrane can turn secretory granules into Ca(2+) oscillators that deliver periodic trains of Ca(2+) release to the cytosol (T. Nguyen, W. C. Chin, and P. Verdugo, 1998, Nature, 395:908-912; I. Quesada, W. C. Chin, J. Steed, P. Campos-Bedolla, and P. Verdugo, 2001, BIOPHYS: J. 80:2133-2139). Here we show that InsP(3) can also turn mast cell granules into proton oscillators. InsP(3)-induced intralumenal [H(+)] oscillations are ATP-independent, result from H(+)/K(+) exchange in the heparin matrix, and produce perigranular pH oscillations with the same frequency. These perigranular pH oscillations are in-phase with intralumenal [H(+)] but out-of-phase with the corresponding perigranular [Ca(2+)] oscillations. The low pH of the secretory compartment has critical implications in a broad range of intracellular processes. However, the association of proton release with InsP(3)-induced Ca(2+) signals, their similar periodic nature, and the sensitivity of important exocytic proteins to the joint action of Ca(2+) and pH strongly suggests that granules might encode a combined Ca(2+)/H(+) intracellular signal. A H(+)/Ca(2+) signal could significantly increase the specificity of the information sent by the granule by transmitting two frequency encoded messages targeted exclusively to proteins like calmodulin, annexins, or syncollin that are crucial for exocytosis and require specific combinations of [Ca(2+)] "and" pH for their action.

  9. Evolutionary conservation of a microbody targeting signal that targets proteins to peroxisomes, glyoxysomes, and glycosomes

    PubMed Central

    1991-01-01

    Peroxisomes, glyoxysomes, glycosomes, and hydrogenosomes have each been classified as microbodies, i.e., subcellular organelles with an electron-dense matrix that is bound by a single membrane. We investigated whether these organelles might share a common evolutionary origin by asking if targeting signals used for translocation of proteins into these microbodies are related. A peroxisomal targeting signal (PTS) consisting of the COOH-terminal tripeptide serine-lysine- leucine-COOH has been identified in a number of peroxisomal proteins (Gould, S.J., G.-A. Keller, N. Hosken, J. Wilkinson, and S. Subramani. 1989. J. Cell Biol. 108:1657-1664). Antibodies raised to a peptide ending in this sequence (SKL-COOH) recognize a number of peroxisomal proteins. Immunocryoelectron microscopy experiments using this anti-SKL antibody revealed the presence of proteins containing the PTS within glyoxysomes of cells from Pichia pastoris, germinating castor bean seeds, and Neurospora crassa, as well as within the glycosomes of Trypanosoma brucei. Western blot analysis of purified organelle fractions revealed the presence of many proteins containing this PTS in both glyoxysomes and glycosomes. These results indicate that at least one of the signals, and therefore the mechanism, for protein translocation into peroxisomes, glyoxysomes, and glycosomes has been conserved, lending support to a common evolutionary origin for these microbodies. Hydrogenosomes, the fourth type of microbody, did not contain proteins that cross-reacted with the anti-PTS antibody, suggesting that this organelle is unrelated to microbodies. PMID:1831458

  10. Regression of Pathological Cardiac Hypertrophy: Signaling Pathways and Therapeutic Targets

    PubMed Central

    Hou, Jianglong; Kang, Y. James

    2012-01-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming. PMID:22750195

  11. Osteocytic signalling pathways as therapeutic targets for bone fragility.

    PubMed

    Plotkin, Lilian I; Bellido, Teresita

    2016-10-01

    Osteocytes are differentiated osteoblasts that become surrounded by matrix during the process of bone formation. Acquisition of the osteocyte phenotype is achieved by profound changes in gene expression that facilitate adaptation to the changing cellular environment and constitute the molecular signature of osteocytes. During osteocytogenesis, the expression of genes that are characteristic of the osteoblast are altered and the expression of genes and/or proteins that impart dendritic cellular morphology, regulate matrix mineralization and control the function of cells at the bone surface are ordely modulated. The discovery of mutations in human osteocytic genes has contributed, in a large part, to our understanding of the role of osteocytes in bone homeostasis. Osteocytes are targets of the mechanical force imposed on the skeleton and have a critical role in integrating mechanosensory pathways with the action of hormones, which thereby leads to the orchestrated response of bone to environmental cues. Current, therapeutic approaches harness this accumulating knowledge by targeting osteocytic signalling pathways and messengers to improve skeletal health.

  12. Targeting Multiple Key Signaling Pathways in Melanoma using Leelamine

    PubMed Central

    Gowda, Raghavendra; Madhunapantula, SubbaRao V.; Kuzu, Omer F.; Sharma, Arati; Robertson, Gavin P.

    2015-01-01

    Melanoma is a highly drug resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The PI3 kinase (PI3K), MAP kinase (MAPK) and STAT3 pathways are constitutively activated in 50–70% of melanomas promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK and STAT3 cascades, a natural product library was screened to identifying leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC50 values of 2 and 9.3 µmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 µmol/L by 40–80% and longer exposure increased apoptosis 600% through a mechanism detailed in the article in the current issue of this journal by Kuzu OF et al. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and, consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease. PMID:24688050

  13. Signal Transduction and Molecular Targets of Selected Flavonoids

    PubMed Central

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  14. Simultaneous chromatic and luminance human electroretinogram responses

    PubMed Central

    Parry, Neil R A; Murray, Ian J; Panorgias, Athanasios; McKeefry, Declan J; Lee, Barry B; Kremers, Jan

    2012-01-01

    The parallel processing of information forms an important organisational principle of the primate visual system. Here we describe experiments which use a novel chromatic–achromatic temporal compound stimulus to simultaneously identify colour and luminance specific signals in the human electroretinogram (ERG). Luminance and chromatic components are separated in the stimulus; the luminance modulation has twice the temporal frequency of the chromatic modulation. ERGs were recorded from four trichromatic and two dichromatic subjects (1 deuteranope and 1 protanope). At isoluminance, the fundamental (first harmonic) response was elicited by the chromatic component in the stimulus. The trichromatic ERGs possessed low-pass temporal tuning characteristics, reflecting the activity of parvocellular post-receptoral mechanisms. There was very little first harmonic response in the dichromats’ ERGs. The second harmonic response was elicited by the luminance modulation in the compound stimulus and showed, in all subjects, band-pass temporal tuning characteristic of magnocellular activity. Thus it is possible to concurrently elicit ERG responses from the human retina which reflect processing in both chromatic and luminance pathways. As well as providing a clear demonstration of the parallel nature of chromatic and luminance processing in the human retina, the differences that exist between ERGs from trichromatic and dichromatic subjects point to the existence of interactions between afferent post-receptoral pathways that are in operation from the earliest stages of visual processing. PMID:22586211

  15. Application of the CLEAN Detector to Low Signal to Noise Ratio Targets

    DTIC Science & Technology

    2010-05-01

    address low signal to noise ( SNR ) targets. The Reformulated CLEAN Detector is presented which is shown to allow the detection of low SNR targets in the...results of the author’s two previous papers on application of the CLEAN Algorithm to the condition of low signal to noise ratio ( SNR ) targets. The first...paper expands on the author?s previous work by adapting the CLEAN algorithm to address low signal to noise ( SNR ) targets. The Reformulated CLEAN

  16. GABAergic Signaling as Therapeutic Target for Autism Spectrum Disorders

    PubMed Central

    Cellot, Giada; Cherubini, Enrico

    2014-01-01

    γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation–chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders. PMID:25072038

  17. Luminance cues constrain chromatic blur discrimination in natural scene stimuli.

    PubMed

    Sharman, Rebecca J; McGraw, Paul V; Peirce, Jonathan W

    2013-03-22

    Introducing blur into the color components of a natural scene has very little effect on its percept, whereas blur introduced into the luminance component is very noticeable. Here we quantify the dominance of luminance information in blur detection and examine a number of potential causes. We show that the interaction between chromatic and luminance information is not explained by reduced acuity or spatial resolution limitations for chromatic cues, the effective contrast of the luminance cue, or chromatic and achromatic statistical regularities in the images. Regardless of the quality of chromatic information, the visual system gives primacy to luminance signals when determining edge location. In natural viewing, luminance information appears to be specialized for detecting object boundaries while chromatic information may be used to determine surface properties.

  18. Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

    PubMed Central

    2014-01-01

    Treatment of myelofibrosis (MF), a BCR-ABL–negative myeloproliferative neoplasm, is challenging. The only current potentially curative option, allogeneic hematopoietic stem cell transplant, is recommended for few patients. The remaining patients are treated with palliative therapies to manage MF-related anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 (JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted the discovery and clinical development of inhibitors that target JAK2. Although treatment with JAK2 inhibitors has been shown to improve symptom response and quality of life in patients with MF, these drugs do not alter the underlying disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling pathway has been shown to play a role in normal hematopoiesis and in the tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh pathway have been shown to inhibit growth and self-renewal capacity in preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical data also suggest that inhibition of the Hh pathway, alone or in combination with JAK2 inhibition, may enable disease modification in patients with MF. Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification. PMID:24598114

  19. THE TOTAL LUMINOUS EFFICIENCY OF LUMINOUS BACTERIA

    PubMed Central

    Harvey, E. Newton

    1925-01-01

    Methods are described for measuring the light emitted by an emulsion of luminous bacteria of given thickness, and calculating the light emitted by a single bacterium, measuring 1.1 x 2.2 micra, provided there is no absorption of light in the emulsion. At the same time, the oxygen consumed by a single bacterium was measured by recording the time for the bacteria to use up .9 of the oxygen dissolved in sea water from air (20 per cent oxygen). The luminescence intensity does not diminish until the oxygen concentration falls below 2 per cent, when the luminescence diminishes rapidly. Above 2 per cent oxygen (when the oxygen dissolving in sea water from pure oxygen at 760 mm. Hg pressure = 100 per cent) the bacteria use equal amounts of oxygen in equal times, while below 2 per cent oxygen it seems very likely that rate of oxygen absorption is proportional to oxygen concentration. By measuring the time for a tube of luminous bacteria of known concentration saturated with air (20 per cent oxygen) to begin to darken (2 per cent oxygen) we can calculate the oxygen absorbed by one bacterium per second. The bacteria per cc. are counted on a blood counting slide or by a centrifugal method, after measuring the volume of a single bacterium (1.695 x 10–12 cc.). Both methods gave results in good agreement with each other. The maximum value for the light from a single bacterium was 24 x 10–14 lumens or 1.9 x 10–14 candles. The maximum value for lumen-seconds per mg. of oxygen absorbed was 14. The average value for lumen-seconds per mg. O2 was 9.25. The maximum values were selected in calculating the efficiency of light production, since some of the bacteria counted may not be producing light, although they may still be using oxygen. The "diet" of the bacteria was 60 per cent glycerol and 40 per cent peptone. To oxidize this mixture each mg. of oxygen would yield 3.38 gm. calories or 14.1 watts per second. 1 lumen per watt is therefore produced by a normal bacterium which

  20. Low number of luminance levels in the luminance noise increases color discrimination thresholds estimated with pseudoisochromatic stimuli.

    PubMed

    Souza, Givago S; Malone, Felecia L; Crawford, Teera L; Miquilini, Letícia; Salomão, Raílson C; Guimarães, Diego L; Ventura, Dora F; Fitzgerald, Malinda E C; Silveira, Luiz Carlos L

    2014-01-01

    In pseudoisochromatic stimuli the presence of spatial and luminance noise forces the subject to discriminate the target from the background solely on the basis of chromaticity difference. Color-blind subjects may show difficulty to identify the target due to the elimination of borders and brightness clues caused by the luminance and spatial noise. Few studies have fully described the features of pseudoisochromatic stimuli. Fewer investigators have focused their studies in the effects of specific pseudoisochromatic parameters on color discrimination. We used the Cambridge Color Test (CCT) to investigate the influence on color discrimination thresholds due to the number of luminance levels present in the luminance noise. The CCT default has six luminance steps; however, in our investigation a total of eight different conditions were tested from 2 to 16 luminance steps. It was found that the CCT provided very robust values for color discrimination thresholds, which were degraded only for very small number of luminance steps. When the number of steps was increased, the color discrimination thresholds improved from 2 to 6 luminance steps and gradually reached a plateau for 10 or more luminance steps. The area of color discrimination ellipses as a function of luminance steps matches the relative proportion of ineffective contrasts between mosaic patches as a function of luminance steps, assuming that contrast becomes ineffective for values 18.6% or less. The lower number of color and luminance interactions in these conditions could explain the measured increase of color discrimination thresholds. The primary conclusion from this investigation was that results from pseudoisochromatic tests should have their parameters described in more detail. This type of description would allow a better understanding of the results provided, interpretations, and therefore cross study comparison of results obtained from different laboratories.

  1. Low number of luminance levels in the luminance noise increases color discrimination thresholds estimated with pseudoisochromatic stimuli

    PubMed Central

    Souza, Givago S.; Malone, Felecia L.; Crawford, Teera L.; Miquilini, Letícia; Salomão, Raílson C.; Guimarães, Diego L.; Ventura, Dora F.; Fitzgerald, Malinda E. C.; Silveira, Luiz Carlos L.

    2014-01-01

    In pseudoisochromatic stimuli the presence of spatial and luminance noise forces the subject to discriminate the target from the background solely on the basis of chromaticity difference. Color-blind subjects may show difficulty to identify the target due to the elimination of borders and brightness clues caused by the luminance and spatial noise. Few studies have fully described the features of pseudoisochromatic stimuli. Fewer investigators have focused their studies in the effects of specific pseudoisochromatic parameters on color discrimination. We used the Cambridge Color Test (CCT) to investigate the influence on color discrimination thresholds due to the number of luminance levels present in the luminance noise. The CCT default has six luminance steps; however, in our investigation a total of eight different conditions were tested from 2 to 16 luminance steps. It was found that the CCT provided very robust values for color discrimination thresholds, which were degraded only for very small number of luminance steps. When the number of steps was increased, the color discrimination thresholds improved from 2 to 6 luminance steps and gradually reached a plateau for 10 or more luminance steps. The area of color discrimination ellipses as a function of luminance steps matches the relative proportion of ineffective contrasts between mosaic patches as a function of luminance steps, assuming that contrast becomes ineffective for values 18.6% or less. The lower number of color and luminance interactions in these conditions could explain the measured increase of color discrimination thresholds. The primary conclusion from this investigation was that results from pseudoisochromatic tests should have their parameters described in more detail. This type of description would allow a better understanding of the results provided, interpretations, and therefore cross study comparison of results obtained from different laboratories. PMID:25566106

  2. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib

    PubMed Central

    Sharman, Jeff; Di Paolo, Julie

    2016-01-01

    The B-cell receptor signaling pathway has emerged as an important therapeutic target in chronic lymphocytic leukemia and other B-cell malignancies. Novel agents have been developed targeting the signaling enzymes spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase, and phosphoinositide 3-kinase delta. This review discusses the rationale for targeting these enzymes, as well as the preclinical and clinical evidence supporting their role as therapeutic targets, with a particular focus on SYK inhibition with entospletinib. PMID:27247756

  3. Regulation of HIV-Gag Expression and Targeting to the Endolysosomal/Secretory Pathway by the Luminal Domain of Lysosomal-Associated Membrane Protein (LAMP-1) Enhance Gag-Specific Immune Response

    PubMed Central

    Lucas, Carolina Gonçalves de Oliveira; Rigato, Paula Ordonhez; Gonçalves, Jorge Luiz Santos; Sato, Maria Notomi; Maciel, Milton; Peçanha, Ligia Maria Torres; August, J. Thomas; de Azevedo Marques, Ernesto Torres; de Arruda, Luciana Barros

    2014-01-01

    We have previously demonstrated that a DNA vaccine encoding HIV-p55gag in association with the lysosomal associated membrane protein-1 (LAMP-1) elicited a greater Gag-specific immune response, in comparison to a DNA encoding the native gag. In vitro studies have also demonstrated that LAMP/Gag was highly expressed and was present in MHCII containing compartments in transfected cells. In this study, the mechanisms involved in these processes and the relative contributions of the increased expression and altered traffic for the enhanced immune response were addressed. Cells transfected with plasmid DNA constructs containing p55gag attached to truncated sequences of LAMP-1 showed that the increased expression of gag mRNA required p55gag in frame with at least 741 bp of the LAMP-1 luminal domain. LAMP luminal domain also showed to be essential for Gag traffic through lysosomes and, in this case, the whole sequence was required. Further analysis of the trafficking pathway of the intact LAMP/Gag chimera demonstrated that it was secreted, at least in part, associated with exosome-like vesicles. Immunization of mice with LAMP/gag chimeric plasmids demonstrated that high expression level alone can induce a substantial transient antibody response, but targeting of the antigen to the endolysosomal/secretory pathways was required for establishment of cellular and memory response. The intact LAMP/gag construct induced polyfunctional CD4+ T cell response, which presence at the time of immunization was required for CD8+ T cell priming. LAMP-mediated targeting to endolysosomal/secretory pathway is an important new mechanistic element in LAMP-mediated enhanced immunity with applications to the development of novel anti-HIV vaccines and to general vaccinology field. PMID:24932692

  4. Regulation of HIV-Gag expression and targeting to the endolysosomal/secretory pathway by the luminal domain of lysosomal-associated membrane protein (LAMP-1) enhance Gag-specific immune response.

    PubMed

    Godinho, Rodrigo Maciel da Costa; Matassoli, Flavio Lemos; Lucas, Carolina Gonçalves de Oliveira; Rigato, Paula Ordonhez; Gonçalves, Jorge Luiz Santos; Sato, Maria Notomi; Maciel, Milton; Peçanha, Ligia Maria Torres; August, J Thomas; Marques, Ernesto Torres de Azevedo; de Arruda, Luciana Barros

    2014-01-01

    We have previously demonstrated that a DNA vaccine encoding HIV-p55gag in association with the lysosomal associated membrane protein-1 (LAMP-1) elicited a greater Gag-specific immune response, in comparison to a DNA encoding the native gag. In vitro studies have also demonstrated that LAMP/Gag was highly expressed and was present in MHCII containing compartments in transfected cells. In this study, the mechanisms involved in these processes and the relative contributions of the increased expression and altered traffic for the enhanced immune response were addressed. Cells transfected with plasmid DNA constructs containing p55gag attached to truncated sequences of LAMP-1 showed that the increased expression of gag mRNA required p55gag in frame with at least 741 bp of the LAMP-1 luminal domain. LAMP luminal domain also showed to be essential for Gag traffic through lysosomes and, in this case, the whole sequence was required. Further analysis of the trafficking pathway of the intact LAMP/Gag chimera demonstrated that it was secreted, at least in part, associated with exosome-like vesicles. Immunization of mice with LAMP/gag chimeric plasmids demonstrated that high expression level alone can induce a substantial transient antibody response, but targeting of the antigen to the endolysosomal/secretory pathways was required for establishment of cellular and memory response. The intact LAMP/gag construct induced polyfunctional CD4+ T cell response, which presence at the time of immunization was required for CD8+ T cell priming. LAMP-mediated targeting to endolysosomal/secretory pathway is an important new mechanistic element in LAMP-mediated enhanced immunity with applications to the development of novel anti-HIV vaccines and to general vaccinology field.

  5. Toxicological disruption of signaling homeostasis: Tyrosine phosphatses as targets

    EPA Science Inventory

    The protein tyrosine phosphatases (PTP) comprised a diverse group of enzymes whose activity opposes that of the tyrosine kinases. As such, the PTP have critical roles in maintaining signaling quiescence in resting cells and in restoring homeostasis by effecting signal termination...

  6. Toxicological disruption of signaling homeostasis: Tyrosine phosphatses as targets

    EPA Science Inventory

    The protein tyrosine phosphatases (PTP) comprised a diverse group of enzymes whose activity opposes that of the tyrosine kinases. As such, the PTP have critical roles in maintaining signaling quiescence in resting cells and in restoring homeostasis by effecting signal termination...

  7. ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

    PubMed Central

    Morrison, Meghan M.; Hutchinson, Katherine; Williams, Michelle M.; Stanford, Jamie C.; Balko, Justin M.; Young, Christian; Kuba, Maria G.; Sánchez, Violeta; Williams, Andrew J.; Hicks, Donna J.; Arteaga, Carlos L.; Prat, Aleix; Perou, Charles M.; Earp, H. Shelton; Massarweh, Suleiman; Cook, Rebecca S.

    2013-01-01

    Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment. PMID:23999432

  8. Role of epigenetic modifications in luminal breast cancer.

    PubMed

    Abdel-Hafiz, Hany A; Horwitz, Kathryn B

    2015-08-01

    Luminal breast cancers represent approximately 75% of cases. Explanations into the causes of endocrine resistance are complex and are generally ascribed to genomic mechanisms. Recently, attention has been drawn to the role of epigenetic modifications in hormone resistance. We review these here. Epigenetic modifications are reversible, heritable and include changes in DNA methylation patterns, modification of histones and altered microRNA expression levels that target the receptors or their signaling pathways. Large-scale analyses indicate distinct epigenomic profiles that distinguish breast cancers from normal and benign tissues. Taking advantage of the reversibility of epigenetic modifications, drugs that target epigenetic modifiers, given in combination with chemotherapies or endocrine therapies, may represent promising approaches to restoration of therapy responsiveness in these cases.

  9. Role of epigenetic modifications in luminal breast cancer

    PubMed Central

    Abdel-Hafiz, Hany A; Horwitz, Kathryn B

    2015-01-01

    Luminal breast cancers represent approximately 75% of cases. Explanations into the causes of endocrine resistance are complex and are generally ascribed to genomic mechanisms. Recently, attention has been drawn to the role of epigenetic modifications in hormone resistance. We review these here. Epigenetic modifications are reversible, heritable and include changes in DNA methylation patterns, modification of histones and altered microRNA expression levels that target the receptors or their signaling pathways. Large-scale analyses indicate distinct epigenomic profiles that distinguish breast cancers from normal and benign tissues. Taking advantage of the reversibility of epigenetic modifications, drugs that target epigenetic modifiers, given in combination with chemotherapies or endocrine therapies, may represent promising approaches to restoration of therapy responsiveness in these cases. PMID:25689414

  10. Identification of peroxisomal targeting signals located at the carboxy terminus of four peroxisomal proteins

    PubMed Central

    1988-01-01

    As part of an effort to understand how proteins are imported into the peroxisome, we have sought to identify the peroxisomal targeting signals in four unrelated peroxisomal proteins: human catalase, rat hydratase:dehydrogenase, pig D-amino acid oxidase, and rat acyl-CoA oxidase. Using gene fusion experiments, we have identified a region of each protein that can direct heterologous proteins to peroxisomes. In each case, the peroxisomal targeting signal is contained at or near the carboxy terminus of the protein. For catalase, the peroxisomal targeting signal is located within the COOH-terminal 27 amino acids of the protein. For hydratase:dehydrogenase, D-amino acid oxidase, and acyl-CoA oxidase, the targeting signals are located within the carboxy- terminal 15, 14, and 15 amino acids, respectively. A tripeptide of the sequence Ser-Lys/His-Leu is present in each of these targeting signals as well as in the peroxisomal targeting signal identified in firefly luciferase (Gould, S.J., G.-A. Keller, and S. Subramani. 1987. J. Cell Biol. 105:2923-2931). When the peroxisomal targeting signal of the hydratase:dehydrogenase is mutated so that the Ser-Lys-Leu tripeptide is converted to Ser-Asn-Leu, it can no longer direct proteins to peroxisomes. We suggest that this tripeptide is an essential element of at least one class of peroxisomal targeting signals. PMID:2901422

  11. Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer

    PubMed Central

    Burke, Lorraine; Butler, Clare T.; Murphy, Adrian; Moran, Bruce; Gallagher, William M.; O'Sullivan, Jacintha; Kennedy, Breandán N.

    2016-01-01

    Colorectal cancer is the third most common cancer worldwide and is associated with significant morbidity and mortality. Current pharmacotherapy options include cytotoxic chemotherapy, anti-VEGF, and anti-EGFR targeting drugs, but these are limited by toxic side effects, limited responses and ultimately resistance. Cysteinyl leukotriene (CysLT) signaling regulates intestinal homeostasis with mounting evidence suggesting that CysLT signaling also plays a role in the pathogenesis of colorectal cancer. Therefore, CysLT signaling represents a novel target for this malignancy. This review evaluates reported links between CysLT signaling and established hallmarks of cancer in addition to its pharmacological potential as a new therapeutic target. PMID:27709113

  12. Targeting the WNT Signaling Pathway in Cancer Therapeutics.

    PubMed

    Tai, David; Wells, Keith; Arcaroli, John; Vanderbilt, Chad; Aisner, Dara L; Messersmith, Wells A; Lieu, Christopher H

    2015-10-01

    The WNT signaling cascade is integral in numerous biological processes including embryonic development, cell cycle regulation, inflammation, and cancer. Hyperactivation of WNT signaling secondary to alterations to varying nodes of the pathway have been identified in multiple tumor types. These alterations converge into increased tumorigenicity, sustained proliferation, and enhanced metastatic potential. This review seeks to evaluate the evidence supporting the WNT pathway in cancer, the therapeutic strategies in modulating this pathway, and potential challenges in drug development.

  13. Multitarget tracking and monopulse signal processing for spawning targets

    NASA Astrophysics Data System (ADS)

    Willett, Peter K.; Blair, William D.; Ogle, Terry

    2004-08-01

    A monopulse radar is able to derive accurate angular measurements via intelligent processing of its sum and difference channel returns. Recently there have emerged techniques for angular estimation of several unresolved targets, meaning targets that are, in principle, merged within the same radar beam, can be extracted separately. The key is the joint exploitation of information in several range bins. Here we show the performance of this approach in a high-fidelity simulation: we observe considerable improvement in track RMSE, but little corresponding gain in track completeness. Coupled with a hidden Markov model on target number, however, the performance is impressive.

  14. Wavelet-Based Signal and Image Processing for Target Recognition

    DTIC Science & Technology

    2002-01-01

    in target recognition applications. Classical spatial and frequency domain image processing algorithms were generalized to process discrete wavelet ... transform (DWT) data. Results include adaptation of classical filtering, smoothing and interpolation techniques to DWT. From 2003 the research

  15. Intelligibility of Target Signals in Sequential and Simultaneous Segregation Tasks

    DTIC Science & Technology

    2009-03-01

    overlap in time, which gives rise to the difficult task of segregating simultaneous speech sounds . In many cases, there is only minimal overlap of target...1.0 Introduction Two mechanisms are generally implicated in sound source segregation: simultaneous and sequential sound source segregation. The former...allow listeners to group together target segments when that are interleaved with segments of the interfering sound . And while it seems obvious that

  16. Targeting the Ron-DEK Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2013-09-01

    The first objective of Task 2 was to test DEK-targeting 1716 Herpes Simplex Viruses (1716HSV) on breast cancer cells. A panel of vectors was...characterized transgenic model wherein wild type Ron is overexpressed selectively in the mammary epithelium by the mouse mammary tumor virus ...degree of knockdown that could be achieved. Three DEK targeting viruses were tested for DEK knockdown in HeLa cells. These included GFP-expressing

  17. Targeting the Ron-DEK Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2013-09-01

    The first objective of Task 2 was to test DEK-targeting 1716 Herpes Simplex Viruses (1716HSV) on breast cancer cells. A panel of vectors was...characterized transgenic model wherein wild type Ron is overexpressed selectively in the mammary epithelium by the mouse mammary tumor virus ...of knockdown that could be achieved. Three DEK targeting viruses were tested for DEK knockdown in HeLa cells. These included GFP-expressing viruses

  18. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  19. Targeting BMP signalling in cardiovascular disease and anaemia

    PubMed Central

    Morrell, Nicholas W.; Bloch, Donald B.; ten Dijke, Peter; Goumans, Marie-Jose T.H.; Hata, Akiko; Smith, Jim; Yu, Paul B.; Bloch, Kenneth D.

    2016-01-01

    Bone morphogenetic proteins (BMPs) and their receptors, known to be essential regulators of embryonal patterning and organogenesis, are also critical for the regulation of cardiovascular structure and function. In addition to their contributions to syndromic disorders of heart and vascular development, BMP signalling is increasingly recognized for its influence on endocrine-like functions in postnatal cardiovascular and metabolic homeostasis. In this Review, we discuss several critical and novel aspects of BMP signalling in cardiovascular health and disease, which highlight the cell- and context-specific nature of BMP signalling. Based on advancing knowledge of the physiological roles and regulation of BMP signaling, we indicate opportunities for therapeutic intervention in a range of cardiovascular conditions including atherosclerosis and pulmonary arterial hypertension, and well as for anaemia of chronic disease. Depending on the context and the repertoire of ligands and receptors involved in specific disease processes, the selective inhibition or enhancement of signaling via particular BMP ligands (such as in atherosclerosis and pulmonary arterial hypertension, respectively) might be beneficial. The development of selective small molecule antagonists of BMP receptors, and the identification of ligands selective for BMP receptor complexes expressed in the vasculature provide the most immediate opportunities for new therapies. PMID:26461965

  20. SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling.

    PubMed

    Zhu, Xiaolong; Ding, Sha; Qiu, Cong; Shi, Yanna; Song, Lin; Wang, Yueyue; Wang, Yuewen; Li, Jinying; Wang, Yiran; Sun, Yi; Qin, Lingfeng; Chen, Jun; Simons, Michael; Min, Wang; Yu, Luyang

    2017-09-01

    The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)-deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a

  1. Targeted Lymphoma Cell Death by Novel Signal Transduction Modifications

    DTIC Science & Technology

    2010-07-14

    CD22-binding peptides that initiate signal transduction and apoptosis in non -Hodgkin’s lymphoma (NHL), 2) optimize CD22-mediated signal transduction...positive non -Hodgkin’s lymphoma (NHL), much as rituximab (Rituxan) is an option to patients with CD20-positive NHL. By sequencing the heavy and...Int J Pept Res Ther (2008) 14:237–246 8. O’Donnell RT, Pearson D, McKnight HC, Ma YP, Tuscano JM. Treatment of non -Hodgkin’s lymphoma xenografts with

  2. Luminous pulses during triggered lightning

    NASA Astrophysics Data System (ADS)

    Winn, W. P.; Eastvedt, E. M.; Trueblood, J. J.; Eack, K. B.; Edens, H. E.; Aulich, G. D.; Hunyady, S. J.; Murray, W. C.

    2012-05-01

    A triggered lightning flash that transferred negative charge to ground in central New Mexico produced more than three levels of branching above the main channel to ground in a 1 km vertical field of view. A high-speed video recording shows that the main channel had about 50 brief luminous pulses, many of which were superimposed on a slowly changing persistent luminosity. In contrast, superposition was rare in the uppermost visible branches because luminous pulses first appeared on preexisting dark channels before merging into a luminous channel. This observation suggests that luminous pulses in triggered and natural lightning originate only on dark branches and that the complexity of the main channel to ground is the result of multiple mergers of dark branches with pulses into luminous branches without pulses. This suggestion is contrary to an earlier conclusion that there are two kinds of luminous pulses. We also observe behavior characteristic of electromagnetic waves on transmission lines: when a downward propagating luminous pulse reaches a junction with another initially dark branch, it travels both upward and downward along that branch. Upon reaching the ground the downward propagating wave produces a bright reflection which also splits at the junctions, producing luminosity for a short distance upward in one direction while propagating much farther upward along the path charged by the downward propagating wave. However, when a downward moving luminous pulse reaches a junction with an initially luminous branch, splitting is not evident, probably due to the greater conductivity of the luminous channel.

  3. Shredding the signal: targeting peptide degradation in mitochondria and chloroplasts.

    PubMed

    Kmiec, Beata; Teixeira, Pedro F; Glaser, Elzbieta

    2014-12-01

    The biogenesis and functionality of mitochondria and chloroplasts depend on the constant turnover of their proteins. The majority of mitochondrial and chloroplastic proteins are imported as precursors via their N-terminal targeting peptides. After import, the targeting peptides are cleaved off and degraded. Recent work has elucidated a pathway involved in the degradation of targeting peptides in mitochondria and chloroplasts, with two proteolytic components: the presequence protease (PreP) and the organellar oligopeptidase (OOP). PreP and OOP are specialized in degrading peptides of different lengths, with the substrate restriction being dictated by the structure of their proteolytic cavities. The importance of the intraorganellar peptide degradation is highlighted by the fact that elimination of both oligopeptidases affects growth and development of Arabidopsis thaliana. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Targeting Signaling to YAP for the Therapy of NF2

    DTIC Science & Technology

    2016-12-01

    nucleus, thus activating YAP-driven transcription and oncogenesis. Genetic epistasis experiments provided evidence that this oncogenic pathway...which loss of Merlin activates mitogenic signaling by using somatic cell genetics and biochemistry. In addition, we have initiated high-throughput

  5. Targeting the Ron-Dek Signaling Axis in Breast Cancer

    DTIC Science & Technology

    2015-09-01

    tumor development, characterized by decreased cell proliferation, diminished metastasis and fewer cells expressing mammary cancer stem cell markers...cancer stem cell numbers and mammosphere formation ability. • Dek expression is important for breast cancer metastasis in vivo and metastatic phenotypes...Waltz SE. HGFL-Ron signaling enhances the therapeutic resistance of breast cancer stem cells . August 2015, Capstone Summer Research Symposium

  6. Microarray meta-analysis identifies evolutionarily conserved BMP signaling targets in developing long bones.

    PubMed

    Prashar, Paritosh; Yadav, Prem Swaroop; Samarjeet, Fnu; Bandyopadhyay, Amitabha

    2014-05-15

    In vertebrates, BMP signaling has been demonstrated to be sufficient for bone formation in several tissue contexts. This suggests that genes necessary for bone formation are expressed in a BMP signaling dependent manner. However, till date no gene has been reported to be expressed in a BMP signaling dependent manner in bone. Our aim was to identify such genes. On searching the literature we found that several microarray experiments have been conducted where the transcriptome of osteogenic cells in absence and presence of BMP signaling activation have been compared. However, till date, there is no evidence to suggest that any of the genes found to be upregulated in presence of BMP signaling in these microarray analyses is indeed a target of BMP signaling in bone. We wanted to utilize this publicly available information to identify candidate BMP signaling target genes in vivo. We performed a meta-analysis of six such comparable microarray datasets. This analysis and subsequent experiments led to the identification of five targets of BMP signaling in bone that are conserved both in mouse and chick. Of these Lox, Klf10 and Gpr97 are likely to be direct transcriptional targets of BMP signaling pathway. Dpysl3, is a novel BMP signaling target identified in our study. Our data demonstrate that Dpysl3 is important for osteogenic differentiation of mesenchymal cells and is involved in cell secretion. We have demonstrated that the expression of Dpysl3 is co-operatively regulated by BMP signaling and Runx2. Based on our experimental data, in silico analysis of the putative promoter-enhancer regions of Bmp target genes and existing literature, we hypothesize that BMP signaling collaborates with multiple signaling pathways to regulate the expression of a unique set of genes involved in endochondral ossification. Copyright © 2014. Published by Elsevier Inc.

  7. Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

    PubMed

    Ruwanpura, Saleela M; McLeod, Louise; Dousha, Lovisa F; Seow, Huei J; Alhayyani, Sultan; Tate, Michelle D; Deswaerte, Virginie; Brooks, Gavin D; Bozinovski, Steven; MacDonald, Martin; Garbers, Christoph; King, Paul T; Bardin, Philip G; Vlahos, Ross; Rose-John, Stefan; Anderson, Gary P; Jenkins, Brendan J

    2016-12-15

    The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. We used the gp130(F/F) genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

  8. AKAP signaling complexes: pointing towards the next generation of therapeutic targets?

    PubMed

    Esseltine, Jessica L; Scott, John D

    2013-12-01

    A-kinase anchoring proteins (AKAPs) streamline signal transduction by localizing signaling enzymes with their substrates. Great strides have been made in elucidating the role of these macromolecular signaling complexes as new binding partners and novel AKAPs are continually being uncovered. The mechanics and dynamics of these multi-enzyme assemblies suggest that AKAP complexes are viable targets for therapeutic intervention. This review will highlight recent advances in AKAP research focusing on local signaling events that are perturbed in disease.

  9. Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer.

    PubMed

    Schalken, Jack; Fitzpatrick, John M

    2016-02-01

    Significant progress has been made in the understanding of the underlying cancer biology of castration-resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.

  10. Deubiquitinases as a signaling target of oxidative stress

    PubMed Central

    Cotto-Rios, Xiomaris M.; Békés, Miklos; Chapman, Jessica; Ueberheide, Beatrix; Huang, Tony T.

    2012-01-01

    SUMMARY Deubiquitinating enzymes (DUBs) constitute a large family of cysteine proteases that have broad impact on numerous biological and pathological processes, including the regulation of genomic stability. DUBs are often assembled onto multiprotein complexes to assist in their localization and substrate selection, yet it remains unclear how the enzymatic activity of DUBs is modulated by intracellular signals. Herein, we show that bursts of reactive oxygen species (ROS) reversibly inactivate DUBs through the oxidation of the catalytic cysteine residue. Importantly, USP1, a key regulator of genomic stability, is reversibly inactivated upon oxidative stress. This, in part, explains the rapid nature of PCNA monoubiquitination-dependent DNA damage tolerance in response to oxidative DNA damage in replicating cells. We propose that DUBs of the cysteine protease family act as ROS sensors in human cells and that ROS-mediated DUB inactivation is a critical mechanism for fine-tuning stress-activated signaling pathways. PMID:23219552

  11. Targeting the PDGF signaling pathway in tumor treatment.

    PubMed

    Heldin, Carl-Henrik

    2013-12-20

    Platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of certain cell types during embryonal development and e.g. tissue repair in the adult. Overactivity of PDGF receptor signaling, by overexpression or mutational events, may drive tumor cell growth. In addition, pericytes of the vasculature and fibroblasts and myofibroblasts of the stroma of solid tumors express PDGF receptors, and PDGF stimulation of such cells promotes tumorigenesis. Inhibition of PDGF receptor signaling has proven to useful for the treatment of patients with certain rare tumors. Whether treatment with PDGF/PDGF receptor antagonists will be beneficial for more common malignancies is the subject for ongoing studies.

  12. Infrared Target Detection: Signal and Noise Sensitivity Analysis

    DTIC Science & Technology

    1989-12-01

    Appendix A: Noise Effective Electrical Bandwidth . . 54 Appendix B: MathCAD Computer Program. .......... 56 Appendix C: Scenario Inputs...............65...18:127- 2 U). Because imaging systems create a reproduction of many localized areas of a scene, the variation between each localized area affects the...signal plus noise. 05 Approach As stated before the problem is to identify, characterize, and determine the effect of the statistical variations of the

  13. Improved pointing at trackable targets by integrating control valve signals

    NASA Technical Reports Server (NTRS)

    Stone, R. W.; Laverty, C. R.; Colby, M. J.

    1982-01-01

    A compact, low-cost add-on electronic module has been developed for the STRAP III control system to improve pointing at trackable targets. The module provides peak-to-peak limit cycle excursions of + or - 5 arcseconds while tracking a +3 magnitude or brighter star. This is achieved without using rate-integrating gyroscopes, thus reducing payload length, weight, cost, and preparation time. This module has flown successfully five times. In May 1981, it improved the performance of a two-startracker attitude control system with TV camera and joystick control which pointed at a nontrackable target. This paper describes the operation of the module, how it alters the ordinary STRAP III operation, and how it was developed using an analog-computer-based rocket flight simulator.

  14. System for Automatic Detection and Analysis of Targets in FMICW Radar Signal

    NASA Astrophysics Data System (ADS)

    Rejfek, Luboš; Mošna, Zbyšek; Urbář, Jaroslav; Koucká Knížová, Petra

    2016-01-01

    This paper presents the automatic system for the processing of the signals from the frequency modulated interrupted continuous wave (FMICW) radar and describes methods for the primary signal processing. Further, we present methods for the detection of the targets in strong noise. These methods are tested both on the real and simulated signals. The real signals were measured using the developed at the IAP CAS experimental prototype of FMICW radar with operational frequency 35.4 GHz. The measurement campaign took place at the TU Delft, the Netherlands. The obtained results were used for development of the system for the automatic detection and analysis of the targets measured by the FMICW radar.

  15. Targeting Signaling to YAP for the Therapy of NF2

    DTIC Science & Technology

    2015-10-01

    targeted therapy in the same way Chronic Myelogenous Leukemia is cured by Gleevec. The prospect of resistance is minimal, as Schwannoma cells do not seem to...by which loss of Merlin induces tumorigenesis to identify small molecule compounds that block YAP/TEAD-dependent transcription by acting at any step...grant, we have generated NF2 mutant cell lines expressing two different types of YAP reporters and tested their suitability for high throughput

  16. Direct targets of pSTAT5 signalling in erythropoiesis

    PubMed Central

    Tuckey, Hugh; Magor, Graham W.; Perkins, Andrew C.

    2017-01-01

    Erythropoietin (EPO) acts through the dimeric erythropoietin receptor to stimulate proliferation, survival, differentiation and enucleation of erythroid progenitor cells. We undertook two complimentary approaches to find EPO-dependent pSTAT5 target genes in murine erythroid cells: RNA-seq of newly transcribed (4sU-labelled) RNA, and ChIP-seq for pSTAT5 30 minutes after EPO stimulation. We found 302 pSTAT5-occupied sites: ~15% of these reside in promoters while the rest reside within intronic enhancers or intergenic regions, some >100kb from the nearest TSS. The majority of pSTAT5 peaks contain a central palindromic GAS element, TTCYXRGAA. There was significant enrichment for GATA motifs and CACCC-box motifs within the neighbourhood of pSTAT5-bound peaks, and GATA1 and/or KLF1 co-occupancy at many sites. Using 4sU-RNA-seq we determined the EPO-induced transcriptome and validated differentially expressed genes using dynamic CAGE data and qRT-PCR. We identified known direct pSTAT5 target genes such as Bcl2l1, Pim1 and Cish, and many new targets likely to be involved in driving erythroid cell differentiation including those involved in mRNA splicing (Rbm25), epigenetic regulation (Suv420h2), and EpoR turnover (Clint1/EpsinR). Some of these new EpoR-JAK2-pSTAT5 target genes could be used as biomarkers for monitoring disease activity in polycythaemia vera, and for monitoring responses to JAK inhibitors. PMID:28732065

  17. High-Risk Human Papillomavirus Targets Crossroads in Immune Signaling

    PubMed Central

    Tummers, Bart; Van Der Burg, Sjoerd H.

    2015-01-01

    Persistent infections with a high-risk type human papillomavirus (hrHPV) can progress to cancer. High-risk HPVs infect keratinocytes (KCs) and successfully suppress host immunity for up to two years despite the fact that KCs are well equipped to detect and initiate immune responses to invading pathogens. Viral persistence is achieved by active interference with KCs innate and adaptive immune mechanisms. To this end hrHPV utilizes proteins encoded by its viral genome, as well as exploits cellular proteins to interfere with signaling of innate and adaptive immune pathways. This results in impairment of interferon and pro-inflammatory cytokine production and subsequent immune cell attraction, as well as resistance to incoming signals from the immune system. Furthermore, hrHPV avoids the killing of infected cells by interfering with antigen presentation to antigen-specific cytotoxic T lymphocytes. Thus, hrHPV has evolved multiple mechanisms to avoid detection and clearance by both the innate and adaptive immune system, the molecular mechanisms of which will be dealt with in detail in this review. PMID:26008697

  18. Cancer cell signaling pathways targeted by spice-derived nutraceuticals.

    PubMed

    Sung, Bokyung; Prasad, Sahdeo; Yadav, Vivek R; Aggarwal, Bharat B

    2012-01-01

    Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1'-acetoxychavicol acetate, anethole, capsaicin, cardamonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer.

  19. Cancer Cell Signaling Pathways Targeted by Spice-Derived Nutraceuticals

    PubMed Central

    Sung, Bokyung; Prasad, Sahdeo; Yadav, Vivek R.; Aggarwal, Bharat B.

    2012-01-01

    Extensive research within the last half a century has revealed that cancer is caused by dysregulation of as many as 500 different gene products. Most natural products target multiple gene products and thus are ideally suited for prevention and treatment of various chronic diseases, including cancer. Dietary agents such as spices have been used extensively in the Eastern world for a variety of ailments for millennia, and five centuries ago they took a golden journey to the Western world. Various spice-derived nutraceuticals, including 1′-acetoxychavicol acetate, anethole, capsaicin, car-damonin, curcumin, dibenzoylmethane, diosgenin, eugenol, gambogic acid, gingerol, thymoquinone, ursolic acid, xanthohumol, and zerumbone derived from galangal, anise, red chili, black cardamom, turmeric, licorice, fenugreek, clove, kokum, ginger, black cumin, rosemary, hop, and pinecone ginger, respectively, are the focus of this review. The modulation of various transcription factors, growth factors, protein kinases, and inflammatory mediators by these spice-derived nutraceuticals are described. The anticancer potential through the modulation of various targets is also the subject of this review. Although they have always been used to improve taste and color and as a preservative, they are now also used for prevention and treatment of a wide variety of chronic inflammatory diseases, including cancer. PMID:22149093

  20. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies.

    PubMed

    Xia, Bing; Qu, Fulian; Yuan, Tian; Zhang, Yizhuo

    2015-12-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3'-kinase and Bruton's tyrosine kinase (BTK). Ibrutinib, an oral irreversible BTK inhibitor, has emerged as a promising targeted therapy for patients with B-cell malignancies. The present review discusses the current understanding of BTK-mediated BCR signaling in the biology and pathobiology of normal and malignant B cells, and the cellular interaction with the tumor microenvironment. The data on ibrutinib in the preclinical and clinical settings is also discussed, and perspectives for the future use of ibrutinib are outlined.

  1. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies

    PubMed Central

    XIA, BING; QU, FULIAN; YUAN, TIAN; ZHANG, YIZHUO

    2015-01-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3′-kinase and Bruton's tyrosine kinase (BTK). Ibrutinib, an oral irreversible BTK inhibitor, has emerged as a promising targeted therapy for patients with B-cell malignancies. The present review discusses the current understanding of BTK-mediated BCR signaling in the biology and pathobiology of normal and malignant B cells, and the cellular interaction with the tumor microenvironment. The data on ibrutinib in the preclinical and clinical settings is also discussed, and perspectives for the future use of ibrutinib are outlined. PMID:26788133

  2. Targeting the BLyS-APRIL signaling pathway in SLE.

    PubMed

    La Cava, Antonio

    2013-09-01

    The B lymphocyte stimulator (BLyS)-A PRoliferation-Inducing Ligand (APRIL) signaling pathway has an important role in the selection, maturation and survival of B cells and plays a significant role in the pathogenesis of systemic lupus erythematosus (SLE). The inhibition of BLyS, a survival factor for transitional and mature B cells, has recently proven to be successful in large phase III clinical trials that led to the approval of an anti-BLyS monoclonal antibody (belimumab) for the treatment of SLE. Yet, there is currently a need to both understand better the mechanisms of action of belimumab in SLE and better define the subsets of patients that are more likely to respond to the drug.

  3. MicroRNAs-novel therapeutic targets of eicosanoid signalling.

    PubMed

    Ochs, Meike J; Steinhilber, Dieter; Suess, Beatrix

    2014-01-01

    MicroRNAs (miRNAs) have emerged as important regulators in human physiological and pathological processes. We summarize the current knowledge about the role of miRNA involved in the control of inflammatory responses with a special focus on eicosanoid signalling. Cyclooxygenase 2 - the key enzyme of the prostanoid pathway - is regulated by different miRNAs such as miRNA-101, miR199a, miR26b and miR-146a. In contrast to this, the understanding of miRNA regulation on enzymes of the leukotriene biosynthesis is just at the beginning. The knowledge of miRNAs regulating enzymes of the eicosanoid pathway offers a new way for the development of new therapeutic concepts for the treatment of inflammatory diseases.

  4. The subfornical organ: a central target for circulating feeding signals.

    PubMed

    Pulman, Katherine J; Fry, W Mark; Cottrell, G Trevor; Ferguson, Alastair V

    2006-02-15

    The mechanisms through which circulating ghrelin relays hunger signals to the CNS are not yet fully understood. In this study, we have examined the potential role of the subfornical organ (SFO), a circumventricular structure that lacks the normal blood-brain barrier, as a CNS site in which ghrelin acts to influence the hypothalamic centers controlling food intake. We report that ghrelin increased intracellular calcium concentrations in 28% (12 of 43) of dissociated SFO neurons and that the SFO expresses mRNA for the growth hormone secretagogue receptor. Whole-cell patch recordings from SFO neurons demonstrated that in 29% (9 of 31) of neurons tested ghrelin induced a mean depolarization of 7.4 +/- 0.69 mV, accompanied by an increase in action potential frequency. Voltage-clamp recordings revealed that ghrelin activates a putative nonselective cationic conductance. Previous reports that the satiety signal amylin exerts similar excitatory effects on SFO neurons led us to examine whether these two peptides influence different subpopulations of SFO neurons. Concentration-dependent depolarizing effects of amylin were observed in 59% (28 of 47) of SFO neurons (mean depolarization, 8.32 +/- 0.60 mV). In contrast to ghrelin, voltage-clamp recordings suggest that amylin influences a voltage-dependent current activated at depolarized potentials. We tested single SFO neurons with both peptides and identified cells responsive only to ghrelin (n = 9) and only to amylin (n = 7) but no cells that responded to both peptides. These data support a role for the SFO as a center at which ghrelin and amylin may influence separate subpopulations of neurons to influence the hypothalamic regulation of feeding.

  5. Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis.

    PubMed

    Finetti, Pascal; Cervera, Nathalie; Charafe-Jauffret, Emmanuelle; Chabannon, Christian; Charpin, Colette; Chaffanet, Max; Jacquemier, Jocelyne; Viens, Patrice; Birnbaum, Daniel; Bertucci, François

    2008-02-01

    Breast cancer is a heterogeneous disease made of various molecular subtypes with different prognosis. However, evolution remains difficult to predict within some subtypes, such as luminal A, and treatment is not as adapted as it should be. Refinement of prognostic classification and identification of new therapeutic targets are needed. Using oligonucleotide microarrays, we profiled 227 breast cancers. We focused our analysis on two major breast cancer subtypes with opposite prognosis, luminal A (n = 80) and basal (n = 58), and on genes encoding protein kinases. Whole-kinome expression separated luminal A and basal tumors. The expression (measured by a kinase score) of 16 genes encoding serine/threonine kinases involved in mitosis distinguished two subgroups of luminal A tumors: Aa, of good prognosis and Ab, of poor prognosis. This classification and its prognostic effect were validated in 276 luminal A cases from three independent series profiled across different microarray platforms. The classification outperformed the current prognostic factors in univariate and multivariate analyses in both training and validation sets. The luminal Ab subgroup, characterized by high mitotic activity compared with luminal Aa tumors, displayed clinical characteristics and a kinase score intermediate between the luminal Aa subgroup and the luminal B subtype, suggesting a continuum in luminal tumors. Some of the mitotic kinases of the signature represent therapeutic targets under investigation. The identification of luminal A cases of poor prognosis should help select appropriate treatment, whereas the identification of a relevant kinase set provides potential targets.

  6. Preprotein mature domains contain translocase targeting signals that are essential for secretion.

    PubMed

    Chatzi, Katerina E; Sardis, Marios Frantzeskos; Tsirigotaki, Alexandra; Koukaki, Marina; Šoštarić, Nikolina; Konijnenberg, Albert; Sobott, Frank; Kalodimos, Charalampos G; Karamanou, Spyridoula; Economou, Anastassios

    2017-05-01

    Secretory proteins are only temporary cytoplasmic residents. They are typically synthesized as preproteins, carrying signal peptides N-terminally fused to their mature domains. In bacteria secretion largely occurs posttranslationally through the membrane-embedded SecA-SecYEG translocase. Upon crossing the plasma membrane, signal peptides are cleaved off and mature domains reach their destinations and fold. Targeting to the translocase is mediated by signal peptides. The role of mature domains in targeting and secretion is unclear. We now reveal that mature domains harbor their own independent targeting signals (mature domain targeting signals [MTSs]). These are multiple, degenerate, interchangeable, linear or 3D hydrophobic stretches that become available because of the unstructured states of targeting-competent preproteins. Their receptor site on the cytoplasmic face of the SecYEG-bound SecA is also of hydrophobic nature and is located adjacent to the signal peptide cleft. Both the preprotein MTSs and their receptor site on SecA are essential for protein secretion. Evidently, mature domains have their own previously unsuspected distinct roles in preprotein targeting and secretion. © 2017 Chatzi et al.

  7. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells.

    PubMed

    Martelli, A M; Evangelisti, C; Follo, M Y; Ramazzotti, G; Fini, M; Giardino, R; Manzoli, L; McCubrey, J A; Cocco, L

    2011-01-01

    Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs.

  8. Luminal ANG II is internalized as a complex with AT1R/AT2R heterodimers to target endoplasmic reticulum in LLC-PK1 cells.

    PubMed

    Ferrão, Fernanda M; Cardoso, Luiza H D; Drummond, Heather A; Li, Xiao C; Zhuo, Jia L; Gomes, Dayene S; Lara, Lucienne S; Vieyra, Adalberto; Lowe, Jennifer

    2017-08-01

    ANG II has many biological effects in renal physiology, particularly in Ca(2+) handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT1 and AT2 receptors (AT1R and AT2R) to stimulate sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT1R/AT2R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK1 cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT1R/AT2R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine-but not Pitstop2-blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT1R, AT2R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT1/AT2 complex to target ER, where it might trigger intracellular Ca(2+) responses. Copyright © 2017 the American Physiological Society.

  9. Targeting Notch signaling as a novel therapy for retinoblastoma

    PubMed Central

    Asnaghi, Laura; Tripathy, Arushi; Yang, Qian; Kaur, Harpreet; Hanaford, Allison; Yu, Wayne; Eberhart, Charles G.

    2016-01-01

    Retinoblastoma is the most common intraocular malignancy of childhood. Notch plays a key role in retinal cells from which retinoblastomas arise, and we therefore studied the role of Notch signaling in promoting retinoblastoma proliferation. Moderate or strong nuclear expression of Hes1 was found in 10 of 11 human retinoblastoma samples analyzed immunohistochemically, supporting a role for Notch in retinoblastoma growth. Notch pathway components were present in WERI Rb1 and Y79 retinoblastoma lines, with Jag2 and DLL4 more highly expressed than other ligands, and Notch1 and Notch2 more abundant than Notch3. The cleaved/active form of Notch1 was detectable in both lines. Inhibition of the pathway, achieved using a γ-secretase inhibitor (GSI) or by downregulating Jag2, DLL4 or CBF1 using short hairpin RNA, potently reduced growth, proliferation and clonogenicity in both lines. Upregulation of CXCR4 and CXCR7 and downregulation of PI3KC2β were identified by microarray upon Jag2 suppression. The functional importance of PI3KC2β was confirmed using shRNA. Synergy was found by combining GSI with Melphalan at their IC50. These findings indicate that Notch pathway is active in WERI Rb1 and Y79, and in most human retinoblastoma samples, and suggest that Notch antagonists may represent a new approach to more effectively treat retinoblastoma. PMID:27661116

  10. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

    PubMed Central

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-01-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities. PMID:27446389

  11. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer.

    PubMed

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-08-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities.

  12. Luminal breast cancer: from biology to treatment.

    PubMed

    Ignatiadis, Michail; Sotiriou, Christos

    2013-09-01

    Oestrogen receptor (ER)-positive--or luminal--tumours represent around two-thirds of all breast cancers. Luminal breast cancer is a highly heterogeneous disease comprising different histologies, gene-expression profiles and mutational patterns, with very varied clinical courses and responses to systemic treatment. Despite adjuvant endocrine therapy and chemotherapy treatment for patients at high risk of relapse, both early and late relapses still occur, a fact that highlights the unmet medical needs of these patients. Ongoing research aims to identify those patients who can be spared adjuvant chemotherapy and who will benefit from extended adjuvant hormone therapy. This research also aims to explore the role of adjuvant bisphosphonates, to interrogate new agents for targeting minimal residual disease, and to address endocrine resistance. Data from next-generation sequencing studies have given us new insight into the biology of luminal breast cancer and, together with advances in preclinical models and the availability of newer targeted agents, have led to the testing of rationally chosen combination treatments in clinical trials. However, a major challenge will be to make sense of the large amount of patient genomic data that is becoming increasingly available. This analysis will be critical to our understanding how intertumour and intratumour heterogeneity can influence treatment response and resistance.

  13. The Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway as a Discovery Target in Stroke.

    PubMed

    Sun, Jing; Nan, Guangxian

    2016-05-01

    Protein kinases are critical modulators of a variety of intracellular and extracellular signal transduction pathways, and abnormal phosphorylation events can contribute to disease progression in a variety of diseases. As a result, protein kinases have emerged as important new drug targets for small molecule therapeutics. The mitogen-activated protein kinase (MAPK) signaling pathway transmits signals from the cell membrane to the nucleus in response to a variety of different stimuli. Because this pathway controls a broad spectrum of cellular processes, including growth, inflammation, and stress responses, it is accepted as a therapeutic target for cancer and peripheral inflammatory disorders. There is also increasing evidence that MAPK is an important regulator of ischemic and hemorrhagic cerebral vascular disease, raising the possibility that it might be a drug discovery target for stroke. In this review, we discuss the MAPK signaling pathway in association with its activation in stroke-induced brain injury.

  14. Synergistic target combination prediction from curated signaling networks: Machine learning meets systems biology and pharmacology.

    PubMed

    Chua, Huey Eng; Bhowmick, Sourav S; Tucker-Kellogg, Lisa

    2017-05-25

    Given a signaling network, the target combination prediction problem aims to predict efficacious and safe target combinations for combination therapy. State-of-the-art in silico methods use Monte Carlo simulated annealing (mcsa) to modify a candidate solution stochastically, and use the Metropolis criterion to accept or reject the proposed modifications. However, such stochastic modifications ignore the impact of the choice of targets and their activities on the combination's therapeutic effect and off-target effects, which directly affect the solution quality. In this paper, we present mascot, a method that addresses this limitation by leveraging two additional heuristic criteria to minimize off-target effects and achieve synergy for candidate modification. Specifically, off-target effects measure the unintended response of a signaling network to the target combination and is often associated with toxicity. Synergy occurs when a pair of targets exerts effects that are greater than the sum of their individual effects, and is generally a beneficial strategy for maximizing effect while minimizing toxicity. mascot leverages on a machine learning-based target prioritization method which prioritizes potential targets in a given disease-associated network to select more effective targets (better therapeutic effect and/or lower off-target effects); and on Loewe additivity theory from pharmacology which assesses the non-additive effects in a combination drug treatment to select synergistic target activities. Our experimental study on two disease-related signaling networks demonstrates the superiority of mascot in comparison to existing approaches. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Caveolins: targeting pro-survival signaling in the heart and brain

    PubMed Central

    Stary, Creed M.; Tsutsumi, Yasuo M.; Patel, Piyush M.; Head, Brian P.; Patel, Hemal H.; Roth, David M.

    2012-01-01

    The present review discusses intracellular signaling moieties specific to membrane lipid rafts (MLRs) and the scaffolding proteins caveolin and introduces current data promoting their potential role in the treatment of pathologies of the heart and brain. MLRs are discreet microdomains of the plasma membrane enriched in gylcosphingolipids and cholesterol that concentrate and localize signaling molecules. Caveolin proteins are necessary for the formation of MLRs, and are responsible for coordinating signaling events by scaffolding and enriching numerous signaling moieties in close proximity. Specifically in the heart and brain, caveolins are necessary for the cytoprotective phenomenon termed ischemic and anesthetic preconditioning. Targeted overexpression of caveolin in the heart and brain leads to induction of multiple pro-survival and pro-growth signaling pathways; thus, caveolins represent a potential novel therapeutic target for cardiac and neurological pathologies. PMID:23060817

  16. Failure of signed chromatic apparent motion with luminance masking.

    PubMed

    Yoshizawa, Tatsuya; Mullen, Kathy T; Baker, Curtis L

    2003-03-01

    It has been suggested that there are two types of chromatic motion mechanisms: signed chromatic motion, in which correspondence across successive frames is based on chromatic content of image regions, and unsigned chromatic motion based on movement of chromatically-defined borders. We investigate whether signed and unsigned red-green chromatic motion are mediated by a genuinely chromatic mechanism. Direction discrimination of signed and unsigned red-green chromatic motion were measured in the presence of a dynamic luminance masking noise. Increasing the luminance noise contrast systematically impaired signed motion, regardless of contrast and speed. This result suggests that signed red-green chromatic motion is derived from a luminance-based signal, rather than a genuinely chromatic motion mechanism. In the case of unsigned chromatic motion, there is no effect of luminance masking noise, indicating there exists a genuine chromatic mechanism for second-order motion perception.

  17. High-luminance LEDs replace incandescent lamps in new applications

    NASA Astrophysics Data System (ADS)

    Evans, David L.

    1997-04-01

    The advent of high luminance AlInGaP and InGaN LED technologies has prompted the use of LED devices in new applications formally illuminated by incandescent lamps. The luminous efficiencies of these new LED technologies equals or exceeds that attainable with incandescent sources, with reliability factors that far exceed those of incandescent sources. The need for a highly efficient, dependable, and cost effective replacement for incandescent lamps is being fulfilled with high luminance LED lamps. This paper briefly described some of the new applications incorporating high luminance LED lamps, traffic signals and roadway signs for traffic management, automotive exterior lighting, active matrix and full color displays for commercial advertising, and commercial aircraft panel lighting and military aircraft NVG compatible lighting.

  18. Nuclease-free target recycling signal amplification for ultrasensitive multiplexing DNA biosensing.

    PubMed

    Zhao, Zhihan; Chen, Shixing; Wang, Jianbang; Su, Jing; Xu, Jiaqiang; Mathur, Sanjay; Fan, Chunhai; Song, Shiping

    2017-08-15

    Ultrasensitive biosensing technologies without gene amplification held great promise for direct detection of DNA. Herein we report a novel biosensing method, combining target recycling signal-amplification strategy and a homemade electrochemical device. Especially, the target recycling was achieved by a strand displacement process, no needing the help of any nucleases. In the presence of target DNA, the recycling system could be activated to generate a cascade of assembly steps with three hairpin DNA segments. Each recycling process were accompanied by a disassembly step that the last hairpin DNA segment displaces target DNA from the complex at the end of each circulation, freeing targets to activate the self-assembly of more trefoil DNA structures. This biosensing method could detect target DNA at aM level and can distinguish target DNA from interfering DNAs, demonstrating its high sensitivity and high selectivity. Importantly, the biosensing method could work well with serum samples. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Endocrine disrupting chemicals targeting estrogen receptor signaling: Identification and mechanisms of action

    PubMed Central

    Shanle, Erin K.; Xu, Wei

    2011-01-01

    Many endocrine disrupting chemicals (EDCs) adversely impact estrogen signaling by interacting with two estrogen receptors (ERs): ERα and ERβ. Though the receptors have similar ligand binding and DNA binding domains, ERα and ERβ have some unique properties in terms of ligand selectivity and target gene regulation. EDCs that target ER signaling can modify genomic and non-genomic ER activity through direct interactions with ERs, indirectly through transcription factors like the aryl hydrocarbon receptor (AhR), or through modulation of metabolic enzymes that are critical for normal estrogen synthesis and metabolism. Many EDCs act through multiple mechanisms as exemplified by chemicals that bind both AhR and ER, such as 3-methylcholanthrene. Other EDCs that target ER signaling include phytoestrogens, bisphenolics, and organochlorine pesticides and many alter normal ER signaling through multiple mechanisms. EDCs can also display tissue-selective ER agonist and antagonist activities similar to selective estrogen receptor modulators (SERMs) designed for pharmaceutical use. Thus, biological effects of EDCs need to be carefully interpreted because EDCs can act through complex tissue-selective modulation of ERs and other signaling pathways in vivo. Current requirements by the U.S. Environmental Protection Agency require some in vitro and cell-based assays to identify EDCs that target ER signaling through direct and metabolic mechanisms. Additional assays may be useful screens for identifying EDCs that act through alternative mechanisms prior to further in vivo study. PMID:21053929

  20. Time-reversal imaging with multiple signal classification considering multiple scattering between the targets

    NASA Astrophysics Data System (ADS)

    Gruber, Fred K.; Marengo, Edwin A.; Devaney, Anthony J.

    2004-06-01

    The time-reversal imaging with multiple signal classification method for the location of point targets developed within the framework of the Born approximation in Lehman and Devaney [``Transmission mode time-reversal super-resolution imaging,'' J. Acoust. Soc. Am. 113, 2742-2753 (2003)] is generalized to incorporate multiple scattering between the targets. It is shown how the same method can be used in the location of point targets even if there is multiple scattering between them. On the other hand, both the conventional images and the calculated values of the target scattering amplitudes are scattering model-dependent.

  1. Target recognition by maximizing heterogeneity of signal samples collected for discrimination with respect to an observed signal

    NASA Astrophysics Data System (ADS)

    Nechval, Nicholas A.

    1995-07-01

    This paper deals with the problem of how to identify targets or signals in noise, which represents, mathematically, the problem of classifying an observed target data sample as coming from one of several populations. Some of the information about the alternative distributions of populations has been obtained from signal data samples collected for discrimination. Each sample is declared to be realization of a specific stochastic process. By this step each sample is attached to just one out of a set of possible signals with distinct characteristics. We are dealing with the case when the alternative distributions of populations are multivariate normal with different mean vectors and covariance matrices. It is assumed that all parameters are unknown. Also, the univariate case is considered. It is shown how certain tests of homogeneity or normality of several samples of the data can be used to transform a set of signal data samples into some statistic that measures either distance from homogeneity or distance from normality of these samples, respectively. This statistic is then used to construct sample based discriminant rule which either maximizes distance from homogeneity or minimizes distance from normality, respectively, with respect to an observed signal. The above discriminant rules are applied to obtain new procedures of target recognition which are relatively simple to carry out and can be easily used, say, for bird recognition by radar in order to preclude the possibility of collisions between aircraft and birds, etc. In those situations when we deal with small samples of the data, the procedures proposed herein are recommended. An illustrative numerical example is given.

  2. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting.

    PubMed

    Jonckheere, Nicolas; Vasseur, Romain; Van Seuningen, Isabelle

    2017-03-01

    RAS belongs to the super family of small G proteins and plays crucial roles in signal transduction from membrane receptors in the cell. Mutations of K-RAS oncogene lead to an accumulation of GTP-bound proteins that maintains an active conformation. In the pancreatic ductal adenocarcinoma (PDAC), one of the most deadly cancers in occidental countries, mutations of the K-RAS oncogene are nearly systematic (>90%). Moreover, K-RAS mutation is the earliest genetic alteration occurring during pancreatic carcinogenetic sequence. In this review, we discuss the central role of K-RAS mutations and their tremendous diversity of biological properties by the interconnected regulation of signaling pathways (MAPKs, NF-κB, PI3K, Ral…). In pancreatic ductal adenocarcinoma, transcriptome analysis and preclinical animal models showed that K-RAS mutation alters biological behavior of PDAC cells (promoting proliferation, migration and invasion, evading growth suppressors, regulating mucin pattern, and miRNA expression). K-RAS also impacts tumor microenvironment and PDAC metabolism reprogramming. Finally we discuss therapeutic targeting strategies of K-RAS that have been developed without significant clinical success so far. As K-RAS is considered as the undruggable target, targeting its multiple effectors and target genes should be considered as potential alternatives.

  3. Signal processing and target discrimination algorithms for a rosette scan tracker

    NASA Astrophysics Data System (ADS)

    Morin, Andre

    A prototype of an infrared rosette scan tracker has been developed to evaluate the immunity of this type of tracker against decoys which can be deployed from a target aircraft. The performance of the tracker depends on the signal processing and the target discrimination algorithms employed to control the tracker. Because of the low resolution of the resulting target image, the rosette scanner does not have the ability to recognize the targets by their shape characteristics. In addition, targets which are too close appear simultaneously in the tracker instantaneous field of view. These targets are then detected in one single pulse signal. To prevent the tracker from breaking its lock onto its target, the transients in amplitude and width of the selected pulses are detected when decoys are deployed from the target. The occurrence of such transients initiates the computation of the drift between the estimated target position and the center of the pulse for the two axes to determine the direction in which the decoy was deployed. The performance of this processing technique is illustrated and some improvements are suggested.

  4. Targeting two-component signal transduction: a novel drug discovery system.

    PubMed

    Okada, Ario; Gotoh, Yasuhiro; Watanabe, Takafumi; Furuta, Eiji; Yamamoto, Kaneyoshi; Utsumi, Ryutaro

    2007-01-01

    We have developed two screening systems for isolating inhibitors that target bacterial two-component signal transduction: (1) a differential growth assay using a temperature-sensitive yycF mutant (CNM2000) of Bacillus subtilis, which is supersensitive to histidine kinase inhibitors, and (2) a high-throughput genetic system for targeting the homodimerization of histidine kinases essential for the bacterial two-component signal transduction. By using these methods, we have been able to identify various types of inhibitors that block the autophosphorylation of histidine kinases with different modes of actions.

  5. Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models

    PubMed Central

    Salavert, Francisco; Hidago, Marta R.; Amadoz, Alicia; Çubuk, Cankut; Medina, Ignacio; Crespo, Daniel; Carbonell-Caballero, Jose; Dopazo, Joaquín

    2016-01-01

    The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org. PMID:27137885

  6. Targeted interception of signaling reactive oxygen species in the vascular endothelium

    PubMed Central

    Han, Jingyan; Shuvaev, Vladimir V; Muzykantov, Vladimir R

    2017-01-01

    Reactive oxygen species (ROS) are implicated as injurious and as signaling agents in human maladies including inflammation, hyperoxia, ischemia-reperfusion and acute lung injury. ROS produced by the endothelium play an important role in vascular pathology. They quench, for example, nitric oxide, and mediate pro-inflammatory signaling. Antioxidant interventions targeted for the vascular endothelium may help to control these mechanisms. Animal studies have demonstrated superiority of targeting ROS-quenching enzymes catalase and superoxide dismutase to endothelial cells over nontargeted formulations. A diverse arsenal of targeted antioxidant formulations devised in the last decade shows promising results for specific quenching of endothelial ROS. In addition to alleviation of toxic effects of excessive ROS, these targeted interventions suppress pro-inflammatory mechanisms, including endothelial cytokine activation and barrier disruption. These interventions may prove useful in experimental biomedicine and, perhaps, in translational medicine. PMID:22834201

  7. Diverse amino acid residues function within the type 1 peroxisomal targeting signal. Implications for the role of accessory residues upstream of the type 1 peroxisomal targeting signal.

    PubMed Central

    Mullen, R T; Lee, M S; Flynn, C R; Trelease, R N

    1997-01-01

    The purpose of this study was to determine whether the plant type 1 peroxisomal targeting signal (PTS1) utilizes amino acid residues that do not strictly adhere to the serine-lysine-leucine (SKL) motif (small-basic-hydrophobic residues). Selected residues were appended to the C terminus of chloramphenicol acetyltransferase (CAT) and were tested for their ability to target CAT fusion proteins to glyoxysomes in tobacco (Nicotiana tabacum L.) cv Bright Yellow 2 suspension-cultured cells. CAT was redirected from the cytosol into glyoxysomes by a wide range of residues, i.e. A/C/G/S/T-H/K/ L/N/R-I/L/M/Y. Although L and N at the -2 position (-SLL, -ANL) do not conform to the SKL motif, both functioned, but in a temporally less-efficient manner. Other SKL divergent residues, however, did not target CAT to glyoxysomes, i.e. F or P at the -3 position (-FKL, -PKL), S or T at the -2 position (-SSI, STL), or D at the -1 position (-SKD). The targeting inefficiency of CAT-ANL could be ameliorated when K was included at the -4 position (-KANL). In summary, the plant PTS1 mostly conforms to the SKL motif. For those PTS1s that possess nonconforming residue(s), other residues upstream of the PTS1 appear to function as accessory sequences that enhance the temporal efficiency of peroxisomal targeting. PMID:9390426

  8. The Inositide Signaling Pathway As a Target for Treating Gastric Cancer and Colorectal Cancer

    PubMed Central

    Kim, Hong Jun; Lee, Suk-young; Oh, Sang Cheul

    2016-01-01

    Gastric cancer and colorectal cancer are the leading cause of cancer mortality and have a dismal prognosis. The introduction of biological agents to treat these cancers has resulted in improved outcomes, and combination chemotherapy with targeted agents and conventional chemotherapeutic agents is regarded as standard therapy. Additional newly clarified mechanisms of oncogenesis and resistance to targeted agents require the development of new biologic agents. Aberrant activation of the inositide signaling pathway by a loss of function PTEN mutation or gain of function mutation/amplification of PIK3CA is an oncogenic mechanism in gastric cancer and colorectal cancer. Clinical trials with biologic agents that target the inositide signaling pathway are being performed to further improve treatment outcomes of patients with advanced gastric cancer and metastatic colorectal cancer (CRC). In this review we summarize the inositide signaling pathway, the targeted agents that inhibit abnormal activation of this signaling pathway and the clinical trials currently being performed in patients with advanced or metastatic gastric cancer and metastatic CRC using these targeted agents. PMID:27242542

  9. Localized signal-to-noise ratio of man and vehicle size targets

    NASA Astrophysics Data System (ADS)

    Estrera, Joseph P.

    2009-05-01

    This paper presents analysis of digital images from single and dual sensor systems of man and vehicle size targets at low light conditions (at or below starlight conditions, 10-4 foot candles). More specifically, the image analysis will focus on measurement and interpretation of localized signal to noise ratio (LSNR) from these targets and connection to target contrast and spatial range. First, this paper will define localized signal to noise ratio and its context to information rich and poor targets to various background scenes. Then this definition will be applied to an artificially generated target to background scene composed of various gray scale square targets with various contrasts and Gaussian noise levels embedded on gray scale background with defined contrast and Gaussian noise level. The next section defines the field experiment and equipment setup to measure localized SNR for actual man and vehicle size targets in low light level conditions using a fused dual sensor system. Initial results of this field experiment shows line shape behavior of localized SNR is better represented by a decaying exponential function to spatial range likely related to Beer-Lambert Law of atmospheric radiation propagation. Finally, localized SNR is greater for fused dual sensor system as compared to its respective single sensor system modes for man and vehicle targets specified in this paper. Paper has been cleared by DOD/OSR for Public Release under OSR Ref: 07-S-1131 on April 16, 2007.

  10. Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

    PubMed Central

    Harris, Peter C.

    2014-01-01

    Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling. PMID:24335972

  11. Modeling signaling pathways leading to wrinkle formation: identification of the skin aging target.

    PubMed

    Chauhan, Pallavi; Shakya, Madhvi

    2009-01-01

    In the present scenario, wrinkle formation, prominent sign of skin ageing, is one of the most demanding areas of research. This burgeoning research demand to reduce, delay and restore the effects of skin ageing has led to the study of various signaling pathways leading to wrinkle formation. Wrinkles appear on skin due to influence of intrinsic and extrinsic factors on mitogenic reactions and signal transduction pathways. The aim of the present study is to analyze each protein involved in the signaling pathway leading to dilapidation of collagen and an attempt has been made to compare different signal transduction pathways to identify a common target for skin ageing. In the present work, bioinformatics tools have been used to extract information from already existing experimental data. The statistical techniques are used for further analysis and make useful predictions for skin ageing. Stressors like UV irradiation, osmotic stress and heat shock have been reported to activate epidermal growth factor receptor, interleukin 1 receptor, tumor necrosis factor receptor, platelet-derived growth factor receptor and platelet activation factor receptor signaling pathways, which lead to the production of matrix metalloproteinases, collagen degradation and, consequently, wrinkle formation. When all the five signaling pathways were modeled, the c-jun part of the AP-1 transcription factor was found to be a common intermediate protein involved in all the signaling cascades. Moreover, it shows differential expression in the skin on response to stressors. We proposed c-jun to be the most potent target for drug designing against wrinkle formation.

  12. The role of cyclic nucleotide signaling pathways in cancer: targets for prevention and treatment.

    PubMed

    Fajardo, Alexandra M; Piazza, Gary A; Tinsley, Heather N

    2014-02-26

    For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms-induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors-is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers.

  13. The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment

    PubMed Central

    Fajardo, Alexandra M.; Piazza, Gary A.; Tinsley, Heather N.

    2014-01-01

    For more than four decades, the cyclic nucleotides cyclic AMP (cAMP) and cyclic GMP (cGMP) have been recognized as important signaling molecules within cells. Under normal physiological conditions, cyclic nucleotides regulate a myriad of biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer. While the distinct molecular alterations responsible for these effects vary depending on the specific cancer type, several studies have demonstrated that activation of cyclic nucleotide signaling through one of three mechanisms—induction of cyclic nucleotide synthesis, inhibition of cyclic nucleotide degradation, or activation of cyclic nucleotide receptors—is sufficient to inhibit proliferation and activate apoptosis in many types of cancer cells. These findings suggest that targeting cyclic nucleotide signaling can provide a strategy for the discovery of novel agents for the prevention and/or treatment of selected cancers. PMID:24577242

  14. Emerging translational approaches to target STAT3 signalling and its impact on vascular disease

    PubMed Central

    Dutzmann, Jochen; Daniel, Jan-Marcus; Bauersachs, Johann; Hilfiker-Kleiner, Denise; Sedding, Daniel G.

    2015-01-01

    Acute and chronic inflammation responses characterize the vascular remodelling processes in atherosclerosis, restenosis, pulmonary arterial hypertension, and angiogenesis. The functional and phenotypic changes in diverse vascular cell types are mediated by complex signalling cascades that initiate and control genetic reprogramming. The signalling molecule's signal transducer and activator of transcription 3 (STAT3) plays a key role in the initiation and continuation of these pathophysiological changes. This review highlights the pivotal involvement of STAT3 in pathological vascular remodelling processes and discusses potential translational therapies, which target STAT3 signalling, to prevent and treat cardiovascular diseases. Moreover, current clinical trials using highly effective and selective inhibitors of STAT3 signalling for distinct diseases, such as myelofibrosis and rheumatoid arthritis, are discussed with regard to their vascular (side-) effects and their potential to pave the way for a direct use of these molecules for the prevention or treatment of vascular diseases. PMID:25784694

  15. Predicting a Luminous Red Nova

    NASA Astrophysics Data System (ADS)

    Van Noord, Daniel; Molnar, Larry; Kinemuchi, Karen; Steenwyk, Steven; Alexander, Cara; Spedden, Chris; Kobulnicky, Henry

    2016-05-01

    Luminous Red Novae (LRN) are rare transient events believed to be caused by the merger of a main sequence contact binary. Since the discovery of the prototype, V838 Mon, only a handful of LRN events have been observed. Tylenda et al. (2011) analyzed the OGLE data preceding the 2008 Novae of V1309 Sco and found that it exhibited a similar light curve to that of a contact binary with one interesting exception, the orbital period of V1309 Sco showed exponential period change going to zero. Unfortunately the system was discovered to be a binary after the merger, preventing any targeted observations to narrow down how the system entered this unusual state. However the extreme period change observed in V1309 Sco gives us a signature to look for in other contact binaries, allowing the discovery of merger candidates for follow up. We will present an analysis of light curves and spectra of KIC 9832227 (NSVS 5597755) that show it is a contact binary system with a negative period derivative that is becoming more extreme with time. These data span more than 15 years and are taken from the NSVS, ASAS, WASP, and Kepler surveys, with ongoing measurements from the Calvin College Observatory and the Apache Point Observatory. The ongoing period change observed in the system is consistent with the exponential model fit from V1309 Sco and the rate of period change has surpassed that of all other measured contact binaries with the exception of V1309 Sco. If the exponential period decay continues the system will likely merge between 2019 and 2022 resulting in a naked eye nova. If this event occurs, this star will present the unprecedented opportunity to study a LRN progenitor and to follow the evolution of the merger.

  16. Dissection of local Ca(2+) signals inside cytosol by ER-targeted Ca(2+) indicator.

    PubMed

    Niwa, Fumihiro; Sakuragi, Shigeo; Kobayashi, Ayana; Takagi, Shin; Oda, Yoichi; Bannai, Hiroko; Mikoshiba, Katsuhiko

    2016-10-07

    Calcium (Ca(2+)) is a versatile intracellular second messenger that operates in various signaling pathways leading to multiple biological outputs. The diversity of spatiotemporal patterns of Ca(2+) signals, generated by the coordination of Ca(2+) influx from the extracellular space and Ca(2+) release from the intracellular Ca(2+) store the endoplasmic reticulum (ER), is considered to underlie the diversity of biological outputs caused by a single signaling molecule. However, such Ca(2+) signaling diversity has not been well described because of technical limitations. Here, we describe a new method to report Ca(2+) signals at subcellular resolution. We report that OER-GCaMP6f, a genetically encoded Ca(2+) indicator (GECI) targeted to the outer ER membrane, can monitor Ca(2+) release from the ER at higher spatiotemporal resolution than conventional GCaMP6f. OER-GCaMP6f was used for in vivo Ca(2+) imaging of C. elegans. We also found that the spontaneous Ca(2+) elevation in cultured astrocytes reported by OER-GCaMP6f showed a distinct spatiotemporal pattern from that monitored by plasma membrane-targeted GCaMP6f (Lck-GCaMP6f); less frequent Ca(2+) signal was detected by OER-GCaMP6f, in spite of the fact that Ca(2+) release from the ER plays important roles in astrocytes. These findings suggest that targeting of GECIs to the ER outer membrane enables sensitive detection of Ca(2+) release from the ER at subcellular resolution, avoiding the diffusion of GECI and Ca(2+). Our results indicate that Ca(2+) imaging with OER-GCaMP6f in combination with Lck-GCaMP6f can contribute to describing the diversity of Ca(2+) signals, by enabling dissection of Ca(2+) signals at subcellular resolution. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Dual-Pump CARS Thermometry in Highly Luminous Flames

    NASA Astrophysics Data System (ADS)

    Kearney, Sean

    2005-11-01

    Dual pump coherent anti-Stokes Raman scattering (CARS) investigations have been conducted in highly luminous flames. While the spatial coherence of the CARS signal permits efficient rejection of many optical background sources, spatially incoherent and spectrally broad interference from highly luminous flames can still be problematic. We have compared two approaches for time-resolved gating of the CARS signal beam against the luminous background from heavily sooting flames; (1) a fast liquid crystal shutter in conjunction with a standard unintensified CCD and (2) an interline-transfer CCD with reduced dynamic range. The fidelity of the dual-pump CARS facility for temperature measurements in these extremely hostile environments is evaluated and the relative merits of both detection approaches are discussed.

  18. Screening of nuclear targeting proteins in Acinetobacter baumannii based on nuclear localization signals.

    PubMed

    Moon, Dong Chan; Gurung, Mamata; Lee, Jung Hwa; Lee, Yong Seok; Choi, Chi Won; Kim, Seung Il; Lee, Je Chul

    2012-05-01

    Nuclear targeting of bacterial proteins is an emerging pathogenic mechanism in bacteria. However, due to the absence of an appropriate screening system for nuclear targeting proteins, systematic approaches to nuclear targeting of bacterial proteins and subsequent host cell pathology are limited. In this study, we developed a screening system for nuclear targeting proteins in Acinetobacter baumannii using a combination of bioinformatic analysis based on nuclear localization signal (NLS) and the Gateway(®) recombinational cloning system. Among 3367 open reading frames of A. baumannii ATCC 17978, 34 functional or hypothetical proteins were predicted to carry the putative NLS sequences. Of the 29 clones generated by the Gateway(®) recombinational cloning system, 14 proteins tagged with green fluorescent protein (GFP) were targeted to nuclei of host cells. Among the 14 nuclear targeting proteins, S21, L20, and L32 ribosomal proteins and transposase carried putative nuclear export signal (NES) sequences, but only transposase harbored the functional NES. After translocation to nuclei of host cells, four A. baumannii proteins induced cytotoxicity. In conclusion, we have developed a screening system for nuclear targeting proteins in A. baumannii. This system may open the way to a new field of bacterial pathogenesis.

  19. Selective Targeting of RANK Signaling Pathways as New Therapeutic Strategies for Osteoporosis

    PubMed Central

    Jules, Joel; Ashley, Jason W.; Feng, Xu

    2010-01-01

    Importance of the field Osteoporosis has become a worldwide health and social issue due to an aging population. Four major antiresorptive drugs (agents capable of inhibiting osteoclast formation and/or function) are currently available on the market: estrogen, selective estrogen receptor modulators (SERMs), bisphosphonates and calcitonin. These drugs either lack satisfactory efficacy or have potential to cause serious side effects. Thus, development of more efficacious and safer drugs is warranted. Areas covered in this review The discovery of the receptor activator of NF-κB Ligand (RANKL) and its two receptors, RANK and osteoprotegerin (OPG), has not only established a crucial role for the RANKL/RANK/OPG axis in osteoclast biology but also created a great opportunity to develop new drugs targeting this system for osteoporosis therapy. This review focuses on discussion of therapeutic targeting of RANK signaling. What the reader will gain An update on the functions of RANKL and an overview of the known RANK signaling pathways in osteoclasts. A discussion of rationales for exploring RANK signaling pathways as potent and specific therapeutic targets to promote future development of better drugs for osteoporosis. Take home message Several RANK signaling components have the potential to serve as potent and specific therapeutic targets for osteoporosis. PMID:20678025

  20. Ultrasensitive fluorescence polarization DNA detection by target assisted exonuclease III-catalyzed signal amplification.

    PubMed

    Zhang, Min; Guan, Yi-Meng; Ye, Bang-Ce

    2011-03-28

    Single stranded DNA sequences can be detected by target assisted exonuclease III-catalyzed signal amplification fluorescence polarization (TAECA-FP). The method offers an impressive detection limit of 83 aM within one hour for DNA detection and exhibits high discrimination ability even against a single base mismatch.

  1. Aptamer/target binding-induced triple helix forming for signal-on electrochemical biosensing.

    PubMed

    Mao, Yinfei; Liu, Jinquan; He, Dinggen; He, Xiaoxiao; Wang, Kemin; Shi, Hui; Wen, Li

    2015-10-01

    Owing to its diversified structures, high affinity, and specificity for binding a wide range of non-nucleic acid targets, aptamer is a useful molecular recognition tool for the design of various biosensors. Herein, we report a new signal-on electrochemical biosensing platform which is based on an aptamer/target binding-induced strand displacement and triple-helix forming. The biosensing platform is composed of a signal transduction probe (STP) modified with a methylene blue (MB) and a sulfhydryl group, a triplex-forming oligonucleotides probe (TFO) and a target specific aptamer probe (Apt). Through hybridization with the TFO probe and the Apt probe, the self-assembled STP on Au electrode via Au-S bonding keeps its rigid structure. The MB on the STP is distal to the Au electrode surface. It is eT off state. Target binding releases the Apt probe and liberates the end of the MB tagged STP to fold back and form a triplex-helix structure with TFO (STP/TFO/STP), allowing MB to approach the Au electrode surface and generating measurable electrochemical signals (eT ON). As test for the feasibility and universality of this signal-on electrochemical biosensing platform, two aptamers which bind to adenosine triphosphate (ATP) and human α-thrombin (Tmb), respectively, are selected as models. The detection limit of ATP was 7.2 nM, whereas the detection limit of Tmb was 0.86 nM.

  2. Hedgehog signaling pathway is a potential therapeutic target for gallbladder cancer

    PubMed Central

    Matsushita, Shojiro; Onishi, Hideya; Nakano, Kenji; Nagamatsu, Iori; Imaizumi, Akira; Hattori, Masami; Oda, Yoshinao; Tanaka, Masao; Katano, Mitsuo

    2014-01-01

    Gallbladder cancer (GBC) is a particularly deadly type of cancer with a 5-year survival rate of only 10%. New effective therapeutic strategies are greatly needed. Recently, we have shown that Hedgehog (Hh) signaling is reactivated in various types of cancer and is a potential therapeutic target. However, little is known about the biological significance of Hh signaling in human GBC. In this study, we determined whether Hh signaling could be a therapeutic target in GBC. The Hh transcription factor Gli1 was detected in the nucleus of GBC cells but not in the nucleus of normal gallbladder cells. The expression levels of Sonic Hh (Shh) and Smoothened (Smo) in human GBC specimens (n = 37) were higher than those in normal gallbladder tissue. The addition of exogenous Shh ligand augmented the anchor-dependent and anchor-independent proliferation and invasiveness of GBC cells in vitro. In contrast, inhibiting the effector Smo decreased the anchor-dependent and anchor-independent proliferation. Furthermore, the suppression of Smo decreased GBC cell invasiveness through the inhibition of MMP-2 and MMP-9 expression and inhibited the epithelial–mesenchymal transition. In a xenograft model, tumor volume in Smo siRNA-transfected GBC cells was significantly lower than in control tumors. These results suggest that Hh signaling is elevated in GBC and may be involved in the acquisition of malignant phenotypes, and that Hh signaling may be a potential therapeutic target for GBC. PMID:24438533

  3. Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin

    PubMed Central

    Grossmann, Tom N.; Yeh, Johannes T.-H.; Bowman, Brian R.; Chu, Qian; Moellering, Raymond E.; Verdine, Gregory L.

    2012-01-01

    Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of β-catenin by interfering with its constitutive degradation. β-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein–protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein–protein interactions is a biologically compelling approach toward suppression of β-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence β-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets β-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway. PMID:23071338

  4. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

    SciTech Connect

    Wang, Yelin; Hu, Chen; Cheng, Jun; Chen, Binquan; Ke, Qinghong; Lv, Zhen; Wu, Jian; Zhou, Yanfeng

    2014-04-18

    Highlights: • MiR-145 expression is down-regulated in HCC tissues and inversely related with IRS1 levels. • MiR-145 directly targets IRS1 in HCC cells. • Restored expression of miR-145 suppressed HCC cell proliferation and growth. • MiR-145 induced IRS1 under-expression potentially reduced downstream AKT signaling. - Abstract: Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.

  5. Targeting the Transforming Growth Factor-β Signaling Pathway in Human Cancer

    PubMed Central

    Nagaraj, Nagathihalli S

    2009-01-01

    The transforming growth factor-β (TGF-β) signaling pathway plays a pivotal role in diverse cellular processes. TGF-β switches its role from tumor suppressor in normal or dysplastic cells to a tumor promoter in advanced cancers. It is widely believed that Smad-dependent pathway is involved in TGF-β tumor suppressive functions, whereas activation of Smad-independent pathways coupled with the loss of tumor suppressor functions of TGF-β is important for its pro-oncogenic functions. TGF-β signaling has been considered as a very suitable therapeutic target. The discovery of oncogenic actions of TGF-β has generated a great deal of enthusiasm for developing TGF-β signaling inhibitors for the treatment of cancer. The challenge is to identify the group of patients where targeted tumors are not only refractory to TGF-β-induced tumor suppressor functions but also responsive to tumor promoting effects of TGF-β. TGF-β pathway inhibitors including small and large molecules have now entered clinical trials. Preclinical studies with these inhibitors have shown promise in a variety of different tumor models. Here we emphasize on the mechanisms of signaling and specific targets of the TGF-β pathway that are critical effectors of tumor progression and invasion. This report also focuses on the therapeutic intervention of TGF-β signaling in human cancers. PMID:20001556

  6. Two-component signal transduction as potential drug targets in pathogenic bacteria.

    PubMed

    Gotoh, Yasuhiro; Eguchi, Yoko; Watanabe, Takafumi; Okamoto, Sho; Doi, Akihiro; Utsumi, Ryutaro

    2010-04-01

    Gene clusters contributing to processes such as cell growth and pathogenicity are often controlled by two-component signal transduction systems (TCSs). Specific inhibitors against TCS systems work differently from conventional antibiotics, and developing them into new drugs that are effective against various drug-resistant bacteria may be possible. Furthermore, inhibitors of TCSs that control virulence factors may reduce virulence without killing the pathogenic bacteria. Previous TCS inhibitors targeting the kinase domain of the histidine kinase sensor suffered from poor selectivity. Recent TCS inhibitors, however, target the sensory domains of the sensors blocking the quorum sensing system, or target the essential response regulator. These new targets are introduced, together with several specific TCSs that have the potential to serve as effective drug targets. Copyright 2010 Elsevier Ltd. All rights reserved.

  7. Tracking and recognition of airborne targets via commercial television and FM radio signals

    NASA Astrophysics Data System (ADS)

    Lanterman, Aaron D.

    1999-07-01

    We formulate a Bayesian approach to the joint tracking and recognition of airborne targets via reflected commercial television and FM radio signals measured by an array of sensors. Such passive system may remain covert, whereas traditional active systems must reveal their presence and location by their transmissions. Since the number of aircraft in the scene is not known a priori, and targets may enter and leave the scene at unknown times, the parameters space is a union of subspaces of varying dimensions as well as varying target classes. Targets tracks are parameterized via both positions and orientations, with the orientations naturally represented as elements of the special orthogonal group. A prior on target tracks is constructed from Newtonian equations of motion. This prior results in a coupling between the position and orientation estimates, yielding a coupling between the tracking and recognition problems.

  8. Targeting miR-155 suppresses proliferation and induces apoptosis of HL-60 cells by targeting Slug/PUMA signal.

    PubMed

    Liang, Hui; Dong, Ziyan; Liu, Jiang-Feng; Chuang, Wei; Gao, Li-Zhen; Ren, Yu-Guo

    2016-10-27

    Recent studies have shown that high miR-155 expression was associated with poor prognosis in patients with acute myelogeneous leukemia (AML). Furthermore, targeting miR-155 results in monocytic differentiation and apoptosis. However, the exact role and mechanisms of miR-155 in human AML remains speculative. HL-60 cells were treated with anti-miR-155 for 72 h. Cell growth and apoptosis in vitro were detected by MTT, BrdU proliferation, colony formation and flow cytometry assay. The effect of anti-miR-155 on growth of HL-60 cells was also evaluated in a leukemia mouse model. Slug cDNA and PUMA siRNA trannsfection was used to assess the signal pathway. Different protein expression was detected by western blot assay and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay. The results shown that targeting miR-155 resulted in a 24-fold decrease of miR-155 expression compared to negative control in the HL-60 cells. Targeting miR-155 significantly downregulated Slug and upregulated PUMA expression, and decreased HL-60 cell growth by 70% , impaired colony formation by approximately 60%, and increased HL-60 cell apoptosis by 45%. Targeting PUMA reversed miR-155 sliencing-induced proliferation and apoptosis of HL-60 cells. Restoration of Slug decreased PUMA expression. In murine engraftment models of HL-60 cells, we showed that targeting miR-155 was able to reduce tumor growth. This was accompanied with decreased Slug expression and increased PUMA expression in these tumors. Collectively, our findings strongly suggest targeting miR-155 exhibited in vivo and in vitro antileukemic activities in AML through a novel mechanism resulting in inhibition of Slug expression and increase of PUMA expression.

  9. Identification of novel plant peroxisomal targeting signals by a combination of machine learning methods and in vivo subcellular targeting analyses.

    PubMed

    Lingner, Thomas; Kataya, Amr R; Antonicelli, Gerardo E; Benichou, Aline; Nilssen, Kjersti; Chen, Xiong-Yan; Siemsen, Tanja; Morgenstern, Burkhard; Meinicke, Peter; Reumann, Sigrun

    2011-04-01

    In the postgenomic era, accurate prediction tools are essential for identification of the proteomes of cell organelles. Prediction methods have been developed for peroxisome-targeted proteins in animals and fungi but are missing specifically for plants. For development of a predictor for plant proteins carrying peroxisome targeting signals type 1 (PTS1), we assembled more than 2500 homologous plant sequences, mainly from EST databases. We applied a discriminative machine learning approach to derive two different prediction methods, both of which showed high prediction accuracy and recognized specific targeting-enhancing patterns in the regions upstream of the PTS1 tripeptides. Upon application of these methods to the Arabidopsis thaliana genome, 392 gene models were predicted to be peroxisome targeted. These predictions were extensively tested in vivo, resulting in a high experimental verification rate of Arabidopsis proteins previously not known to be peroxisomal. The prediction methods were able to correctly infer novel PTS1 tripeptides, which even included novel residues. Twenty-three newly predicted PTS1 tripeptides were experimentally confirmed, and a high variability of the plant PTS1 motif was discovered. These prediction methods will be instrumental in identifying low-abundance and stress-inducible peroxisomal proteins and defining the entire peroxisomal proteome of Arabidopsis and agronomically important crop plants.

  10. Active targeting in a random porous medium by chemical swarm robots with secondary chemical signaling

    NASA Astrophysics Data System (ADS)

    Grančič, Peter; Štěpánek, František

    2011-08-01

    The multibody dynamics of a system of chemical swarm robots in a porous environment is investigated. The chemical swarm robots are modeled as Brownian particles capable of delivering an encapsulated chemical payload toward a given target location and releasing it in response to an external stimulus. The presence of chemical signals (chemo-attractant) in the system plays a crucial role in coordinating the collective movement of the particles via chemotaxis. For a number of applications, such as distributed chemical processing and targeted drug delivery, the understanding of factors that govern the collective behavior of the particles, especially their ability to localize a given target, is of immense importance. A hybrid modeling methodology based on the combination of the Brownian dynamics method and diffusion problem coupled through the chemotaxis phenomena is used to analyze the impact of a varying signaling threshold and the strength of chemotaxis on the ability of the chemical robots to fulfill their target localization mission. The results demonstrate that the selected performance criteria (the localization half time and the success rate) can be improved when an appropriate signaling process is chosen. Furthermore, for an optimum target localization strategy, the topological complexity of the porous environment needs to be reflected.

  11. Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target

    PubMed Central

    Cassano, Tommaso; Calcagnini, Silvio; Pace, Lorenzo; De Marco, Federico; Romano, Adele; Gaetani, Silvana

    2017-01-01

    As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically. Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis. In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration. For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases. PMID:28210207

  12. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family

    PubMed Central

    Shepard, H. Michael; Brdlik, Cathleen M.; Schreiber, Hans

    2008-01-01

    The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family–targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences. PMID:18982164

  13. Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway.

    PubMed

    Stegner, David; Haining, Elizabeth J; Nieswandt, Bernhard

    2014-08-01

    Coronary artery thrombosis and ischemic stroke are often initiated by the disruption of an atherosclerotic plaque and consequent intravascular platelet activation. Thus, antiplatelet drugs are central in the treatment and prevention of the initial, and subsequent, vascular events. However, novel pharmacological targets for platelet inhibition remain an important goal of cardiovascular research because of the negative effect of existing antiplatelet drugs on primary hemostasis. One promising target is the platelet collagen receptor glycoprotein VI. Blockade or antibody-mediated depletion of this receptor in circulating platelets is beneficial in experimental models of thrombosis and thrombo-inflammatory diseases, such as stroke, without impairing hemostasis. In this review, we summarize the importance of glycoprotein VI and (hem)immunoreceptor tyrosine-based activation motif signaling in hemostasis, thrombosis, and thrombo-inflammatory processes and discuss the targeting strategies currently under development for inhibiting glycoprotein VI and its signaling.

  14. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family.

    PubMed

    Shepard, H Michael; Brdlik, Cathleen M; Schreiber, Hans

    2008-11-01

    The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family-targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences.

  15. Concepts of protein sorting or targeting signals and membrane topology in undergraduate teaching*.

    PubMed

    Tang, Bor Luen; Teng, Felicia Yu Hsuan

    2005-05-01

    The process of protein biogenesis culminates in its correct targeting to specific subcellular locations where it serves a function. Contemporary molecular and cell biology investigations often involve the exogenous expression of epitope- or fluorescent protein-tagged recombinant molecules as well as subsequent analysis of protein-protein interactions in vitro and in vivo. Fundamental knowledge of targeting signals that direct a polypeptide to various organelles or membrane domains is essential for the proper design of such recombinant molecules. A fundamental concept of membrane compartmentalization is also often useful for the interpretation of the preliminary results of interaction screens. Knowledge in targeting signals and post-translational dynamics of proteins should therefore be given sufficient emphasis in an undergraduate biochemistry or molecular biology curriculum. Such knowledge is essential, particularly for undergraduates or fresh graduates embarking on research projects in a cell and molecular biology laboratory. Copyright © 2005 International Union of Biochemistry and Molecular Biology, Inc.

  16. Impact of targeting insulin-like growth factor signaling in head and neck cancers.

    PubMed

    Limesand, Kirsten H; Chibly, Alejandro Martinez; Fribley, Andrew

    2013-10-01

    The IGF system has been shown to have either negative or negligible impact on clinical outcomes of tumor development depending on specific tumor sites or stages. This review focuses on the clinical impact of IGF signaling in head and neck cancer, the effects of IGF targeted therapies, and the multi-dimensional role of IRS 1/2 signaling as a potential mechanism in resistance to targeted therapies. Similar to other tumor sites, both negative and positive correlations between levels of IGF-1/IGF-1-R and clinical outcomes in head and neck cancer have been reported. In addition, utilization of IGF targeted therapies has not demonstrated significant clinical benefit; therefore the prognostic impact of the IGF system on head and neck cancer remains uncertain.

  17. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2)

    PubMed Central

    Lamming, Dudley W.; Demirkan, Gokhan; Boylan, Joan M.; Mihaylova, Maria M.; Peng, Tao; Ferreira, Jonathan; Neretti, Nicola; Salomon, Arthur; Sabatini, David M.; Gruppuso, Philip A.

    2014-01-01

    The mechanistic target of rapamycin (mTOR) exists in two complexes that regulate diverse cellular processes. mTOR complex 1 (mTORC1), the canonical target of rapamycin, has been well studied, whereas the physiological role of mTORC2 remains relatively uncharacterized. In mice in which the mTORC2 component Rictor is deleted in liver [Rictor-knockout (RKO) mice], we used genomic and phosphoproteomic analyses to characterize the role of hepatic mTORC2 in vivo. Overnight food withdrawal followed by refeeding was used to activate mTOR signaling. Rapamycin was administered before refeeding to specify mTORC2-mediated events. Hepatic mTORC2 regulated a complex gene expression and post-translational network that affects intermediary metabolism, ribosomal biogenesis, and proteasomal biogenesis. Nearly all changes in genes related to intermediary metabolic regulation were replicated in cultured fetal hepatocytes, indicating a cell-autonomous effect of mTORC2 signaling. Phosphoproteomic profiling identified mTORC2-related signaling to 144 proteins, among which were metabolic enzymes and regulators. A reduction of p38 MAPK signaling in the RKO mice represents a link between our phosphoproteomic and gene expression results. We conclude that hepatic mTORC2 exerts a broad spectrum of biological effects under physiological conditions. Our findings provide a context for the development of targeted therapies to modulate mTORC2 signaling.—Lamming, D. W., Demirkan, G., Boylan, J. M., Mihaylova, M. M., Peng, T., Ferreira, J., Neretti, N., Salomon, A., Sabatini, D. M., Gruppuso, P. A. Hepatic signaling by the mechanistic target of rapamycin complex 2 (mTORC2). PMID:24072782

  18. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects.

    PubMed

    Banerjee, Shubhasree; Biehl, Ann; Gadina, Massimo; Hasni, Sarfaraz; Schwartz, Daniella M

    2017-04-01

    The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.

  19. Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer

    PubMed Central

    Campbell, Laura M.; Maxwell, Pamela J.; Waugh, David J.J.

    2013-01-01

    It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations. PMID:24276377

  20. Targeting the B cell receptor signaling pathway in B lymphoid malignancies

    PubMed Central

    Buchner, Maike; Müschen, Markus

    2014-01-01

    PURPOSE OF REVIEW Normal B cells that failed to productively rearrange immunoglobulin V region genes, encoding a functional B cell receptor (BCR) are destined to die. Likewise, the majority of B cell malignancies remain dependent on functional BCR signaling, while in some subtypes BCR expression is missing and, apparently, counterselected. Here we summarize recent the experimental evidence for the importance of BCR signaling and clinical concepts to target the BCR pathway in B cell leukemia and lymphoma. RECENT FINDINGS While the dependency on pre-BCR signaling in pre-B acute lymphoblastic leukemia (ALL) seems to be limited to few ALL subtypes (e.g. TCF3-PBX1), most mature B cell lymphomas rely on BCR signaling provided by different stimuli e.g. tonic B cell signaling, chronic (auto)-antigen exposure, and self-binding properties of the BCR. The finding that in chronic lymphocytic leukemia (CLL), BCRs bind to an epitope on the BCR itself unravels a novel concept for CLL pathogenesis. SUMMARY Targeting of the B cell receptor tyrosine kinases SYK, BTK, and PI3K achieve promising clinical responses in various mature B cell malignancies and might also be useful in defined subsets of ALL. However, further understanding of the BCR signal integration in the different disease groups are required to accurately predict, which groups of patients will benefit from BCR pathway-inhibition. PMID:24811161

  1. Cell signalling in insulin secretion: the molecular targets of ATP, cAMP and sulfonylurea.

    PubMed

    Seino, S

    2012-08-01

    Clarification of the molecular mechanisms of insulin secretion is crucial for understanding the pathogenesis and pathophysiology of diabetes and for development of novel therapeutic strategies for the disease. Insulin secretion is regulated by various intracellular signals generated by nutrients and hormonal and neural inputs. In addition, a variety of glucose-lowering drugs including sulfonylureas, glinide-derivatives, and incretin-related drugs such as dipeptidyl peptidase IV (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists are used for glycaemic control by targeting beta cell signalling for improved insulin secretion. There has been a remarkable increase in our understanding of the basis of beta cell signalling over the past two decades following the application of molecular biology, gene technology, electrophysiology and bioimaging to beta cell research. This review discusses cell signalling in insulin secretion, focusing on the molecular targets of ATP, cAMP and sulfonylurea, an essential metabolic signal in glucose-induced insulin secretion (GIIS), a critical signal in the potentiation of GIIS, and the commonly used glucose-lowering drug, respectively.

  2. WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets

    PubMed Central

    Suzuki, Akiko; Pelikan, Richard C.

    2015-01-01

    Molecules involved in WNT/β-catenin signaling show specific spatiotemporal expression and play vital roles in myogenesis; however, it is still largely unknown how WNT/β-catenin signaling regulates each step of myogenesis. Here, we show that WNT/β-catenin signaling can control diverse biological processes of myogenesis by regulating step-specific molecules. In order to identify the temporally specific roles of WNT/β-catenin signaling molecules in muscle development and homeostasis, we used in vitro culture systems for both primary mouse myoblasts and C2C12 cells, which can differentiate into myofibers. We found that a blockade of WNT/β-catenin signaling in the proliferating cells decreases proliferation activity, but does not induce cell death, through the regulation of genes cyclin A2 (Ccna2) and cell division cycle 25C (Cdc25c). During muscle differentiation, the inhibition of WNT/β-catenin signaling blocks myoblast fusion through the inhibition of the Fermitin family homolog 2 (Fermt2) gene. Blocking WNT/β-catenin signaling in the well-differentiated myofibers results in the failure of maintenance of their structure by disruption of cadherin/β-catenin/actin complex formation, which plays a crucial role in connecting a myofiber's cytoskeleton to the surrounding extracellular matrix. Thus, our results indicate that WNT/β-catenin signaling can regulate multiple steps of myogenesis, including cell proliferation, myoblast fusion, and homeostasis, by targeting step-specific molecules. PMID:25755281

  3. WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets.

    PubMed

    Suzuki, Akiko; Pelikan, Richard C; Iwata, Junichi

    2015-05-01

    Molecules involved in WNT/β-catenin signaling show specific spatiotemporal expression and play vital roles in myogenesis; however, it is still largely unknown how WNT/β-catenin signaling regulates each step of myogenesis. Here, we show that WNT/β-catenin signaling can control diverse biological processes of myogenesis by regulating step-specific molecules. In order to identify the temporally specific roles of WNT/β-catenin signaling molecules in muscle development and homeostasis, we used in vitro culture systems for both primary mouse myoblasts and C2C12 cells, which can differentiate into myofibers. We found that a blockade of WNT/β-catenin signaling in the proliferating cells decreases proliferation activity, but does not induce cell death, through the regulation of genes cyclin A2 (Ccna2) and cell division cycle 25C (Cdc25c). During muscle differentiation, the inhibition of WNT/β-catenin signaling blocks myoblast fusion through the inhibition of the Fermitin family homolog 2 (Fermt2) gene. Blocking WNT/β-catenin signaling in the well-differentiated myofibers results in the failure of maintenance of their structure by disruption of cadherin/β-catenin/actin complex formation, which plays a crucial role in connecting a myofiber's cytoskeleton to the surrounding extracellular matrix. Thus, our results indicate that WNT/β-catenin signaling can regulate multiple steps of myogenesis, including cell proliferation, myoblast fusion, and homeostasis, by targeting step-specific molecules.

  4. Spectropolarimetry of hot, luminous stars

    NASA Technical Reports Server (NTRS)

    Schulte-Ladbeck, Regina E.

    1994-01-01

    I review polarimetric observations of presumably single, hot luminous stars. The stellar types discussed are OB stars. B(e) supergiants, Luminous Blue Variables (LBV), Wolf-Rayet (W-R) stars, and type II supernovae (SN). It is shown that variable, intrinsic polarization is a common phenomenon in that part of the Hertzsprung-Russell (HR) diagram which these stars occupy. However, much observational work remains to be done before we can answer the most basic, statistical questions about the polarimetric properties of different groups of hot, luminous stars. Insight into the diagnostic power of polarization observations has been gained, but cannot be exploited without detailed models. Thus, while polarimetric observations do tell us that the mass-loss processes of all types of massive stars are time-dependent and anisotropic, the significance that this might have for the accuracy of their stellar parameters and evolutionary paths remains elusive.

  5. [Two-component signal transduction as attractive drug targets in pathogenic bacteria].

    PubMed

    Utsumi, Ryutaro; Igarashi, Masayuki

    2012-01-01

    Gene clusters contributing to processes such as cell growth and pathogenicity are often controlled by two-component signal transduction systems (TCSs). TCS consists of a histidine kinase (HK) and a response regulator (RR). TCSs are attractive as drug targets for antimicrobials because many HK and RR genes are coded on the bacterial genome though few are found in lower eukaryotes. The HK/RR signal transduction system is distinct from serine/threonine and tyrosine phosphorylation in higher eukaryotes. Specific inhibitors against TCS systems work differently from conventional antibiotics, and developing them into new drugs that are effective against various drug-resistant bacteria may be possible. Furthermore, inhibitors of TCSs that control virulence factors may reduce virulence without killing the pathogenic bacteria. Previous TCS inhibitors targeting the kinase domain of the histidine kinase sensor suffered from poor selectivity. Recent TCS inhibitors, however, target the sensory domains of the sensors blocking the quorum sensing system, or target the essential response regulator. These new targets are introduced, together with several specific TCSs that have the potential to serve as effective drug targets.

  6. Target detection, shape discrimination, and signal characteristics of an echolocating false killer whale (Pseudorca crassidens).

    PubMed

    Brill, R L; Pawloski, J L; Helweg, D A; Au, W W; Moore, P W

    1992-09-01

    This study demonstrated the ability of a false killer whale (Pseudorca crassidens) to discriminate between two targets and investigated the parameters of the whale's emitted signals for changes related to test conditions. Target detection performance comparable to the bottlenose dolphin's (Tursiops truncatus) has previously been reported for echolocating false killer whales. No other echolocation capabilities have been reported. A false killer whale, naive to conditioned echolocation tasks, was initially trained to detect a cylinder in a "go/no-go" procedure over ranges of 3 to 8 m. The transition from a detection task to a discrimination task was readily achieved by introducing a spherical comparison target. Finally, the cylinder was successfully compared to spheres of two different sizes and target strengths. Multivariate analyses were used to evaluate the parameters of emitted signals. Duncan's multiple range tests showed significant decreases (df = 185, p less than 0.05) in both source level and bandwidth in the transition from detection to discrimination. Analysis of variance revealed a significant decrease in the number of clicks over test conditions [F(5.26) = 5.23, p less than 0.0001]. These data suggest that the whale relied on cues relevant to target shape as well as target strength, that changes in source level and bandwidth were task-related, that the decrease in clicks was associated with learning experience, and that Pseudorca's ability to discriminate shapes using echolocation may be comparable to that of Tursiops truncatus.

  7. Mitochondrial and chloroplastic targeting signals of NADP+-dependent isocitrate dehydrogenase.

    PubMed

    McKinnon, David J; Brzezowski, Pawel; Wilson, Kenneth E; Gray, Gordon R

    2009-12-01

    Many mitochondrial and chloroplast proteins are encoded in the nucleus and subsequently imported into the organelles via active protein transport systems. While usually highly specific, some proteins are dual-targeted to both organelles. In tobacco (Nicotiana tabacum L.), the cDNA encoding the mitochondrial isoform of NADP+-dependent isocitrate dehydrogenase (NADP+-ICDH) contains two translational ATG start sites, suggesting the possibility of tandem targeting signals. In this work, the putative mitochondrial and chloroplastic targeting signals from NADP+-ICDH were fused to a yellow fluorescent protein (YFP) reporter to generate a series of constructs and introduced into tobacco leaves by Agrobacterium-mediated transient transformation. The subsequent sub-cellular locations of the ICDH:YFP fusion proteins were then examined using confocal microscopy. Constructs predicted to be targeted to the chloroplast all localized to the chloroplast. However, this was not the case for all of the constructs that were predicted to be mitochondrial targeted. Although some constructs localized to mitochondria as expected, others appeared to be chloroplast localized. This was attributed to an additional 50 amino acid residues of the mature NADP+-ICDH protein that were present in those constructs, generated from either 'Xanthi' or 'Petit Havana' cultivars of tobacco. The results of this study raise interesting questions regarding the targeting and processing of organellar isoforms of NADP+-ICDH.

  8. Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer.

    PubMed

    Onishi, Hideya; Katano, Mitsuo

    2014-03-07

    Pancreatic cancer is one of the most aggressive and difficult cancers to treat. Despite numerous research efforts, limited success has been achieved in the therapeutic management of patients with this disease. In the current review, we focus on one component of morphogenesis signaling, Hedgehog (Hh), with the aim of developing novel, effective therapies for the treatment of pancreatic cancer. Hh signaling contributes to the induction of a malignant phenotype in pancreatic cancer and is responsible for maintaining pancreatic cancer stem cells. In addition, we propose a novel concept linking Hh signaling and tumor hypoxic conditions, and discuss the effects of Hh inhibitors in clinical trials. The Hh signaling pathway may represent a potential therapeutic target for patients with refractory pancreatic cancer.

  9. Microbial effectors target multiple steps in the salicylic acid production and signaling pathway

    PubMed Central

    Tanaka, Shigeyuki; Han, Xiaowei; Kahmann, Regine

    2015-01-01

    Microbes attempting to colonize plants are recognized through the plant immune surveillance system. This leads to a complex array of global as well as specific defense responses, which are often associated with plant cell death and subsequent arrest of the invader. The responses also entail complex changes in phytohormone signaling pathways. Among these, salicylic acid (SA) signaling is an important pathway because of its ability to trigger plant cell death. As biotrophic and hemibiotrophic pathogens need to invade living plant tissue to cause disease, they have evolved efficient strategies to downregulate SA signaling by virulence effectors, which can be proteins or secondary metabolites. Here we review the strategies prokaryotic pathogens have developed to target SA biosynthesis and signaling, and contrast this with recent insights into how plant pathogenic eukaryotic fungi and oomycetes accomplish the same goal. PMID:26042138

  10. Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations.

    PubMed

    Hu, Fang; Liu, Feng

    2014-01-01

    It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissue-specific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.

  11. mTORC1 signaling and IL-17 expression: Defining pathways and possible therapeutic targets.

    PubMed

    Ren, Wenkai; Yin, Jie; Duan, Jielin; Liu, Gang; Tan, Bie; Yang, Guan; Wu, Guoyao; Bazer, Fuller W; Peng, Yuanyi; Yin, Yulong

    2016-02-01

    IL-17 mediates immune responses against extracellular pathogens, and it is associated with the development and pathogenesis of various autoimmune diseases. The expression of IL-17 is regulated by various intracellular signaling cascades. Recently, it has been shown that mechanistic target of rapamycin (mTOR) signaling, comprised mainly of mTORC1 signaling, plays a critical role in IL-17 expression. Here, we review the current knowledge regarding mechanisms by which mTORC1 regulates IL-17 expression. mTORC1 positively modulates IL-17 expression through several pathways, i.e. STAT3, -HIF-1α, -S6K1, and -S6K2. Amino acids (AAs) also regulate IL-17 expression by being the energy source for Th17 cells, and by activating mTORC1 signaling. Altogether, the AA-mTORC1-IL-17 axis has broad therapeutic implications for IL-17-associated diseases, such as EAE, allergies, and colitis.

  12. Fibroblast growth factor receptor signaling as therapeutic targets in gastric cancer

    PubMed Central

    Yashiro, Masakazu; Matsuoka, Tasuku

    2016-01-01

    Fibroblast growth factor receptors (FGFRs) regulate a variety of cellular functions, from embryogenesis to adult tissue homeostasis. FGFR signaling also plays significant roles in the proliferation, invasion, and survival of several types of tumor cells. FGFR-induced alterations, including gene amplification, chromosomal translocation, and mutations, have been shown to be associated with the tumor initiation and progression of gastric cancer, especially in diffuse-type cancers. Therefore, the FGFR signaling pathway might be one of the therapeutic targets in gastric cancer. This review aims to provide an overview of the role of FGFR signaling in tumorigenesis, tumor progression, proliferation, and chemoresistance. We also discuss the accumulating evidence that demonstrates the effectiveness of using clinical therapeutic agents to inhibit FGFR signaling for the treatment of gastric cancer. PMID:26937130

  13. A novel multipitch measurement algorithm for acoustic signals of moving targets

    NASA Astrophysics Data System (ADS)

    Huang, Jingchang; Guo, Feng; Zu, Xingshui; Li, Haiyan; Liu, Huawei; Li, Baoqing

    2016-12-01

    In this paper, a novel multipitch measurement (MPM) method is proposed for acoustic signals. Starting from the analysis of moving targets' acoustic signatures, a pitch-based harmonics representation model of acoustic signal is put forward. According to the proposed harmonics model, a modified greatest common divisor (MGCD) method is developed to obtain an initial multipitch set (IMS). Subsequently, the harmonic number vector (HNV) associated with the IMS is determined by maximizing the objective function formulated as a multi-impulse-train weighted symmetric average magnitude sum function (SAMSF) of the observed signal. The frequencies of SAMSF are determined by the target acoustic signal, the periods of the multi-impulse-train are governed by the estimated IMS harmonics and the maximization of the objective function is figured out through a time-domain matching of periodicities of the multi-impulse-train with that of the SAMSF. Finally, by using the obtained IMS and its HNV, a precise fundamental frequency set is achieved. Evaluation of the algorithm performances in comparison with state-of-the-art methods indicates that MPM is practical for the multipitch extraction of moving targets.

  14. Signaling cross-talk in the resistance to HER family receptor targeted therapy.

    PubMed

    Yamaguchi, H; Chang, S-S; Hsu, J L; Hung, M-C

    2014-02-27

    Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) have an important role in the initiation and progression of various types of cancer. Inhibitors targeting these receptor tyrosine kinases are some of the most successful targeted anticancer drugs widely used for cancer treatment; however, cancer cells have mechanisms of intrinsic and acquired drug resistance that pose as major obstacles in drug efficacy. Extensive studies from both clinical and laboratory research have identified several molecular mechanisms underlying resistance. Among them is the role of signaling cross-talk between the EGFR/HER2 and other signaling pathways. In this review, we focus particularly on this signaling cross-talk at the receptor, mediator and effector levels, and further discuss alternative approaches to overcome resistance. In addition to well-recognized signaling cross-talk involved in the resistance, we also introduce the cross-talk between EGFR/HER2-mediated pathways and pathways triggered by other types of receptors, including those of the Notch, Wnt and TNFR/IKK/NF-κB pathways, and discuss the potential role of targeting this cross-talk to sensitize cells to EGFR/HER2 inhibitors.

  15. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.

    PubMed

    Chew, Wee Siong; Wang, Wei; Herr, Deron R

    2016-11-01

    Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P1). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation S1P receptor modulators have been under development in an effort to provide improved safety and efficacy profiles for MS, and to broaden their use to other autoimmune indications. Beyond the development of S1P1-modulators, there has been considerable effort in targeting other components of the S1P signaling pathway for the treatment of other diseases, such as cardiovascular disease, sepsis, and cancer. This manuscript provides an overview of the clinical and preclinical development of drugs targeting S1P signaling.

  16. Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth.

    PubMed

    Obinata, D; Takayama, K; Fujiwara, K; Suzuki, T; Tsutsumi, S; Fukuda, N; Nagase, H; Fujimura, T; Urano, T; Homma, Y; Aburatani, H; Takahashi, S; Inoue, S

    2016-12-08

    Androgen receptor (AR) functions as a ligand-dependent transcription factor to regulate its downstream signaling for prostate cancer progression. AR complex formation by multiple transcription factors is important for enhancer activity and transcriptional regulation. However, the significance of such collaborative transcription factors has not been fully understood. In this study, we show that Oct1, an AR collaborative factor, coordinates genome-wide AR signaling for prostate cancer growth. Using global analysis by chromatin immunoprecipitation sequencing (ChIP-seq), we found that Oct1 is recruited to AR-binding enhancer/promoter regions and facilitates androgen signaling. Moreover, a major target of AR/Oct1 complex, acyl-CoA synthetase 3 (ACSL3), contributes to tumor growth in nude mice, and its high expression is associated with poor prognosis in prostate cancer patients. Next, we examined the therapeutic effects of pyrrole-imidazole polyamides that target the Oct1-binding sequence identified in the center of the ACSL3 AR-binding site. We observed that treatment with Oct1 polyamide severely blocked the Oct1 binding at the ACSL3 enhancer responsible for its transcriptional activity and ACSL3 induction. In addition, Oct1 polyamides suppressed castration-resistant tumor growth and specifically repressed global Oct1 chromatin association and androgen signaling in prostate cancer cells, with few nonspecific effects on basal promoter activity. Thus, targeting Oct1 binding could be a novel therapeutic strategy for AR-activated castration-resistant prostate cancer.

  17. Local luminance effect on spatial summation in the foveal vision and its implication on image artifact classification

    NASA Astrophysics Data System (ADS)

    Chen, Chien-Chung; Lin, San-Yuan; Han, Hui-Ya G.; Kuo, Sheng-Tzung; Huang, Kuo-Chung

    2006-02-01

    We investigated the spatial summation effect on pedestals with difference luminance. The targets were luminance modulation defined by Gaussian functions. The size of the Gaussian spot was determined by the scale parameter (standard deviation, σ) which ranged from 0.13°to 1.04°. The local luminance pedestal (2° radius) had mean luminance ranged from 2.9 to 29cd/m2. The no-pedestal condition had a mean luminance 58cd/m2. We used a QUEST adaptive threshold seeking procedure and 2AFC paradigm to measure the target contrast threshold at different target sizes (spatial summation curve) and pedestal luminance. The target threshold decreased as the target spatial extent increased with a slope -0.5 on log-log coordinates. However, if the target size was large enough (σ>0.3°), there was little, if any, threshold reduction as the target size further increased. The spatial summation curve had the same shape at all pedestal luminance levels. The effect of the pedestal was to shift the summation curve vertically on log-log coordinates. Hence, the size and the luminance effects on target detection are separable. The visibility of the Gaussian spot can be modeled by a function with a form f(L)*g(σ) where f(L) is a function of local luminance and g(σ) is a function of size.

  18. Targeting cell death signalling in cancer: minimising ‘Collateral damage'

    PubMed Central

    Fox, Joanna L; MacFarlane, Marion

    2016-01-01

    Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents. PMID:27140313

  19. Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.

    PubMed

    Raynal, Noël J-M; Lee, Justin T; Wang, Youjun; Beaudry, Annie; Madireddi, Priyanka; Garriga, Judith; Malouf, Gabriel G; Dumont, Sarah; Dettman, Elisha J; Gharibyan, Vazganush; Ahmed, Saira; Chung, Woonbok; Childers, Wayne E; Abou-Gharbia, Magid; Henry, Ryan A; Andrews, Andrew J; Jelinek, Jaroslav; Cui, Ying; Baylin, Stephen B; Gill, Donald L; Issa, Jean-Pierre J

    2016-03-15

    Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer cells, we found three classical epigenetic targeted drugs (DNA methylation and histone deacetylase inhibitors) and 11 other drugs that induced methylated and silenced CpG island promoters driving a reporter gene (GFP) as well as endogenous TSGs in multiple cancer cell lines. These newly identified drugs, most prominently cardiac glycosides, did not change DNA methylation locally or histone modifications globally. Instead, all 11 drugs altered calcium signaling and triggered calcium-calmodulin kinase (CamK) activity, leading to MeCP2 nuclear exclusion. Blocking CamK activity abolished gene reactivation and cancer cell killing by these drugs, showing that triggering calcium fluxes is an essential component of their epigenetic mechanism of action. Our data identify calcium signaling as a new pathway that can be targeted to reactivate TSGs in cancer.

  20. Suppression of TLR signaling by targeting TIR domain-containing proteins.

    PubMed

    Fekonja, Ota; Avbelj, Monika; Jerala, Roman

    2012-12-01

    Toll-like receptors (TLRs) recognize molecules specific to pathogens and endogenous danger signals. Binding of agonists to the ectodomain of the receptor initiates TLR activation and is followed by the association of receptor cytosolic Toll/Interleukin-1 receptor (TIR) domains with TIR domains of adapter proteins leading to the assembly of signaling cascade of protein kinases that ultimately trigger the activation of transcription factors and expression of genes involved in the immune response. Excessive activation of TIR-domain mediated signaling has been implicated in inflammatory diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, colitis) as well as in the development of cancer. Targeting receptor-adapter interactions represents a potential strategy for the therapeutic TLR/IL-1R-specific inhibition due to the unique interacting domains involved. Peptide and protein-domain binding TLR inhibitors originating from the interacting surfaces of TIR-domain containing proteins can bind to the site on their target interacting protein thereby preventing the assembly of the functional signaling complex. Here we review protein-domain, peptide and peptidomimetic inhibitors targeting TIR-domain mediated interactions and their application demonstrated on in vitro and in vivo models. Recent structural data and elucidation of the molecular mechanisms of TIR-domain mediated signaling enabled the development of peptide inhibitors from TIR domains of TLRs and adapters, MyD88 intermediary domain as well as improved protein inhibitors based on TIR domain dimerization, mimicking bacterial TIR-domain containing immunosuppressors (TCPs) which we discuss with challenges concerning the delivery and specificity of inhibitors targeting TLR adapters.

  1. Suppression of TLR Signaling by Targeting TIR domain-Containing Proteins

    PubMed Central

    Fekonja, Ota; Avbelj, Monika; Jerala, Roman

    2012-01-01

    Toll-like receptors (TLRs) recognize molecules specific to pathogens and endogenous danger signals. Binding of agonists to the ectodomain of the receptor initiates TLR activation and is followed by the association of receptor cytosolic Toll/Interleukin-1 receptor (TIR) domains with TIR domains of adapter proteins leading to the assembly of signaling cascade of protein kinases that ultimately trigger the activation of transcription factors and expression of genes involved in the immune response. Excessive activation of TIR-domain mediated signaling has been implicated in inflammatory diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, colitis) as well as in the development of cancer. Targeting receptor-adapter interactions represents a potential strategy for the therapeutic TLR/IL-1R-specific inhibition due to the unique interacting domains involved. Peptide and protein-domain binding TLR inhibitors originating from the interacting surfaces of TIR-domain containing proteins can bind to the site on their target interacting protein thereby preventing the assembly of the functional signaling complex. Here we review protein-domain, peptide and peptidomimetic inhibitors targeting TIR-domain mediated interactions and their application demonstrated on in vitro and in vivo models. Recent structural data and elucidation of the molecular mechanisms of TIR-domain mediated signaling enabled the development of peptide inhibitors from TIR domains of TLRs and adapters, MyD88 intermediary domain as well as improved protein inhibitors based on TIR domain dimerization, mimicking bacterial TIR-domain containing immunosuppressors (TCPs) which we discuss with challenges concerning the delivery and specificity of inhibitors targeting TLR adapters. PMID:23305364

  2. Promising Druggable Target in Head and Neck Squamous Cell Carcinoma: Wnt Signaling

    PubMed Central

    Aminuddin, Amnani; Ng, Pei Yuen

    2016-01-01

    Canonical Wnt signaling pathway, also known as Wnt/β-catenin signaling pathway, is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. Furthermore, the canonical Wnt signaling pathway has also been described as one of the critical signaling pathways for regulation of normal stem cells as well as cancer cells with stem cell-like features, termed cancer stem cells (CSC). In this review, we will briefly describe the basic mechanisms of Wnt signaling pathway and its crucial roles in the normal regulation of cellular processes as well as in the development of cancer. Next, we will highlight the roles of canonical Wnt signaling pathway in the regulation of CSC properties namely self-renewal, differentiation, metastasis, and drug resistance abilities, particularly in head and neck squamous cell carcinoma. Finally, we will examine the findings of several recent studies which explore druggable targets in the canonical Wnt signaling pathway which could be valuable to improve the treatment outcome for head and neck cancer. PMID:27570510

  3. Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy.

    PubMed

    Li, Li; Tang, Ping; Li, Shun; Qin, Xiang; Yang, Hong; Wu, Chunhui; Liu, Yiyao

    2017-09-16

    Notch signaling pathway is evolutionarily conserved in mammals, which plays an important role in cell development and differentiation. In recent years, increasing evidence has shown that aberrant activation of Notch is associated with tumor process. Aberrant activation of Notch signaling pathway has been found in many different solid tumors can induce cell proliferation, metastasis and epithelial-mesenchymal transition. Notch receptor and its ligand are both single transmembrane protein, and Notch is activated when it binds to the Notch ligand of neighbor cells. The signal transduction of Notch signaling pathway is only between cells that are in contact with each other, which is independent of second messengers. Thus, Notch needs to cross talk with other signaling pathways, including PI3K/AKT, NF-κB, integrin and miRNAs, to precisely regulate cell fate. In this review, we summarize the roles of Notch signaling pathway in tumor metastasis and its regulatory mechanisms and discuss the current treatment strategies targeting Notch signal pathway.

  4. Genes targeted by the Hedgehog-signaling pathway can be regulated by Estrogen related receptor β.

    PubMed

    Lu, Yuan; Li, Jilong; Cheng, Jianlin; Lubahn, Dennis B

    2015-11-23

    Nuclear receptor family member, Estrogen related receptor β, and the Hedgehog signal transduction pathway are both reported to relate to tumorigenesis and induced pluripotent stem cell reprogramming. We hypothesize that Estrogen related receptor β can modulate the Hedgehog signaling pathway and affect Hedgehog driven downstream gene expression. We established an estrogen related receptor β-expressing Hedgehog-responsive NIH3T3 cell line by Esrrb transfection, and performed mRNA profiling using RNA-Seq after Hedgehog ligand conditioned medium treatment. Esrrb expression altered 171 genes, while Hedgehog signaling activation alone altered 339 genes. Additionally, estrogen related receptor β expression in combination with Hedgehog signaling activation affects a group of 109 Hedgehog responsive mRNAs, including Hsd11b1, Ogn, Smoc2, Igf1, Pdcd4, Igfbp4, Stmn1, Hp, Hoxd8, Top2a, Tubb4b, Sfrp2, Saa3, Prl2c3 and Dpt. We conclude that Estrogen related receptor β is capable of interacting with Hh-signaling downstream targets. Our results suggest a new level of regulation of Hedgehog signaling by Estrogen related receptor β, and indicate modulation of Estrogen related receptor β can be a new strategy to regulate various functions driven by the Hedgehog signaling pathway.

  5. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity

    PubMed Central

    Soethoudt, Marjolein; Grether, Uwe; Fingerle, Jürgen; Grim, Travis W.; Fezza, Filomena; de Petrocellis, Luciano; Ullmer, Christoph; Rothenhäusler, Benno; Perret, Camille; van Gils, Noortje; Finlay, David; MacDonald, Christa; Chicca, Andrea; Gens, Marianela Dalghi; Stuart, Jordyn; de Vries, Henk; Mastrangelo, Nicolina; Xia, Lizi; Alachouzos, Georgios; Baggelaar, Marc P.; Martella, Andrea; Mock, Elliot D.; Deng, Hui; Heitman, Laura H.; Connor, Mark; Di Marzo, Vincenzo; Gertsch, Jürg; Lichtman, Aron H.; Maccarrone, Mauro; Pacher, Pal; Glass, Michelle; van der Stelt, Mario

    2017-01-01

    The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research. PMID:28045021

  6. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity.

    PubMed

    Soethoudt, Marjolein; Grether, Uwe; Fingerle, Jürgen; Grim, Travis W; Fezza, Filomena; de Petrocellis, Luciano; Ullmer, Christoph; Rothenhäusler, Benno; Perret, Camille; van Gils, Noortje; Finlay, David; MacDonald, Christa; Chicca, Andrea; Gens, Marianela Dalghi; Stuart, Jordyn; de Vries, Henk; Mastrangelo, Nicolina; Xia, Lizi; Alachouzos, Georgios; Baggelaar, Marc P; Martella, Andrea; Mock, Elliot D; Deng, Hui; Heitman, Laura H; Connor, Mark; Di Marzo, Vincenzo; Gertsch, Jürg; Lichtman, Aron H; Maccarrone, Mauro; Pacher, Pal; Glass, Michelle; van der Stelt, Mario

    2017-01-03

    The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.

  7. Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities.

    PubMed

    Kumar, Ankit; Kumar Singh, Umesh; Chaudhary, Anurag

    2013-05-01

    Honokiol (3,5-di-(2-propenyl)-1,1-biphenyl-2,2-diol) is a natural bioactive neolignan isolated from the genus Magnolia. In recent studies, honokiol has been observed to have anti-angiogenic, anticancer, anti-inflammatory, neuroprotective and GABA-modulating properties in vitro and in preclinical models. Honokiol and its analogs target multiple signaling pathways including NF-κB, STAT3, EGFR, mTOR and caspase-mediated common pathway, which regulate cancer initiation and progression. Honokiol and its targets of action may be helpful in the development of effective analogs and targeted cancer therapy. In this review, recent data describing the molecular targets of honokiol and its analogs with anticancer and some other bioactivities are discussed.

  8. Differential usage of signal transduction pathways defines two types of serum response factor target gene.

    PubMed

    Gineitis, D; Treisman, R

    2001-07-06

    Activation of the transcription factor serum response factor (SRF) is dependent on Rho-controlled changes in actin dynamics. We used pathway-specific inhibitors to compare the roles of actin dynamics, extracellular signal-regulated kinase (ERK) signaling, and phosphatidylinositol 3-kinase in signaling either to SRF itself or to four cellular SRF target genes. Serum, lysophosphatidic acid, platelet-derived growth factor, and phorbol 12-myristate 13-acetate (PMA) each activated transcription of a stably integrated SRF reporter gene dependent on functional RhoA GTPase. Inhibition of mitogen-activated protein kinase-ERK kinase (MEK) signalling reduced activation of the SRF reporter by all stimuli by about 50%, except for PMA, which was effectively blocked. Inhibition of phosphatidylinositol 3-kinase slightly reduced reporter activation by serum and lysophosphatidic acid but substantially inhibited activation by platelet-derived growth factor and PMA. Reporter induction by all stimuli was absolutely dependent on actin dynamics. Regulation of the SRF (srf) and vinculin (vcl) genes was similar to that of the SRF reporter gene; activation by all stimuli was Rho-dependent and required actin dynamics but was largely independent of MEK activity. In contrast, activation of fos and egr1 occurred independently of RhoA and actin polymerization but was almost completely dependent on MEK activation. These results show that at least two classes of SRF target genes can be distinguished on the basis of their relative sensitivity to RhoA-actin and MEK-ERK signaling pathways.

  9. '2A-Like' Signal Sequences Mediating Translational Recoding: A Novel Form of Dual Protein Targeting.

    PubMed

    Roulston, Claire; Luke, Garry A; de Felipe, Pablo; Ruan, Lin; Cope, Jonathan; Nicholson, John; Sukhodub, Andriy; Tilsner, Jens; Ryan, Martin D

    2016-08-01

    We report the initial characterization of an N-terminal oligopeptide '2A-like' sequence that is able to function both as a signal sequence and as a translational recoding element. Owing to this translational recoding activity, two forms of nascent polypeptide are synthesized: (i) when 2A-mediated translational recoding has not occurred: the nascent polypeptide is fused to the 2A-like N-terminal signal sequence and the fusion translation product is targeted to the exocytic pathway, and, (ii) a translation product where 2A-mediated translational recoding has occurred: the 2A-like signal sequence is synthesized as a separate translation product and, therefore, the nascent (downstream) polypeptide lacks the 2A-like signal sequence and is localized to the cytoplasm. This type of dual-functional signal sequence results, therefore, in the partitioning of the translation products between the two sub-cellular sites and represents a newly described form of dual protein targeting.

  10. The similarity between N-terminal targeting signals for protein import into different organelles and its evolutionary relevance

    PubMed Central

    Kunze, Markus; Berger, Johannes

    2015-01-01

    The proper distribution of proteins between the cytosol and various membrane-bound compartments is crucial for the functionality of eukaryotic cells. This requires the cooperation between protein transport machineries that translocate diverse proteins from the cytosol into these compartments and targeting signal(s) encoded within the primary sequence of these proteins that define their cellular destination. The mechanisms exerting protein translocation differ remarkably between the compartments, but the predominant targeting signals for mitochondria, chloroplasts and the ER share the N-terminal position, an α-helical structural element and the removal from the core protein by intraorganellar cleavage. Interestingly, similar properties have been described for the peroxisomal targeting signal type 2 mediating the import of a fraction of soluble peroxisomal proteins, whereas other peroxisomal matrix proteins encode the type 1 targeting signal residing at the extreme C-terminus. The structural similarity of N-terminal targeting signals poses a challenge to the specificity of protein transport, but allows the generation of ambiguous targeting signals that mediate dual targeting of proteins into different compartments. Dual targeting might represent an advantage for adaptation processes that involve a redistribution of proteins, because it circumvents the hierarchy of targeting signals. Thus, the co-existence of two equally functional import pathways into peroxisomes might reflect a balance between evolutionary constant and flexible transport routes. PMID:26441678

  11. p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies.

    PubMed

    Wander, Seth A; Zhao, Dekuang; Slingerland, Joyce M

    2011-01-01

    Phosphorylation of the cyclin-dependent kinase inhibitor p27 by upstream mitogenic signaling pathways regulates its stability, localization, and biological function. In human cancers, loss of the antiproliferative action of p27 can arise through reduced protein levels and/or cytoplasmic mislocalization, leading to increased cell proliferation and/or cell migration, respectively. Reduced p27 expression levels and p27 mislocalization have potential prognostic and therapeutic implications in various types of human cancers. This review highlights mechanisms of functional deregulation of p27 by oncogenic signaling that provide an important molecular rationale for pathway targeting in cancer treatment. ©2010 AACR.

  12. From Fly Wings to Targeted Cancer Therapies: A Centennial for Notch Signaling

    PubMed Central

    Ntziachristos, Panagiotis; Lim, Jing Shan; Sage, Julien; Aifantis, Iannis

    2014-01-01

    Since Notch phenotypes in Drosophila melanogaster were identified 100 years, Notch signaling has been extensively characterized as a regulator of cell fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this Perspective, we discuss the pro-tumorigenic and tumor suppressive functions of Notch signaling and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. PMID:24651013

  13. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling.

    PubMed

    Moreno, Estefanía; Andradas, Clara; Medrano, Mireia; Caffarel, María M; Pérez-Gómez, Eduardo; Blasco-Benito, Sandra; Gómez-Cañas, María; Pazos, M Ruth; Irving, Andrew J; Lluís, Carme; Canela, Enric I; Fernández-Ruiz, Javier; Guzmán, Manuel; McCormick, Peter J; Sánchez, Cristina

    2014-08-08

    The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.

  14. Glycans in post-Golgi apical targeting: sorting signals or structural props?

    PubMed

    Rodriguez-Boulan, E; Gonzalez, A

    1999-08-01

    A recent model proposed that N-glycans serve as apical targeting signals for soluble and membrane proteins in epithelial cells and neurons by interacting with lectin sorters in the trans-Golgi network. However, we believe that a number of experimental observations support an alternative hypothesis, that N-glycans play a facilitative role, by providing structural support or preventing aggregation of the proteins for example, thereby allowing interaction of proteinaceous apical sorting signals with the sorting machinery. This article discusses the experimental data currently available and how they relate to the proposed models.

  15. Substrate-Activated Conformational Switch on Chaperones Encodes aTargeting Signal in Type III Secretion

    PubMed Central

    Chen, Li; Ai, Xuanjun; Portaliou, Athina G.; Minetti, Conceicao A.S.A.; Remeta, David P.; Economou, Anastassios; Kalodimos, Charalampos G.

    2013-01-01

    SUMMARY Targeting of type III secretion proteins at the injectisome is an important process in bacterial virulence. Nevertheless, how the injectisome specifically recognizes TTS substrates among all bacterial proteins is unknown. A TTS peripheral membrane ATPase protein located at the base of the injectisome has been implicated in the targeting process. We have investigated the targeting of the EspA filament protein and its cognate chaperone CesAB to the EscN ATPase of the enteropathogenic E. coli (EPEC). We show that EscN selectively engages the EspA-loaded CesAB, but not the unliganded CesAB. Structure analysis revealed that the targeting signal is encoded in a disorder-order structural transition in CesAB that is elicited only upon binding of its physiological substrate, EspA. Abrogation of the interaction between the CesAB–EspA complex and EscN resulted in severe secretion and infection defects. We further show that the targeting and secretion signals are distinct and the two processes are likely regulated by different mechanisms. PMID:23523349

  16. Spectral and spatial selectivity of luminance vision in reef fish

    PubMed Central

    Siebeck, Ulrike E.; Wallis, Guy Michael; Litherland, Lenore; Ganeshina, Olga; Vorobyev, Misha

    2014-01-01

    Luminance vision has high spatial resolution and is used for form vision and texture discrimination. In humans, birds and bees luminance channel is spectrally selective—it depends on the signals of the long-wavelength sensitive photoreceptors (bees) or on the sum of long- and middle-wavelength sensitive cones (humans), but not on the signal of the short-wavelength sensitive (blue) photoreceptors. The reasons of such selectivity are not fully understood. The aim of this study is to reveal the inputs of cone signals to high resolution luminance vision in reef fish. Sixteen freshly caught damselfish, Pomacentrus amboinensis, were trained to discriminate stimuli differing either in their color or in their fine patterns (stripes vs. cheques). Three colors (“bright green”, “dark green” and “blue”) were used to create two sets of color and two sets of pattern stimuli. The “bright green” and “dark green” were similar in their chromatic properties for fish, but differed in their lightness; the “dark green” differed from “blue” in the signal for the blue cone, but yielded similar signals in the long-wavelength and middle-wavelength cones. Fish easily learned to discriminate “bright green” from “dark green” and “dark green” from “blue” stimuli. Fish also could discriminate the fine patterns created from “dark green” and “bright green”. However, fish failed to discriminate fine patterns created from “blue” and “dark green” colors, i.e., the colors that provided contrast for the blue-sensitive photoreceptor, but not for the long-wavelength sensitive one. High resolution luminance vision in damselfish, Pomacentrus amboinensis, does not have input from the blue-sensitive cone, which may indicate that the spectral selectivity of luminance channel is a general feature of visual processing in both aquatic and terrestrial animals. PMID:25324727

  17. Spectral and spatial selectivity of luminance vision in reef fish.

    PubMed

    Siebeck, Ulrike E; Wallis, Guy Michael; Litherland, Lenore; Ganeshina, Olga; Vorobyev, Misha

    2014-01-01

    Luminance vision has high spatial resolution and is used for form vision and texture discrimination. In humans, birds and bees luminance channel is spectrally selective-it depends on the signals of the long-wavelength sensitive photoreceptors (bees) or on the sum of long- and middle-wavelength sensitive cones (humans), but not on the signal of the short-wavelength sensitive (blue) photoreceptors. The reasons of such selectivity are not fully understood. The aim of this study is to reveal the inputs of cone signals to high resolution luminance vision in reef fish. Sixteen freshly caught damselfish, Pomacentrus amboinensis, were trained to discriminate stimuli differing either in their color or in their fine patterns (stripes vs. cheques). Three colors ("bright green", "dark green" and "blue") were used to create two sets of color and two sets of pattern stimuli. The "bright green" and "dark green" were similar in their chromatic properties for fish, but differed in their lightness; the "dark green" differed from "blue" in the signal for the blue cone, but yielded similar signals in the long-wavelength and middle-wavelength cones. Fish easily learned to discriminate "bright green" from "dark green" and "dark green" from "blue" stimuli. Fish also could discriminate the fine patterns created from "dark green" and "bright green". However, fish failed to discriminate fine patterns created from "blue" and "dark green" colors, i.e., the colors that provided contrast for the blue-sensitive photoreceptor, but not for the long-wavelength sensitive one. High resolution luminance vision in damselfish, Pomacentrus amboinensis, does not have input from the blue-sensitive cone, which may indicate that the spectral selectivity of luminance channel is a general feature of visual processing in both aquatic and terrestrial animals.

  18. The Bcl10/Malt1 signaling pathway as a drug target in lymphoma.

    PubMed

    Jost, P; Peschel, C; Ruland, J

    2006-10-01

    The development of lymphomas and leukemias is frequently caused by chromosomal translocations that deregulate cellular pathways of differentiation, proliferation or survival. The molecules that are involved in these aberrations provide rational targets for selective drug therapies. Recently, several disease specific translocations have been identified in human MALT lymphoma. These aberrations either upregulate the expression of BCL10 or MALT1 or induce the formation of API2-MALT1 fusion proteins. Genetic and biochemical experiments identified BCL10 and MALT1 as central components of an oligomerization-ubiquitinylation-phosphorylation cascade that activates the transcription factor NF-kappaB in response to antigen receptor ligation. Deregulation of the signaling cascade is directly associated with antigen independent MALT lymphoma growth. Here we provide an overview of the physiological and pathological functions of BCL10/MALT1 signal transduction and discuss the potential of this pathway as a drug target.

  19. Differential Targeting of Gβγ-Subunit Signaling with Small Molecules

    NASA Astrophysics Data System (ADS)

    Bonacci, Tabetha M.; Mathews, Jennifer L.; Yuan, Chujun; Lehmann, David M.; Malik, Sundeep; Wu, Dianqing; Font, Jose L.; Bidlack, Jean M.; Smrcka, Alan V.

    2006-04-01

    G protein βγ subunits have potential as a target for therapeutic treatment of a number of diseases. We performed virtual docking of a small-molecule library to a site on Gβγ subunits that mediates protein interactions. We hypothesized that differential targeting of this surface could allow for selective modulation of Gβγ subunit functions. Several compounds bound to Gβγ subunits with affinities from 0.1 to 60 μM and selectively modulated functional Gβγ-protein-protein interactions in vitro, chemotactic peptide signaling pathways in HL-60 leukocytes, and opioid receptor-dependent analgesia in vivo. These data demonstrate an approach for modulation of G protein-coupled receptor signaling that may represent an important therapeutic strategy.

  20. Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients.

    PubMed

    Zhou, Wen-Ya; Zheng, Hong; Du, Xiao-Ling; Yang, Ji-Long

    2016-06-01

    The fibroblast growth factor receptor (FGFR) family plays important roles in regulating cell growth, proliferation, survival, differentiation and angiogenesis. Deregulation of the FGF/FGFR signaling pathway has been associated with multiple development syndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored. However, few studies on the FGF/FGFR pathway have been conducted in sarcoma, which has a poor outcome with traditional treatments such as surgery, chemotherapy, and radiotherapy. Hence, in the present review, we provide an overview of the role of the FGF/FGFR pathway signal in sarcoma and FGFR inhibitors, which might be new targets for the treatment of sarcomas according to recent research.

  1. Determining human target facing orientation using bistatic radar micro-Doppler signals

    NASA Astrophysics Data System (ADS)

    Fairchild, Dustin P.; Narayanan, Ram M.

    2014-06-01

    Micro-Doppler radar signals can be used to separate moving human targets from stationary clutter and also to identify and classify human movements. Traditional micro-Doppler radar systems which use a single sensor, monostatic system, suffer from the drawback that only the radial component of the micro-Doppler signal will be observed by the radar operator. This reduces the sensitivity of human activity recognition if the movements are not directly towards or away with respect to the line-of-sight to the radar antenna. In this paper, we propose the use of two bistatic micro-Doppler sensors to overcome this limitation. By using multiple sensors, the orientation of oscillating targets with respect to the radar line-of-sight can be inferred, thereby providing additional information to the radar operator. This approach can be used to infer the facing direction of the human with respect to the radar beam.

  2. Characterization of FGFR signaling pathway as therapeutic targets for sarcoma patients

    PubMed Central

    Zhou, Wen-Ya; Zheng, Hong; Du, Xiao-Ling; Yang, Ji-Long

    2016-01-01

    The fibroblast growth factor receptor (FGFR) family plays important roles in regulating cell growth, proliferation, survival, differentiation and angiogenesis. Deregulation of the FGF/FGFR signaling pathway has been associated with multiple development syndromes and cancers, and thus therapeutic strategies targeting FGFs and FGFR in human cancer are currently being explored. However, few studies on the FGF/FGFR pathway have been conducted in sarcoma, which has a poor outcome with traditional treatments such as surgery, chemotherapy, and radiotherapy. Hence, in the present review, we provide an overview of the role of the FGF/FGFR pathway signal in sarcoma and FGFR inhibitors, which might be new targets for the treatment of sarcomas according to recent research. PMID:27458533

  3. [Therapeutic target for endothelium-derived hyperpolarizing factor signaling in diabetic vascular complication].

    PubMed

    Matsumoto, Takayuki

    2010-06-01

    Vascular tone is tightly regulated by endothelium-derived factors. These include relaxing factors (EDRFs) such as nitric oxide (NO), hyperpolarizing factors (EDHFs), and contracting factors (EDCFs). Although EDHF is a prominent vasodilator, particularly in smaller arteries, little attention has been paid to the potential role of EDHF responses in diabetes. EDHF signaling may involve various factors, including several diffusible factors and non-diffusible factors (e.g., gap junctions). It has been demonstrated that the alterations in EDHF relaxation seen in mesenteric arteries from diabetic rats may be attributable to an increase in phosphodiesterase 3 (PDE3) activity, leading to a reduction in the action of adenosine 3',5'-cyclic monophosphate (cAMP), and consequently the activity of protein kinase A (PKA) is decreased in such arteries. Moreover, it has been suggested that the imbalance between EDRFs and EDCFs is present in mesenteric arteries from type 2 diabetic rats and the EDHF relaxation can be partly reversed by suppression of EDCF signaling. Indeed, chronic treatment with metformin, eicosapentaenoic acid, or thromboxane synthase inhibitor can reduce EDCF signaling and normalize EDHF signaling in mesenteric arteries from type 2 diabetic rats. Although the improvement or restoration of EDHF responses has not been the direct subject of any pharmaceutical effort, increasing cAMP/PKA signaling (e.g., by inhibiting PDE3 activity) or reducing EDCFs signaling has potential as an interesting therapeutic target in diabetic vasculopathy.

  4. Structural Requirements for Interaction of Peroxisomal Targeting Signal 2 and Its Receptor PEX7*

    PubMed Central

    Kunze, Markus; Neuberger, Georg; Maurer-Stroh, Sebastian; Ma, Jianmin; Eck, Thomas; Braverman, Nancy; Schmid, Johannes A.; Eisenhaber, Frank; Berger, Johannes

    2011-01-01

    The import of a subset of peroxisomal matrix proteins is mediated by the peroxisomal targeting signal 2 (PTS2). The results of our sequence and physical property analysis of known PTS2 signals and of a mutational study of the least characterized amino acids of a canonical PTS2 motif indicate that PTS2 forms an amphipathic helix accumulating all conserved residues on one side. Three-dimensional structural modeling of the PTS2 receptor PEX7 reveals a groove with an evolutionarily conserved charge distribution complementary to PTS2 signals. Mammalian two-hybrid assays and cross-complementation of a mutation in PTS2 by a compensatory mutation in PEX7 confirm the interaction site. An unstructured linker region separates the PTS2 signal from the core protein. This additional information on PTS2 signals was used to generate a PTS2 prediction algorithm that enabled us to identify novel PTS2 signals within human proteins and to describe KChIP4 as a novel peroxisomal protein. PMID:22057399

  5. Targeting tissue oxidative damage by means of cell signaling modulators: the antioxidant concept revisited.

    PubMed

    Leonarduzzi, Gabriella; Sottero, Barbara; Poli, Giuseppe

    2010-11-01

    The complex system of molecular communications underlying cell biochemistry and function includes numerous components, kinases, phosphatases and transcription factors, that have been conclusively proven to be sensitive to cellular and tissue redox changes. Reactive oxygen species (ROS), whose constitutive generation in cells and tissues is amplified under pro-oxidant conditions, are now unanimously recognized to be important triggers and modulators of cell signaling, and consequently of cell behavior. This review considers the major signaling pathways that mediate gene regulation in response to ROS, and analyzes their modulation by the most important non-enzymatic molecules having an antioxidant effect. Because of the primary role played by ROS-mediated signaling and gene expression in pathophysiology, the so-called "antioxidant compounds" may significantly interfere with cell signal transduction, not simply by quenching ROS generation and propagation but also by intercepting reactive species at the level of critical signaling pathways. Notably, a third mechanism of action has recently emerged that is independent of antioxidant properties, i.e. direct chemical interaction of the "antioxidant" with signaling enzymes and transcription factors. However, severe inhibition of ROS production might interfere with certain physiological cellular and organ functions, and would thus eventually be detrimental rather than beneficial. To address the need for appropriate administration of non-enzymatic antioxidants, the most advanced technologies for their targeted delivery are analyzed and reported.

  6. Molecular targets and signaling pathways regulated by interleukin (IL)-24 in mediating its antitumor activities

    PubMed Central

    2013-01-01

    Cancer remains a major health issue in the world and the effectiveness of current therapies is limited resulting in disease recurrence and resistance to therapy. Therefore to overcome disease recurrence and have improved treatment efficacy there is a continued effort to develop and test new anticancer drugs that are natural or synthetic - (conventional chemotherapeutics, small molecule inhibitors) and biologic (antibody, tumor suppressor genes, oligonucleotide) product. In parallel, efforts for identifying molecular targets and signaling pathways to which cancer cells are “addicted” are underway. By inhibiting critical signaling pathways that is crucial for cancer cell survival, it is expected that the cancer cells will undergo a withdrawal symptom akin to “de-addiction” resulting in cell death. Thus, the key for having an improved and greater control on tumor growth and metastasis is to develop a therapeutic that is able to kill tumor cells efficiently by modulating critical signaling pathways on which cancer cells rely for their survival. Currently several small molecule inhibitors targeted towards unique molecular signaling pathways have been developed and tested in the clinic. Few of these inhibitors have shown efficacy while others have failed. Thus, targeting a single molecule or pathway may be insufficient to completely block cancer cell proliferation and survival. It is therefore important to identify and test an anticancer drug that can inhibit multiple signaling pathways in a cancer cell, control growth of both primary and metastatic tumors and is safe. One biologic agent that has the characteristics of serving as a potent anticancer drug is interleukin (IL)-24. IL-24 suppresses multiple signaling pathways in a broad-spectrum of human cancer cells leading to tumor cell death, inhibition of tumor angiogenesis and metastasis. Additionally, combining IL-24 with other therapies demonstrated additive to synergistic antitumor activity. Clinical testing

  7. A waveform detector that targets template–decorrelated signals and achieves its predicted performance, Part I: Demonstration with IMS data

    SciTech Connect

    Carmichael, Joshua Daniel

    2016-01-01

    Here, waveform correlation detectors used in seismic monitoring scan multichannel data to test two competing hypotheses: that data contain (1) a noisy, amplitude-scaled version of a template waveform, or, (2) only noise. In reality, seismic wavefields include signals triggered by non-target sources (background seismicity) and targets signals that are only partially correlated with the waveform template.

  8. Targeting Ligand Dependent and Ligand Independent Androgen Receptor Signaling in Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    or replace the effect of a natural peptide. A classic example is the human analogue of insulin , admin- istered to patients with insulin - dependent ... diabetes . Initially purified from bovine and porcine (44), insulin is now routinely manufactured via recombinant methods as pro- insulin (45). However...2014 4. TITLE AND SUBTITLE Targeting Ligand Dependent and Ligand Independent Androgen Receptor Signaling in Prostate Cancer 5a. CONTRACT NUMBER

  9. Unbiased Combinatorial Genomic Approaches to Identify Alternative Therapeutic Targets within the TSC Signaling Network

    DTIC Science & Technology

    2015-09-01

    using phospho-AKT, dpERK, and phospho-S6K antibodies (months 24-36) COMPLETED -Expand the synthetic lethal screen to the Insulin network (months 24-36...Drosophila cells with the aim of generating knockout cell lines for five tumor suppressors (TSC1, TSC2/gig, Nf1, Lkb1 and Pten) within the TSC/ Insulin ...is the target of 4EBP regulation downstream of insulin signaling, indicating a likely mechanism for the observed synthetic lethality. Task 2

  10. Teratogen-mediated inhibition of target tissue response to Shh signaling.

    PubMed

    Cooper, M K; Porter, J A; Young, K E; Beachy, P A

    1998-06-05

    Veratrum alkaloids and distal inhibitors of cholesterol biosynthesis have been studied for more than 30 years as potent teratogens capable of inducing cyclopia and other birth defects. Here, it is shown that these compounds specifically block the Sonic hedgehog (Shh) signaling pathway. These teratogens did not prevent the sterol modification of Shh during autoprocessing but rather inhibited the response of target tissues to Shh, possibly acting through the sterol sensing domain within the Patched protein regulator of Shh response.

  11. Insulin, IGF-1 and GLP-1 signaling in neurodegenerative disorders: targets for disease modification?

    PubMed

    Bassil, Fares; Fernagut, Pierre-Olivier; Bezard, Erwan; Meissner, Wassilios G

    2014-07-01

    Insulin and Insulin Growth Factor-1 (IGF-1) play a major role in body homeostasis and glucose regulation. They also have paracrine/autocrine functions in the brain. The Insulin/IGF-1 signaling pathway contributes to the control of neuronal excitability, nerve cell metabolism and cell survival. Glucagon like peptide-1 (GLP-1), known as an insulinotropic hormone has similar functions and growth like properties as insulin/IGF-1. Growing evidence suggests that dysfunction of these pathways contribute to the progressive loss of neurons in Alzheimer's disease (AD) and Parkinson's disease (PD), the two most frequent neurodegenerative disorders. These findings have led to numerous studies in preclinical models of neurodegenerative disorders targeting insulin/IGF-1 and GLP-1 signaling with currently available anti-diabetics. These studies have shown that administration of insulin, IGF-1 and GLP-1 agonists reverses signaling abnormalities and has positive effects on surrogate markers of neurodegeneration and behavioral outcomes. Several proof-of-concept studies are underway that attempt to translate the encouraging preclinical results to patients suffering from AD and PD. In the first part of this review, we discuss physiological functions of insulin/IGF-1 and GLP-1 signaling pathways including downstream targets and receptors distribution within the brain. In the second part, we undertake a comprehensive overview of preclinical studies targeting insulin/IGF-1 or GLP-1 signaling for treating AD and PD. We then detail the design of clinical trials that have used anti-diabetics for treating AD and PD patients. We close with future considerations that treat relevant issues for successful translation of these encouraging preclinical results into treatments for patients with AD and PD.

  12. Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway.

    PubMed

    Lee, Cheol-Jung; Lee, Mee-Hyun; Yoo, Sun-Mi; Choi, Kyung-Il; Song, Ji-Hong; Jang, Jeong-Hoon; Oh, Sei-Ryang; Ryu, Hyung-Won; Lee, Hye-Suk; Surh, Young-Joon; Cho, Yong-Yeon

    2015-08-08

    Magnolin is a natural compound abundantly found in Magnolia flos, which has been traditionally used in oriental medicine to treat headaches, nasal congestion and anti-inflammatory reactions. Our recent results have demonstrated that magnolin targets the active pockets of ERK1 and ERK2, which are important signaling molecules in cancer cell metastasis. The aim of this study is to evaluate the effects of magnolin on cell migration and to further explore the molecular mechanisms involved. Magnolin-mediated signaling inhibition was confirmed by Western blotting using RSK2(+/+) and RSK2(-/-) MEFs, A549 and NCI-H1975 lung cancer cells, and by NF-κB and Cox-2 promoter luciferase reporter assays. Inhibition of cell migration by magnolin was examined by wound healing and/or Boyden Chamber assays using JB6 Cl41 and A549 human lung cancer cells. The molecular mechanisms involved in cell migration and epithelial-to-mesenchymal transition were determined by zymography, Western blotting, real-time PCR and immunocytofluorescence. Magnolin inhibited NF-κB transactivation activity by suppressing the ERKs/RSK2 signaling pathway. Moreover, magnolin abrogated the increase in EGF-induced COX-2 protein levels and wound healing. In human lung cancer cells such as A549 and NCI-H1975, which harbor constitutive active Ras and EGFR mutants, respectively, magnolin suppressed wound healing and cell invasion as seen by a Boyden chamber assay. In addition, it was observed that magnolin inhibited MMP-2 and -9 gene expression and activity. The knockdown or knockout of RSK2 in A549 lung cancer cells or MEFs revealed that magnolin targeting ERKs/RSK2 signaling suppressed epithelial-to-mesenchymal transition by modulating EMT marker proteins such as N-cadherin, E-cadherin, Snail, Vimentin and MMPs. These results demonstrate that magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway.

  13. MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis.

    PubMed

    Severin, Mary E; Lee, Priscilla W; Liu, Yue; Selhorst, Amanda J; Gormley, Matthew G; Pei, Wei; Yang, Yuhong; Guerau-de-Arellano, Mireia; Racke, Michael K; Lovett-Racke, Amy E

    2016-06-01

    Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. 78 FR 69710 - Luminant Generation Company, LLC

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-20

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Luminant Generation Company, LLC AGENCY: U.S. Nuclear Regulatory Commission (NRC). ACTION... consecutive weeks of a combined license (COL) application from Luminant Generation Company, LLC....

  15. 78 FR 66785 - Luminant Generation Company, LLC

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-06

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Luminant Generation Company, LLC AGENCY: Nuclear Regulatory Commission. ACTION: Notice of receipt... consecutive weeks of ] a combined license (COL) application from Luminant Generation Company, LLC....

  16. 78 FR 70964 - Luminant Generation Company, LLC

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-27

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Luminant Generation Company, LLC AGENCY: Nuclear Regulatory Commission. ACTION: Combined license... for four consecutive weeks of a combined license (COL) application from Luminant Generation...

  17. 78 FR 68100 - Luminant Generation Company, LLC

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-13

    ... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Luminant Generation Company, LLC AGENCY: U.S. Nuclear Regulatory Commission (NRC). ACTION... consecutive weeks of a combined license (COL) application from Luminant Generation Company, LLC....

  18. Targeting stem cell signaling pathways for drug discovery: advances in the Notch and Wnt pathways.

    PubMed

    An, Songzhu Michael; Ding, Qiang; Zhang, Jie; Xie, JingYi; Li, LingSong

    2014-06-01

    Signaling pathways transduce extracellular stimuli into cells through molecular cascades to regulate cellular functions. In stem cells, a small number of pathways, notably those of TGF-β/BMP, Hedgehog, Notch, and Wnt, are responsible for the regulation of pluripotency and differentiation. During embryonic development, these pathways govern cell fate specifications as well as the formation of tissues and organs. In adulthood, their normal functions are important for tissue homeostasis and regeneration, whereas aberrations result in diseases, such as cancer and degenerative disorders. In complex biological systems, stem cell signaling pathways work in concert as a network and exhibit crosstalk, such as the negative crosstalk between Wnt and Notch. Over the past decade, genetic and genomic studies have identified a number of potential drug targets that are involved in stem cell signaling pathways. Indeed, discovery of new targets and drugs for these pathways has become one of the most active areas in both the research community and pharmaceutical industry. Remarkable progress has been made and several promising drug candidates have entered into clinical trials. This review focuses on recent advances in the discovery of novel drugs which target the Notch and Wnt pathways.

  19. Dendritic cell specific targeting of MyD88 signalling pathways in vivo.

    PubMed

    Arnold-Schrauf, Catharina; Berod, Luciana; Sparwasser, Tim

    2015-01-01

    Dendritic cells (DCs) are key regulators of both innate and adaptive immunity. During infection, DCs recognise pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) including the Toll-like receptor (TLR) family. TLRs mainly signal via the adaptor protein MyD88. This signalling pathway is required for immune protection during many infections, which are lethal in the absence of MyD88. However, the cell type specific importance of this pathway during both innate and adaptive immune responses against pathogens in vivo remains ill-defined. We discuss recent findings from conditional KO or gain-of-function mouse models targeting TLR/MyD88 signalling pathways in DCs and other myeloid cells during infection. While the general assumption that MyD88-dependent recognition by DCs is essential for inducing protective immunity holds true in some instances, the results surprisingly indicate a much more complex context-dependent requirement for this pathway in DCs and other myeloid or lymphoid cell-types in vivo. Furthermore, we highlight the advantages of Cre-mediated DC targeting approaches and their possible limitations. We also present future perspectives on the development of new genetic mouse models to target distinct DC subsets in vivo. Such models will serve to understand the functional heterogeneity of DCs in vivo.

  20. Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains

    PubMed Central

    Gao, Yang; Teschendorff, Andrew E.

    2017-01-01

    Cancer is characterized by both genetic and epigenetic alterations. While cancer driver mutations and copy-number alterations have been studied at a systems-level, relatively little is known about the systems-level patterns exhibited by their epigenetic counterparts. Here we perform a pan-cancer wide systems-level analysis, mapping candidate cancer-driver DNA methylation (DNAm) alterations onto a human interactome. We demonstrate that functional DNAm alterations in cancer tend to map to nodes of lower connectivity and inter-connectivity, compared to the corresponding alterations at the genomic level. We find that epigenetic alterations are relatively over-represented in extracellular and transmembrane signaling domains, whereas cancer genes undergoing amplification or deletion tend to be enriched within the intracellular domain. A pan-cancer wide meta-analysis identifies WNT and chemokine signaling, as two key pathways where epigenetic deregulation preferentially targets extracellular components. We further pinpoint specific chemokine ligands/receptors whose epigenetic deregulation associates with key epigenetic enzymes, representing potential targets for epigenetic therapy. Our results suggest that epigenetic deregulation in cancer not only targets tissue-specific transcription factors, but also modulates signaling within the extra-cellular domain, providing novel system-level insight into the potential distinctive role of genetic and epigenetic alterations in cancer. PMID:27899617

  1. MicroRNA-99 Family Targets AKT/mTOR Signaling Pathway in Dermal Wound Healing

    PubMed Central

    Chen, Dan; Fang, Zong Juan; Zhao, Yan; Dragas, Dragan; Dai, Yang; Marucha, Phillip T.; Zhou, Xiaofeng

    2013-01-01

    Recent studies suggest that microRNAs play important roles in dermal wound healing and microRNA deregulation has been linked with impaired wound repair. Here, using a mouse experimental wound healing model, we identified a panel of 63 differentially expressed microRNAs during dermal wound healing, including members of miR-99 family (miR-99a, miR-99b, miR-100). We further demonstrated that miR-99 family members regulate cell proliferation, cell migration, and AKT/mTOR signaling. Combined experimental and bioinformatics analyses revealed that miR-99 family members regulate AKT/mTOR signaling by targeting multiple genes, including known target genes (e.g., IGF1R, mTOR) and a new target (AKT1). The effects of miR-99 family members on the expression of IGF1R, mTOR and AKT1 were validated at both the mRNA and protein levels. Two adjacent miR-99 family targeting sites were identified in the 3′-UTR of the AKT1 mRNA. The direct interaction of miR-100 with these targeting sites was confirmed using luciferase reporter assays. The microRNA-100-directed recruitment of AKT1 mRNA to the RNAi-induced silencing complex (RISC) was confirmed by a ribonucleoprotein-IP assay. In summary, we identified a panel of differentially expressed microRNAs which may play important roles in wound healing. We provide evidence that miR-99 family members contribute to wound healing by regulating the AKT/mTOR signaling. PMID:23724047

  2. The p53 tumor suppressor targets a novel regulator of G protein signaling

    PubMed Central

    Buckbinder, Leonard; Velasco-Miguel, Susana; Chen, Yan; Xu, Ningzhi; Talbott, Randy; Gelbert, Larry; Gao, Jizong; Seizinger, Bernd R.; Gutkind, J. Silvio; Kley, Nikolai

    1997-01-01

    Heterotrimeric G proteins transduce multiple growth-factor-receptor-initiated and intracellular signals that may lead to activation of the mitogen-activated or stress-activated protein kinases. Herein we report on the identification of a novel p53 target gene (A28-RGS14) that is induced in response to genotoxic stress and encodes a novel member of a family of regulators of G protein signaling (RGS) proteins with proposed GTPase-activating protein activity. Overexpression of A28-RGS14p protein inhibits both Gi- and Gq-coupled growth-factor-receptor-mediated activation of the mitogen-activated protein kinase signaling pathway in mammalian cells. Thus, through the induction of A28-RGS14, p53 may regulate cellular sensitivity to growth and/or survival factors acting through G protein-coupled receptor pathways. PMID:9223279

  3. Methylglyoxal Activates the Target of Rapamycin Complex 2-Protein Kinase C Signaling Pathway in Saccharomyces cerevisiae

    PubMed Central

    Nomura, Wataru

    2015-01-01

    Methylglyoxal is a typical 2-oxoaldehyde derived from glycolysis. We show here that methylglyoxal activates the Pkc1-Mpk1 mitogen-activated protein (MAP) kinase cascade in a target of rapamycin complex 2 (TORC2)-dependent manner in the budding yeast Saccharomyces cerevisiae. We demonstrate that TORC2 phosphorylates Pkc1 at Thr1125 and Ser1143. Methylglyoxal enhanced the phosphorylation of Pkc1 at Ser1143, which transmitted the signal to the downstream Mpk1 MAP kinase cascade. We found that the phosphorylation status of Pkc1T1125 affected the phosphorylation of Pkc1 at Ser1143, in addition to its protein levels. Methylglyoxal activated mammalian TORC2 signaling, which, in turn, phosphorylated Akt at Ser473. Our results suggest that methylglyoxal is a conserved initiator of TORC2 signaling among eukaryotes. PMID:25624345

  4. MAPK Signaling in Cardiovascular Health and Disease: Molecular Mechanisms and Therapeutic Targets

    PubMed Central

    Muslin, Anthony J.

    2009-01-01

    Intracellular mitogen-activated protein kinase (MAPK) signaling cascades likely play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signaling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In this review, the role of the MAPKs extracellular signal-regulated kinase (ERK), C-jun N-terminal kinase (JNK) and p38 MAPK in cardiac hypertrophy, cardiac remodeling after myocardial infarction, atherosclerosis and vascular restenosis will be examined with attention paid to genetically-modified murine model systems and to the use of pharmacologic inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging. PMID:18752467

  5. Methylglyoxal activates the target of rapamycin complex 2-protein kinase C signaling pathway in Saccharomyces cerevisiae.

    PubMed

    Nomura, Wataru; Inoue, Yoshiharu

    2015-04-01

    Methylglyoxal is a typical 2-oxoaldehyde derived from glycolysis. We show here that methylglyoxal activates the Pkc1-Mpk1 mitogen-activated protein (MAP) kinase cascade in a target of rapamycin complex 2 (TORC2)-dependent manner in the budding yeast Saccharomyces cerevisiae. We demonstrate that TORC2 phosphorylates Pkc1 at Thr(1125) and Ser(1143). Methylglyoxal enhanced the phosphorylation of Pkc1 at Ser(1143), which transmitted the signal to the downstream Mpk1 MAP kinase cascade. We found that the phosphorylation status of Pkc1(T1125) affected the phosphorylation of Pkc1 at Ser(1143), in addition to its protein levels. Methylglyoxal activated mammalian TORC2 signaling, which, in turn, phosphorylated Akt at Ser(473). Our results suggest that methylglyoxal is a conserved initiator of TORC2 signaling among eukaryotes.

  6. Genetic/molecular alterations of meningiomas and the signaling pathways targeted

    PubMed Central

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2015-01-01

    Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features. PMID:25965831

  7. Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals.

    PubMed

    Weisman, Ronit

    2016-10-01

    All organisms can respond to the availability of nutrients by regulating their metabolism, growth, and cell division. Central to the regulation of growth in response to nutrient availability is the target of rapamycin (TOR) signaling that is composed of two structurally distinct complexes: TOR complex 1 (TORC1) and TOR complex 2 (TORC2). The TOR genes were first identified in yeast as target of rapamycin, a natural product of a soil bacterium, which proved beneficial as an immunosuppressive and anticancer drug and is currently being tested for a handful of other pathological conditions including diabetes, neurodegeneration, and age-related diseases. Studies of the TOR pathway unraveled a complex growth-regulating network. TOR regulates nutrient uptake, transcription, protein synthesis and degradation, as well as metabolic pathways, in a coordinated manner that ensures that cells grow or cease growth in response to nutrient availability. The identification of specific signals and mechanisms that stimulate TOR signaling is an active and exciting field of research that has already identified nitrogen and amino acids as key regulators of TORC1 activity. The signals, as well as the cellular functions of TORC2, are far less well understood. Additional open questions in the field concern the relationships between TORC1 and TORC2, as well as the links with other nutrient-responsive pathways. Here I review the main features of TORC1 and TORC2, with a particular focus on yeasts as model organisms.

  8. Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

    PubMed Central

    Bruntz, Ronald C.; Lindsley, Craig W.

    2014-01-01

    Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein–coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions. PMID:25244928

  9. Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer.

    PubMed

    Bruntz, Ronald C; Lindsley, Craig W; Brown, H Alex

    2014-10-01

    Phospholipase D is a ubiquitous class of enzymes that generates phosphatidic acid as an intracellular signaling species. The phospholipase D superfamily plays a central role in a variety of functions in prokaryotes, viruses, yeast, fungi, plants, and eukaryotic species. In mammalian cells, the pathways modulating catalytic activity involve a variety of cellular signaling components, including G protein-coupled receptors, receptor tyrosine kinases, polyphosphatidylinositol lipids, Ras/Rho/ADP-ribosylation factor GTPases, and conventional isoforms of protein kinase C, among others. Recent findings have shown that phosphatidic acid generated by phospholipase D plays roles in numerous essential cellular functions, such as vesicular trafficking, exocytosis, autophagy, regulation of cellular metabolism, and tumorigenesis. Many of these cellular events are modulated by the actions of phosphatidic acid, and identification of two targets (mammalian target of rapamycin and Akt kinase) has especially highlighted a role for phospholipase D in the regulation of cellular metabolism. Phospholipase D is a regulator of intercellular signaling and metabolic pathways, particularly in cells that are under stress conditions. This review provides a comprehensive overview of the regulation of phospholipase D activity and its modulation of cellular signaling pathways and functions.

  10. Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.

    PubMed

    Ponnurangam, Sivapriya; Dandawate, Prasad R; Dhar, Animesh; Tawfik, Ossama W; Parab, Rajashri R; Mishra, Prabhu Dutt; Ranadive, Prafull; Sharma, Rajiv; Mahajan, Girish; Umar, Shahid; Weir, Scott J; Sugumar, Aravind; Jensen, Roy A; Padhye, Subhash B; Balakrishnan, Arun; Anant, Shrikant; Subramaniam, Dharmalingam

    2016-01-19

    Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins.

  11. Engineering self-contained DNA circuit for proximity recognition and localized signal amplification of target biomolecules.

    PubMed

    Ang, Yan Shan; Yung, Lin-Yue Lanry

    2014-08-01

    Biomolecular interactions have important cellular implications, however, a simple method for the sensing of such proximal events is lacking in the current molecular toolbox. We designed a dynamic DNA circuit capable of recognizing targets in close proximity to initiate a pre-programmed signal transduction process resulting in localized signal amplification. The entire circuit was engineered to be self-contained, i.e. it can self-assemble onto individual target molecules autonomously and form localized signal with minimal cross-talk. α-thrombin was used as a model protein to evaluate the performance of the individual modules and the overall circuit for proximity interaction under physiologically relevant buffer condition. The circuit achieved good selectivity in presence of non-specific protein and interfering serum matrix and successfully detected for physiologically relevant α-thrombin concentration (50 nM-5 μM) in a single mixing step without any further washing. The formation of localized signal at the interaction site can be enhanced kinetically through the control of temperature and probe concentration. This work provides a basic general framework from which other circuit modules can be adapted for the sensing of other biomolecular or cellular interaction of interest.

  12. The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity

    PubMed Central

    Slack, Cathy; Alic, Nazif; Foley, Andrea; Cabecinha, Melissa; Hoddinott, Matthew P.; Partridge, Linda

    2015-01-01

    Summary Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals. Video Abstract PMID:26119340

  13. MicroRNA expression, target genes, and signaling pathways in infants with a ventricular septal defect.

    PubMed

    Chai, Hui; Yan, Zhaoyuan; Huang, Ke; Jiang, Yuanqing; Zhang, Lin

    2017-08-18

    This study aimed to systematically investigate the relationship between miRNA expression and the occurrence of ventricular septal defect (VSD), and characterize the miRNA target genes and pathways that can lead to VSD. The miRNAs that were differentially expressed in blood samples from VSD and normal infants were screened and validated by implementing miRNA microarrays and qRT-PCR. The target genes regulated by differentially expressed miRNAs were predicted using three target gene databases. The functions and signaling pathways of the target genes were enriched using the GO database and KEGG database, respectively. The transcription and protein expression of specific target genes in critical pathways were compared in the VSD and normal control groups using qRT-PCR and western blotting, respectively. Compared with the normal control group, the VSD group had 22 differentially expressed miRNAs; 19 were downregulated and three were upregulated. The 10,677 predicted target genes participated in many biological functions related to cardiac development and morphogenesis. Four target genes (mGLUR, Gq, PLC, and PKC) were involved in the PKC pathway and four (ECM, FAK, PI3 K, and PDK1) were involved in the PI3 K-Akt pathway. The transcription and protein expression of these eight target genes were significantly upregulated in the VSD group. The 22 miRNAs that were dysregulated in the VSD group were mainly downregulated, which may result in the dysregulation of several key genes and biological functions related to cardiac development. These effects could also be exerted via the upregulation of eight specific target genes, the subsequent over-activation of the PKC and PI3 K-Akt pathways, and the eventual abnormal cardiac development and VSD.

  14. Ubiquitylation as a Rheostat for TCR Signaling: From Targeted Approaches Toward Global Profiling

    PubMed Central

    O’Leary, Claire E.; Lewis, Emma L.; Oliver, Paula M.

    2015-01-01

    T cell receptor (TCR) signaling must be precisely tuned to limit collateral damage and prevent reactivity to self, while still allowing robust protective immune responses that control pathogen invasion. One process that can be used to promote, modify, or terminate TCR signaling is ubiquitylation. During ubiquitylation, ubiquitin is covalently attached to target proteins through a multistep process, in which E3 ubiquitin ligases promote the formation of ubiquitin chains on selected substrates. Ubiquitylation can facilitate protein–protein interactions, direct a protein to a specific subcellular location, or initiate protein destruction. Like phosphorylation, ubiquitylation is a reversible process – deubiquitylating enzymes counteract ligase function by removing ubiquitin chains. This reversibility also allows for ubiquitin chain “editing.” Based on an emerging wealth of information from genetic loss-of-function studies showing that deregulation of ubiquitylation pathways leads to immune dysfunction, it has become increasingly apparent that the dynamic process of ubiquitylation is critical for normal immune cell function. In this review, we will describe how ubiquitylation acts as a key modulator and integrator of signaling downstream of TCR engagement. Specifically, we highlight the known roles of the substrate-specific E3 ligases and deubiquitylating enzymes in TCR signaling and T cell activation. While it is clear that ubiquitin enzymes tune T cell signaling and T cell function, elucidating the molecular mechanisms by which these proteins modulate T cells has met with significant challenges. Identifying substrates of these enzymes has been a particular challenge, and thus substrates of many E3 ligases and deubiquitylating enzymes remain largely unknown. To that end, we discuss the promise, and some practical considerations, of using proteomics-based techniques for unbiased identification of putative substrates of ubiquitin cascade proteins within

  15. Ubiquitylation as a Rheostat for TCR Signaling: From Targeted Approaches Toward Global Profiling.

    PubMed

    O'Leary, Claire E; Lewis, Emma L; Oliver, Paula M

    2015-01-01

    T cell receptor (TCR) signaling must be precisely tuned to limit collateral damage and prevent reactivity to self, while still allowing robust protective immune responses that control pathogen invasion. One process that can be used to promote, modify, or terminate TCR signaling is ubiquitylation. During ubiquitylation, ubiquitin is covalently attached to target proteins through a multistep process, in which E3 ubiquitin ligases promote the formation of ubiquitin chains on selected substrates. Ubiquitylation can facilitate protein-protein interactions, direct a protein to a specific subcellular location, or initiate protein destruction. Like phosphorylation, ubiquitylation is a reversible process - deubiquitylating enzymes counteract ligase function by removing ubiquitin chains. This reversibility also allows for ubiquitin chain "editing." Based on an emerging wealth of information from genetic loss-of-function studies showing that deregulation of ubiquitylation pathways leads to immune dysfunction, it has become increasingly apparent that the dynamic process of ubiquitylation is critical for normal immune cell function. In this review, we will describe how ubiquitylation acts as a key modulator and integrator of signaling downstream of TCR engagement. Specifically, we highlight the known roles of the substrate-specific E3 ligases and deubiquitylating enzymes in TCR signaling and T cell activation. While it is clear that ubiquitin enzymes tune T cell signaling and T cell function, elucidating the molecular mechanisms by which these proteins modulate T cells has met with significant challenges. Identifying substrates of these enzymes has been a particular challenge, and thus substrates of many E3 ligases and deubiquitylating enzymes remain largely unknown. To that end, we discuss the promise, and some practical considerations, of using proteomics-based techniques for unbiased identification of putative substrates of ubiquitin cascade proteins within primary T

  16. Calibration of imaging luminance measuring devices (ILMD)

    NASA Astrophysics Data System (ADS)

    Liu, Liying; Zheng, Feng; Zhu, Lingxi; Li, Ye; Huan, Kewei; Shi, Xiaoguang

    2015-11-01

    A method of calibration of imaging luminance measuring devices has been studied. By the device-independent color space transformation, the color image by digital camera could be converted to the CIE's absolute color space lab. Then, the calibration model is fitted between ln(L/t) and luminance. At last, luminance image is obtained and the dynamic range of luminance image could be adjusted by shutter speed.

  17. Retinal ganglion cell adaptation to small luminance fluctuations.

    PubMed

    Freeman, Daniel K; Graña, Gilberto; Passaglia, Christopher L

    2010-08-01

    To accommodate the wide input range over which the visual system operates within the narrow output range of spiking neurons, the retina adjusts its sensitivity to the mean light level so that retinal ganglion cells can faithfully signal contrast, or relative deviations from the mean luminance. Given the large operating range of the visual system, the majority of work on luminance adaptation has involved logarithmic changes in light level. We report that luminance gain controls are recruited for remarkably small fluctuations in luminance as well. Using spike recordings from the rat optic tract, we show that ganglion cell responses to a brief flash of light are modulated in amplitude by local background fluctuations as little as 15% contrast. The time scale of the gain control is rapid (<125 ms), at least for on cells. The retinal locus of adaptation precedes the ganglion cell spike generator because response gain changes of on cells were uncorrelated with firing rate. The mechanism seems to reside within the inner retinal network and not in the photoreceptors, because the adaptation profiles of on and off cells differed markedly. The response gain changes follow Weber's law, suggesting that network mechanisms of luminance adaptation described in previous work modulates retinal ganglion cell sensitivity, not just when we move between different lighting environments, but also as our eyes scan a visual scene. Finally, we show that response amplitude is uniformly reduced for flashes on a modulated background that has spatial contrast, indicating that another gain control that integrates luminance signals nonlinearly over space operates within the receptive field center of rat ganglion cells.

  18. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors.

    PubMed

    Rimkus, Tadas K; Carpenter, Richard L; Qasem, Shadi; Chan, Michael; Lo, Hui-Wen

    2016-02-15

    The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

  19. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

    PubMed Central

    Rimkus, Tadas K.; Carpenter, Richard L.; Qasem, Shadi; Chan, Michael; Lo, Hui-Wen

    2016-01-01

    The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials. PMID:26891329

  20. Yeast carboxypeptidase Y vacuolar targeting signal is defined by four propeptide amino acids

    PubMed Central

    1990-01-01

    The amino-terminal propeptide of carboxypeptidase Y (CPY) is necessary and sufficient for targeting this glycoprotein to the vacuole of Saccharomyces cerevisiae. A 16 amino acid stretch of the propeptide was subjected to region-directed mutagenesis using randomized oligonucleotides. Mutations altering any of four contiguous amino acids, Gln-Arg-Pro-Leu, resulted in secretion of the encoded CPY precursor (proCPY), demonstrating that these residues form the core of the vacuolar targeting signal. Cells that simultaneously synthesize both wild-type and sorting-defective forms of proCPY efficiently sort and deliver only the wild-type molecule to the vacuole. These results indicate that the PRC1 missorting mutations are cis-dominant, implying that the mutant forms of proCPY are secreted as a consequence of failing to interact with the sorting apparatus, rather than a general poisoning of the vacuolar protein targeting system. PMID:2199455

  1. The CB₁ receptor-mediated endocannabinoid signaling and NGF: the novel targets of curcumin.

    PubMed

    Hassanzadeh, Parichehr; Hassanzadeh, Anna

    2012-05-01

    Increasing interest has recently been attracted towards the identification of natural compounds including those with antidepressant properties. Curcumin has shown promising antidepressant effect, however, its molecular target(s) have not been well defined. Based on the interaction between the neurotrophins and endocannabinoid system as well as their contribution to the emotional reactivity and antidepressant action, here we show that 4-week treatment with curcumin, similar to the classical antidepressant amitriptyline, results in the sustained elevation of brain nerve growth factor (NGF) and endocannabinoids in dose-dependent and brain region-specific fashion. Pretreatment with cannabinoid CB(1) receptor neutral antagonist AM4113, but not the CB(2) antagonist SR144528, prevents the enhancement of brain NGF contents. AM4113 exerts no effect by itself. Our findings by presenting the CB(1) receptor-mediated endocannabinoid signaling and NGF as novel targets for curcumin, suggest that more attention should be focused on the therapeutic potential of herbal medicines including curcumin.

  2. Signaling completion of a message transfer from an origin compute node to a target compute node

    DOEpatents

    Blocksome, Michael A.

    2011-02-15

    Signaling completion of a message transfer from an origin node to a target node includes: sending, by an origin DMA engine, an RTS message, the RTS message specifying an application message for transfer to the target node from the origin node; receiving, by the origin DMA engine, a remote get message containing a data descriptor for the message and a completion notification descriptor, the completion notification descriptor specifying a local memory FIFO data transfer operation for transferring data locally on the origin node; inserting, by the origin DMA engine in an injection FIFO buffer, the data descriptor followed by the completion notification descriptor; transferring, by the origin DMA engine to the target node, the message in dependence upon the data descriptor; and notifying, by the origin DMA engine, the application that transfer of the message is complete in dependence upon the completion notification descriptor.

  3. Signaling completion of a message transfer from an origin compute node to a target compute node

    DOEpatents

    Blocksome, Michael A.; Parker, Jeffrey J.

    2011-05-24

    Signaling completion of a message transfer from an origin node to a target node includes: sending, by an origin DMA engine, an RTS message, the RTS message specifying an application message for transfer to the target node from the origin node; receiving, by the origin DMA engine, a remote get message containing a data descriptor for the message and a completion notification descriptor, the completion notification descriptor specifying a local direct put transfer operation for transferring data locally on the origin node; inserting, by the origin DMA engine in an injection FIFO buffer, the data descriptor followed by the completion notification descriptor; transferring, by the origin DMA engine to the target node, the message in dependence upon the data descriptor; and notifying, by the origin DMA engine, the application that transfer of the message is complete in dependence upon the completion notification descriptor.

  4. USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

    PubMed Central

    Herhaus, Lina; Al-Salihi, Mazin A.; Dingwell, Kevin S.; Cummins, Timothy D.; Wasmus, Lize; Vogt, Janis; Ewan, Richard; Bruce, David; Macartney, Thomas; Weidlich, Simone; Smith, James C.; Sapkota, Gopal P.

    2014-01-01

    Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis. PMID:24850914

  5. USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling.

    PubMed

    Herhaus, Lina; Al-Salihi, Mazin A; Dingwell, Kevin S; Cummins, Timothy D; Wasmus, Lize; Vogt, Janis; Ewan, Richard; Bruce, David; Macartney, Thomas; Weidlich, Simone; Smith, James C; Sapkota, Gopal P

    2014-05-01

    Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis.

  6. Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

    PubMed Central

    Reuter, C W M; Morgan, M A; Eckardt, A

    2007-01-01

    Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients. PMID:17224925

  7. Drug discovery approaches to target Wnt signaling in cancer stem cells.

    PubMed

    Curtin, Joshua C; Lorenzi, Matthew V

    2010-11-01

    Cancer stem cells (CSCs) represent a unique subset of cells within a tumor that possess self-renewal capacity and pluripotency, and can drive tumor initiation and maintenance. First identified in hematological malignancies, CSCs are now thought to play an important role in a wide variety of solid tumors such as NSCLC, breast and colorectal cancer. The role of CSCs in driving tumor formation illustrates the dysregulation of differentiation in tumorigenesis. The Wnt, Notch and Hedgehog (HH) pathways are developmental pathways that are commonly activated in many types of cancer. While substantial progress has been made in developing therapeutics targeting Notch and HH, the Wnt pathway has remained an elusive therapeutic target. This review will focus on the clinical relevance of the Wnt pathway in CSCs and tumor cell biology, as well as points of therapeutic intervention and recent advances in targeting Wnt/β-catenin signaling.

  8. Monodisperse Magnetite Nanoparticles Coupled with Nuclear Localization Signal Peptide for Cell-Nucleus Targeting

    PubMed Central

    Xu, Chenjie; Xie, Jin; Kohler, Nathan; Walsh, Edward G.; Chin, Y. Eugene; Sun, Shouheng

    2009-01-01

    Functionalization of monodisperse superparamagnetic magnetite (Fe3O4) nanoparticles for cell specific targeting is crucial for cancer diagnostics and therapeutics. Targeted magnetic nanoparticles can be used to enhance the tissue contrast in magnetic resonance imaging (MRI), to improve the efficiency in anticancer drug delivery, and to eliminate tumor cells by magnetic fluid hyperthermia. Herein we report the nucleus-targeting Fe3O4 nanoparticles functionalized with protein and nuclear localization signal (NLS) peptide. These NLS-coated nanoparticles were introduced into the HeLa cell cytoplasm and nucleus, where the particles were monodispersed and non-aggregated. The success of labeling was examined and identified by fluorescence microscopy and MRI. The work demonstrates that monodisperse magnetic nanoparticles can be readily functionalized and stabilized for potential diagnostic and therapeutic applications. PMID:18080259

  9. Color Discrimination Is Affected by Modulation of Luminance Noise in Pseudoisochromatic Stimuli.

    PubMed

    Cormenzana Méndez, Iñaki; Martín, Andrés; Charmichael, Teaire L; Jacob, Mellina M; Lacerda, Eliza M C B; Gomes, Bruno D; Fitzgerald, Malinda E C; Ventura, Dora F; Silveira, Luiz C L; O'Donell, Beatriz M; Souza, Givago S

    2016-01-01

    Pseudoisochromatic stimuli have been widely used to evaluate color discrimination and to identify color vision deficits. Luminance noise is one of the stimulus parameters used to ensure that subject's response is due to their ability to discriminate target stimulus from the background based solely on the hue between the colors that compose such stimuli. We studied the influence of contrast modulation of the stimulus luminance noise on threshold and reaction time color discrimination. We evaluated color discrimination thresholds using the Cambridge Color Test (CCT) at six different stimulus mean luminances. Each mean luminance condition was tested using two protocols: constant absolute difference between maximum and minimum luminance of the luminance noise (constant delta protocol, CDP), and constant contrast modulation of the luminance noise (constant contrast protocol, CCP). MacAdam ellipses were fitted to the color discrimination thresholds in the CIE 1976 color space to quantify the color discrimination ellipses at threshold level. The same CDP and CCP protocols were applied in the experiment measuring RTs at three levels of stimulus mean luminance. The color threshold measurements show that for the CDP, ellipse areas decreased as a function of the mean luminance and they were significantly larger at the two lowest mean luminances, 10 cd/m(2) and 13 cd/m(2), compared to the highest one, 25 cd/m(2). For the CCP, the ellipses areas also decreased as a function of the mean luminance, but there was no significant difference between ellipses areas estimated at six stimulus mean luminances. The exponent of the decrease of ellipse areas as a function of stimulus mean luminance was steeper in the CDP than CCP. Further, reaction time increased linearly with the reciprocal of the length of the chromatic vectors varying along the four chromatic half-axes. It decreased as a function of stimulus mean luminance in the CDP but not in the CCP. The findings indicated that visual

  10. Color Discrimination Is Affected by Modulation of Luminance Noise in Pseudoisochromatic Stimuli

    PubMed Central

    Cormenzana Méndez, Iñaki; Martín, Andrés; Charmichael, Teaire L.; Jacob, Mellina M.; Lacerda, Eliza M. C. B.; Gomes, Bruno D.; Fitzgerald, Malinda E. C.; Ventura, Dora F.; Silveira, Luiz C. L.; O'Donell, Beatriz M.; Souza, Givago S.

    2016-01-01

    Pseudoisochromatic stimuli have been widely used to evaluate color discrimination and to identify color vision deficits. Luminance noise is one of the stimulus parameters used to ensure that subject's response is due to their ability to discriminate target stimulus from the background based solely on the hue between the colors that compose such stimuli. We studied the influence of contrast modulation of the stimulus luminance noise on threshold and reaction time color discrimination. We evaluated color discrimination thresholds using the Cambridge Color Test (CCT) at six different stimulus mean luminances. Each mean luminance condition was tested using two protocols: constant absolute difference between maximum and minimum luminance of the luminance noise (constant delta protocol, CDP), and constant contrast modulation of the luminance noise (constant contrast protocol, CCP). MacAdam ellipses were fitted to the color discrimination thresholds in the CIE 1976 color space to quantify the color discrimination ellipses at threshold level. The same CDP and CCP protocols were applied in the experiment measuring RTs at three levels of stimulus mean luminance. The color threshold measurements show that for the CDP, ellipse areas decreased as a function of the mean luminance and they were significantly larger at the two lowest mean luminances, 10 cd/m2 and 13 cd/m2, compared to the highest one, 25 cd/m2. For the CCP, the ellipses areas also decreased as a function of the mean luminance, but there was no significant difference between ellipses areas estimated at six stimulus mean luminances. The exponent of the decrease of ellipse areas as a function of stimulus mean luminance was steeper in the CDP than CCP. Further, reaction time increased linearly with the reciprocal of the length of the chromatic vectors varying along the four chromatic half-axes. It decreased as a function of stimulus mean luminance in the CDP but not in the CCP. The findings indicated that visual

  11. Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis

    PubMed Central

    Iqbal, Waqas; Alkarim, Saleh; AlHejin, Ahmed; Mukhtar, Hasan; Saini, Kulvinder S

    2016-01-01

    Tumor comprises of heterogeneous population of cells where not all the disseminated cancer cells have the prerogative and “in-build genetic cues” to form secondary tumors. Cells with stem like properties complemented by key signaling molecules clearly have shown to exhibit selective growth advantage to form tumors at distant metastatic sites. Thus, defining the role of cancer stem cells (CSC) in tumorigenesis and metastasis is emerging as a major thrust area for therapeutic intervention. Precise relationship and regulatory mechanisms operating in various signal transduction pathways during cancer dissemination, extravasation and angiogenesis still remain largely enigmatic. How the crosstalk amongst circulating tumor cells (CTC), epithelial mesenchymal transition (EMT) process and CSC is coordinated for initiating the metastasis at secondary tissues, and during cancer relapse could be of great therapeutic interest. The signal transduction mechanisms facilitating the dissemination, infiltration of CSC into blood stream, extravasations, progression of metastasis phenotype and angiogenesis, at distant organs, are the key pathologically important vulnerabilities being elucidated. Therefore, current new drug discovery focus has shifted towards finding “key driver genes” operating in parallel signaling pathways, during quiescence, survival and maintenance of stemness in CSC. Understanding these mechanisms could open new horizons for tackling the issue of cancer recurrence and metastasis-the cause of ~90% cancer associated mortality. To design futuristic & targeted therapies, we propose a multi-pronged strategy involving small molecules, RNA interference, vaccines, antibodies and other biotechnological modalities against CSC and the metastatic signal transduction cascade. PMID:27486983

  12. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes

    PubMed Central

    Shigetomi, Eiji; Kracun, Sebastian; Sofroniew, Michael V; Khakh, Baljit S

    2010-01-01

    Calcium signaling is studied as a potential form of astrocyte excitability that may control astrocyte involvement in synaptic and cerebrovascular regulation. Fundamental questions remain unanswered about astrocyte calcium signaling, as current methods can not resolve calcium in small volume compartments, such as near the cell membrane and in distal cell processes. We modified the genetically encoded calcium sensor GCaMP2 with a membrane-tethering domain, Lck, increasing the level of Lck-GCaMP2 near the plasma membrane tenfold as compared with conventional GCaMP2. Using Lck-GCaMP2 in rat hippocampal astrocyte-neuron cocultures, we measured near-membrane calcium signals that were evoked pharmacologically or by single action potential–mediated neurotransmitter release. Moreover, we identified highly localized and frequent spontaneous calcium signals in astrocyte somata and processes that conventional GCaMP2 failed to detect. Lck-GCaMP2 acts as a genetically targeted calcium sensor for monitoring calcium signals in previously inaccessible parts of astrocytes, including fine processes. PMID:20495558

  13. Ghrelin receptor signaling: a promising therapeutic target for metabolic syndrome and cognitive dysfunction

    PubMed Central

    Cong, Wei-na; Golden, Erin; Pantaleo, Nick; White, Caitlin M.; Maudsley, Stuart; Martin, Bronwen

    2010-01-01

    The neuroendocrine hormone ghrelin is an octanoylated 28-residue peptide that exerts numerous physiological functions. Ghrelin exerts its effects on the body mainly through a highly conserved G protein-coupled receptor known as the growth hormone secretagagogue receptor subtype 1a (GHS-R1a). Ghrelin and GSH-R1a are widely expressed in both peripheral and central tissues/organs, and ghrelin signaling plays a critical role in maintaining energy balance and neuronal health. The multiple orexigenic effects of ghrelin and its receptor have been studied in great detail, and GHS-R1a-mediated ghrelin signaling has long been a promising target for the treatment of metabolic disorders, such as obesity. In addition to its well-characterized metabolic effects, there is also mounting evidence that ghrelin-mediated GHS-R1a signaling exerts neuroprotective effects on the brain. In this review, we will summarize some of the effects of ghrelin-mediated GSH-R1a signaling on peripheral energy balance and cognitive function. We will also discuss the potential pharmacotherapeutic role of GSH-R1a-mediated ghrelin signaling for the treatment of complex neuroendocrine disorders. PMID:20632971

  14. Targeting insulin and insulin-like growth factor signaling in breast cancer

    PubMed Central

    Yang, Yuzhe; Yee, Douglas

    2012-01-01

    The insulin and insulin like growth factor (IGF) signaling systems are implicated in breast cancer biology. Thus, disrupting IGF/insulin signaling has been shown to have promise in a number of preclinical models. However, human clinical trials have been less promising. Despite evidence of some activity in early phase trials, randomized phase III studies have thus far been unable to show a benefit of blocking IGF signaling in combination with conventional strategies. In breast cancer, combination anti IGF/insulin signaling agents with hormone therapy has not yet proven to have benefit. This inability to translate the preclinical findings into useful clinical strategies calls attention to the need for a deeper understanding of this complex pathway. Development of predictive biomarkers and optimal inhibitory strategies of the IGF/insulin system should yield better clinical strategies. Furthermore, unraveling the interaction between the IGF/insulin pathway and other critical signaling pathways in breast cancer biology, namely estrogen receptor-α (ERα) and epidermal growth factor receptor (EGFR) pathways, provides additional new concepts in designing combination therapies. In this review, we will briefly summarize the current strategies targeting the IGF/insulin system, discuss the possible reasons of success or failure of the existing therapies, and provide potential future direction for research and clinical trials. PMID:23054135

  15. WT1 targets Gas1 to maintain nephron progenitor cells by modulating FGF signals.

    PubMed

    Kann, Martin; Bae, Eunnyung; Lenz, Maximilian O; Li, Liangji; Trannguyen, BaoTran; Schumacher, Valerie A; Taglienti, Mary E; Bordeianou, Liliana; Hartwig, Sunny; Rinschen, Markus M; Schermer, Bernhard; Benzing, Thomas; Fan, Chen-Ming; Kreidberg, Jordan A

    2015-04-01

    Development of the metanephric kidney depends on tightly regulated interplay between self-renewal and differentiation of a nephron progenitor cell (NPC) pool. Several key factors required for the survival of NPCs have been identified, including fibroblast growth factor (FGF) signaling and the transcription factor Wilms' tumor suppressor 1 (WT1). Here, we present evidence that WT1 modulates FGF signaling by activating the expression of growth arrest-specific 1 (Gas1), a novel WT1 target gene and novel modulator of FGF signaling. We show that WT1 directly binds to a conserved DNA binding motif within the Gas1 promoter and activates Gas1 mRNA transcription in NPCs. We confirm that WT1 is required for Gas1 expression in kidneys in vivo. Loss of function of GAS1 in vivo results in hypoplastic kidneys with reduced nephron mass due to premature depletion of NPCs. Although kidney development in Gas1 knockout mice progresses normally until E15.5, NPCs show decreased rates of proliferation at this stage and are depleted as of E17.5. Lastly, we show that Gas1 is selectively required for FGF-stimulated AKT signaling in vitro. In summary, our data suggest a model in which WT1 modulates receptor tyrosine kinase signaling in NPCs by directing the expression of Gas1. © 2015. Published by The Company of Biologists Ltd.

  16. Targeting signaling pathways in T-cell acute lymphoblastic leukemia initiating cells.

    PubMed

    Martelli, Alberto M; Lonetti, Annalisa; Buontempo, Francesca; Ricci, Francesca; Tazzari, Pier Luigi; Evangelisti, Camilla; Bressanin, Daniela; Cappellini, Alessandra; Orsini, Ester; Chiarini, Francesca

    2014-09-01

    Leukemia initiating cells (LICs) represent a reservoir that is believed to drive relapse and resistance to chemotherapy in blood malignant disorders. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to the T-cell lineage. T-ALL comprises about 15% of pediatric and 25% of adult ALL cases and is prone to early relapse. Although the prognosis of T-ALL has improved especially in children due to the use of new intensified treatment protocols, the outcome of relapsed T-ALL cases is still poor. Putative LICs have been identified also in T-ALL. LICs are mostly quiescent and for this reason highly resistant to chemotherapy. Therefore, they evade treatment and give rise to disease relapse. At present great interest surrounds the development of targeted therapies against signaling networks aberrantly activated in LICs and important for their survival and drug-resistance. Both the Notch1 pathway and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) network are involved in T-ALL LIC survival and drug-resistance and could be targeted by small molecules. Thus, Notch1 and PI3K/Akt/mTOR inhibitors are currently being developed for clinical use either as single agents or in combination with conventional chemotherapy for T-ALL patient treatment. In this review, we summarize the existing knowledge of the relevance of Notch1 and PI3K/Akt/mTOR signaling in T-ALL LICs and we examine the rationale for targeting these key signal transduction networks by means of selective pharmacological inhibitors. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Chromospheres of Luminous Cool Stars

    NASA Astrophysics Data System (ADS)

    Dupree, Andrea K.; Avrett, Eugene

    2015-08-01

    Ultraviolet imaging of Alpha Orionis (Betelgeuse) reveals a complex variable chromospheric structure. Such atmospheres in luminous cool stars can affect features in the optical spectrum. Constructing semi-empiricalmodel atmospheres of luminous stars including the temperature rise due to a chromosphere allows us to predict potential effects on optical transitions. The radiative transfer code, PANDORA, calculates line strengths in a LTE or non-LTE formulation, spherical symmetry, and includes velocity fields when present. Various aspects of the line calculations and their impact on equivalent widths will be discussed including developing appropriate chromospheric models, comparison to a pure radiative equilibrium model, transitions sensitive to non-LTE and the effects of a realistic spherical non-LTE approximation as compared to a plane-parallel approximation. We discuss the extent to which a chromosphere can impact the determination of stellar abundances.

  18. Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors

    PubMed Central

    Baldelli, Elisa; Bellezza, Guido; Haura, Eric B.; Crinó, Lucio; Cress, W. Douglas; Deng, Jianghong; Ludovini, Vienna; Sidoni, Angelo; Schabath, Matthew B.; Puma, Francesco; Vannucci, Jacopo; Siggillino, Annamaria; Liotta, Lance A.; Petricoin, Emanuel F.; Pierobon, Mariaelena

    2015-01-01

    Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets. Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to laser capture microdissection and reverse phase protein microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC). Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02). This finding was verified in an independent population by IHC (p=0.03). KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications. PMID:26468985

  19. E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

    PubMed Central

    Dominguez-Brauer, Carmen; Khatun, Rahima; Elia, Andrew J.; Thu, Kelsie L.; Ramachandran, Parameswaran; Baniasadi, Shakiba P.; Hao, Zhenyue; Jones, Lisa D.; Haight, Jillian; Sheng, Yi; Mak, Tak W.

    2017-01-01

    Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule’s influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis. PMID:28137882

  20. The Type I Interferon Signaling Pathway Is a Target for Glucocorticoid Inhibition ▿

    PubMed Central

    Flammer, Jamie R.; Dobrovolna, Jana; Kennedy, Megan A.; Chinenov, Yurii; Glass, Christopher K.; Ivashkiv, Lionel B.; Rogatsky, Inez

    2010-01-01

    Type I interferon (IFN) is essential for host defenses against viruses; however, dysregulated IFN signaling is causally linked to autoimmunity, particularly systemic lupus erythematosus. Autoimmune disease treatments rely on glucocorticoids (GCs), which act via the GC receptor (GR) to repress proinflammatory cytokine gene transcription. Conversely, cytokine signaling through cognate Jak/STAT pathways is reportedly unaffected or even stimulated by GR. Unexpectedly, we found that GR dramatically inhibited IFN-stimulated gene (ISG) expression in macrophages. The target of inhibition, the heterotrimeric STAT1-STAT2-IRF9 (ISGF3) transcription complex, utilized the GR cofactor GRIP1/TIF2 as a coactivator. Consequently, GRIP1 knockdown, genetic ablation, or depletion by GC-activated GR attenuated ISGF3 promoter occupancy, preinitiation complex assembly, and ISG expression. Furthermore, this regulatory loop was restricted to cell types such as macrophages expressing the GRIP1 protein at extremely low levels, and pharmacological disruption of the GR-GRIP1 interaction or transient introduction of GRIP1 restored RNA polymerase recruitment to target ISGs and the subsequent IFN response. Thus, type I IFN is a cytokine uniquely controlled by GR at the levels of not only production but also signaling through antagonism with the ISGF3 effector function, revealing a novel facet of the immunosuppressive properties of GCs. PMID:20679482

  1. IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma

    PubMed Central

    2013-01-01

    Background High-grade osteosarcoma is an aggressive tumor most often developing in the long bones of adolescents, with a second peak in the 5th decade of life. Better knowledge on cellular signaling in this tumor may identify new possibilities for targeted treatment. Methods We performed gene set analysis on previously published genome-wide gene expression data of osteosarcoma cell lines (n=19) and pretreatment biopsies (n=84). We characterized overexpression of the insulin-like growth factor receptor (IGF1R) signaling pathways in human osteosarcoma as compared with osteoblasts and with the hypothesized progenitor cells of osteosarcoma – mesenchymal stem cells. This pathway plays a key role in the growth and development of bone. Since most profound differences in mRNA expression were found at and upstream of the receptor of this pathway, we set out to inhibit IR/IGF1R using OSI-906, a dual inhibitor for IR/IGF1R, on four osteosarcoma cell lines. Inhibitory effects of this drug were measured by Western blotting and cell proliferation assays. Results OSI-906 had a strong inhibitory effect on proliferation of 3 of 4 osteosarcoma cell lines, with IC50s below 100 nM at 72 hrs of treatment. Phosphorylation of IRS-1, a direct downstream target of IGF1R signaling, was inhibited in the responsive osteosarcoma cell lines. Conclusions This study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma. PMID:23688189

  2. Peptide Immunoaffinity Enrichment and Targeted Mass Spectrometry Enables Multiplex, Quantitative Pharmacodynamic Studies of Phospho-Signaling*

    PubMed Central

    Whiteaker, Jeffrey R.; Zhao, Lei; Yan, Ping; Ivey, Richard G.; Voytovich, Uliana J.; Moore, Heather D.; Lin, Chenwei; Paulovich, Amanda G.

    2015-01-01

    In most cell signaling experiments, analytes are measured one Western blot lane at a time in a semiquantitative and often poorly specific manner, limiting our understanding of network biology and hindering the translation of novel therapeutics and diagnostics. We show the feasibility of using multiplex immuno-MRM for phospho-pharmacodynamic measurements, establishing the potential for rapid and precise quantification of cell signaling networks. A 69-plex immuno-MRM assay targeting the DNA damage response network was developed and characterized by response curves and determinations of intra- and inter-assay repeatability. The linear range was ≥3 orders of magnitude, the median limit of quantification was 2.0 fmol/mg, the median intra-assay variability was 10% CV, and the median interassay variability was 16% CV. The assay was applied in proof-of-concept studies to immortalized and primary human cells and surgically excised cancer tissues to quantify exposure–response relationships and the effects of a genomic variant (ATM kinase mutation) or pharmacologic (kinase) inhibitor. The study shows the utility of multiplex immuno-MRM for simultaneous quantification of phosphorylated and nonmodified peptides, showing feasibility for development of targeted assay panels to cell signaling networks. PMID:25987412

  3. SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

    PubMed Central

    Popovic, Jelena; Schwirtlich, Marija; Rankovic, Branislava; Stevanovic, Milena

    2015-01-01

    Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation. PMID:26588701

  4. Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC.

    PubMed

    Ciuffreda, Ludovica; Incani, Ursula Cesta; Steelman, Linda S; Abrams, Stephen L; Falcone, Italia; Curatolo, Anais Del; Chappell, William H; Franklin, Richard A; Vari, Sabrina; Cognetti, Francesco; McCubrey, James A; Milella, Michele

    2014-01-01

    The RAS/RAF/MEK/ ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes, such as cell proliferation, differentiation, metabolism, cytoskeleton reorganization and cell death and survival. Constitutive activation of these signal transduction pathways is a required hallmark of cancer and dysregulation, on either genetic or epigenetic grounds, of these pathways has been implicated in the initiation, progression and metastastic spread of lung cances. Targeting components of the MAPK and PI3K cascades is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer, although the use of single pathway inhibitors has met with limited clinical success so far. Indeed, the presence of intra- and inter-pathway compensatory loops that re-activate the very same cascade, either upstream or downstream the point of pharmacological blockade, or activate the alternate pathway following the blockade of one signaling cascade has been demonstrated, potentially driving preclinical (and possibly clinical) resistance. Therefore, the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect, and thus potentially overcome and/or delay clinical resistance, as compared with single agent. The current review aims at summarizing the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in NSCLC and the rationale for combined therapeutic pathway targeting.

  5. Network quantification of EGFR signaling unveils potential for targeted combination therapy

    PubMed Central

    Klinger, Bertram; Sieber, Anja; Fritsche-Guenther, Raphaela; Witzel, Franziska; Berry, Leanne; Schumacher, Dirk; Yan, Yibing; Durek, Pawel; Merchant, Mark; Schäfer, Reinhold; Sers, Christine; Blüthgen, Nils

    2013-01-01

    The epidermal growth factor receptor (EGFR) signaling network is activated in most solid tumors, and small-molecule drugs targeting this network are increasingly available. However, often only specific combinations of inhibitors are effective. Therefore, the prediction of potent combinatorial treatments is a major challenge in targeted cancer therapy. In this study, we demonstrate how a model-based evaluation of signaling data can assist in finding the most suitable treatment combination. We generated a perturbation data set by monitoring the response of RAS/PI3K signaling to combined stimulations and inhibitions in a panel of colorectal cancer cell lines, which we analyzed using mathematical models. We detected that a negative feedback involving EGFR mediates strong cross talk from ERK to AKT. Consequently, when inhibiting MAPK, AKT activity is increased in an EGFR-dependent manner. Using the model, we predict that in contrast to single inhibition, combined inactivation of MEK and EGFR could inactivate both endpoints of RAS, ERK and AKT. We further could demonstrate that this combination blocked cell growth in BRAF- as well as KRAS-mutated tumor cells, which we confirmed using a xenograft model. PMID:23752269

  6. Redox modulation of cellular metabolism through targeted degradation of signaling proteins by the proteasome

    SciTech Connect

    Squier, Thomas C.

    2006-02-01

    Under conditions of oxidative stress, the 20S proteasome plays a critical role in maintaining cellular homeostasis through the selective degradation of oxidized and damaged proteins. This adaptive stress response is distinct from ubiquitin-dependent pathways in that oxidized proteins are recognized and degraded in an ATP-independent mechanism, which can involve the molecular chaperone Hsp90. Like the regulatory complexes 19S and 11S REG, Hsp90 tightly associates with the 20S proteasome to mediate the recognition of aberrant proteins for degradation. In the case of the calcium signaling protein calmodulin, proteasomal degradation results from the oxidation of a single surface exposed methionine (i.e., Met145); oxidation of the other eight methionines has a minimal effect on the recognition and degradation of calmodulin by the proteasome. Since cellular concentrations of calmodulin are limiting, the targeted degradation of this critical signaling protein under conditions of oxidative stress will result in the downregulation of cellular metabolism, serving as a feedback regulation to diminish the generation of reactive oxygen species. The targeted degradation of critical signaling proteins, such as calmodulin, can function as sensors of oxidative stress to downregulate global rates of metabolism and enhance cellular survival.

  7. Moving target detection method for bistatic radar using random stepped-frequency chirp signal

    NASA Astrophysics Data System (ADS)

    Lin, Caiyong; Tian, Ruiqi; Wang, Dinghe; Bao, Qinglong; Chen, Zengping

    2016-10-01

    As random stepped-frequency chirp (RSFC) signal is used in wide-band radar applications such as synthetic aperture radar (SAR) and inverse SAR. RSFC has advantages over the linear stepped-frequency chirp, including suppressing the range ambiguity, decoupling the range-Doppler coupling, and reducing the signal interference. RSFC is usually descrambled and then fed to the inverse fast Fourier transform (IFFT) to achieve a coherent integration as well as a high-resolution range. However, this method needs frequency descrambling and accurate velocity pre-estimation for moving target detection. We propose a coherent integration method based on time-dechirping for bistatic radar. This method can detect moving targets without frequency descrambling or accurate velocity pre-estimation. This paper first models the target echo mathematically and outlines the difficulties associated with the processing of IFFT for RSFC. Then the detailed principles of the proposed method are introduced and the flowchart is given. Finally, numerical simulations are conducted to verify the effectiveness of the proposed method and show its detecting ability in the presence of noise.

  8. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy

    PubMed Central

    Dandawate, Prasad R.; Subramaniam, Dharmalingam; Jensen, Roy A.; Anant, Shrikant

    2017-01-01

    Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3′-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development. PMID:27609747

  9. Two Direct Targets of Cytokinin Signaling Regulate Symbiotic Nodulation in Medicago truncatula[W][OA

    PubMed Central

    Ariel, Federico; Brault-Hernandez, Marianne; Laffont, Carole; Huault, Emeline; Brault, Mathias; Plet, Julie; Moison, Michael; Blanchet, Sandrine; Ichanté, Jean Laurent; Chabaud, Mireille; Carrere, Sébastien; Crespi, Martin; Chan, Raquel L.; Frugier, Florian

    2012-01-01

    Cytokinin regulates many aspects of plant development, and in legume crops, this phytohormone is necessary and sufficient for symbiotic nodule organogenesis, allowing them to fix atmospheric nitrogen. To identify direct links between cytokinins and nodule organogenesis, we determined a consensus sequence bound in vitro by a transcription factor (TF) acting in cytokinin signaling, the nodule-enhanced Medicago truncatula Mt RR1 response regulator (RR). Among genes rapidly regulated by cytokinins and containing this so-called RR binding site (RRBS) in their promoters, we found the nodulation-related Type-A RR Mt RR4 and the Nodulation Signaling Pathway 2 (NSP2) TF. Site-directed mutagenesis revealed that RRBS cis-elements in the RR4 and NSP2 promoters are essential for expression during nodule development and for cytokinin induction. Furthermore, a microRNA targeting NSP2 (miR171 h) is also rapidly induced by cytokinins and then shows an expression pattern anticorrelated with NSP2. Other primary targets regulated by cytokinins depending on the Cytokinin Response1 (CRE1) receptor were a cytokinin oxidase/dehydrogenase (CKX1) and a basic Helix-Loop-Helix TF (bHLH476). RNA interference constructs as well as insertion of a Tnt1 retrotransposon in the bHLH gene led to reduced nodulation. Hence, we identified two TFs, NSP2 and bHLH476, as direct cytokinin targets acting at the convergence of phytohormonal and symbiotic cues. PMID:23023168

  10. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain.

    PubMed

    Miller, Miles A; Moss, Marcia L; Powell, Gary; Petrovich, Robert; Edwards, Lori; Meyer, Aaron S; Griffith, Linda G; Lauffenburger, Douglas A

    2015-10-19

    Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, "decoy" antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.

  11. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain

    NASA Astrophysics Data System (ADS)

    Miller, Miles A.; Moss, Marcia L.; Powell, Gary; Petrovich, Robert; Edwards, Lori; Meyer, Aaron S.; Griffith, Linda G.; Lauffenburger, Douglas A.

    2015-10-01

    Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, “decoy” antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.

  12. Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain

    PubMed Central

    Miller, Miles A.; Moss, Marcia L.; Powell, Gary; Petrovich, Robert; Edwards, Lori; Meyer, Aaron S.; Griffith, Linda G.; Lauffenburger, Douglas A.

    2015-01-01

    Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, “decoy” antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling. PMID:26477568

  13. Targeting Signal Transduction Pathways in Metastatic Breast Cancer: A Comprehensive Review

    PubMed Central

    Rosen, Lee S.; Ashurst, Helen Louise

    2010-01-01

    Greater understanding of the underlying etiology and biology of breast cancer is enabling the clinical development of targeted therapies for metastatic breast cancer (MBC). Following the successful introduction of trastuzumab, the first human epidermal growth factor receptor (HER) biologically targeted therapy to become widely used in MBC patients, other agents have been developed. Novel agents include monoclonal antibodies such as pertuzumab, which bind to receptors on the cell surface, and tyrosine kinase inhibitors (TKIs) such as lapatinib, which target intracellular pathways such as that of the epidermal growth factor receptor. There is also growing clinical experience with antiangiogenic agents, particularly in combination with chemotherapy. These include the monoclonal antibody bevacizumab, which targets vascular endothelial growth factor receptor, and multitargeted TKIs with antiangiogenic and antiproliferative activities, such as sunitinib. Combination treatment with multiple agents targeting both the HER family and angiogenic pathways (e.g., trastuzumab plus bevacizumab) is also showing activity in the clinical setting. Despite recent advances, there are unanswered questions regarding the management of MBC with targeted agents. Future studies are necessary to determine the optimal combinations, doses, and schedules required to maximize clinical activity while minimizing toxicity. Despite the temptation to use a targeted agent in all patients, identification of patient subgroups most likely to benefit must be a key goal and will be critical to the successful future use of these treatments. The aim of this review is to summarize some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for MBC. PMID:20200040

  14. Modification of gibberellin signalling (metabolism & signal transduction) in sugar beet: analysis of potential targets for crop improvement.

    PubMed

    Mutasa-Gottgens, Effie; Qi, Aiming; Mathews, Ann; Thomas, Stephen; Phillips, Andrew; Hedden, Peter

    2009-04-01

    Sugar beet, Beta vulgaris spp. vulgaris is a biennial long day plant with an obligate requirement for vernalization (prolonged exposure to low temperature). As a spring crop in temperate European climates, it is vulnerable to vernalization-induced premature bolting and flowering, resulting in reduced crop yield and quality. Gibberellins (GAs) play important roles in key physiological processes including stem elongation (bolting) and flowering and are, therefore, potential targets for controlling reproductive growth in sugar beet. We show that the BvGA20ox gene, which encodes an enzyme necessary for GA biosynthesis, was transcriptionally activated in apices of sugar beet plants after vernalization and that GA metabolism can be manipulated to delay bolting in vernalized plants. We demonstrate that down-regulation of GA responses by transformation with the Arabidopsis thaliana gai gene (which represses GA signalling), under its own promoter (pgai::gai) or deactivation of GA by over-expression of the Phaseolus coccineus (bean) GA2ox1 gene, which inactivates GA, increased the required post vernalization thermal time (an accurate and stable measure of physiological time), to bolt by approximately 300 degrees Cd. This resulted in agronomically significant bolting time delays of approximately 2 weeks and 3 weeks in the pgai::gai and 35S::PcGA2ox1 plants, respectively. Our data represent the first transgenic sugar beet model to (1) show that GA signalling can be used to improve crops by manipulation of the transition to reproductive growth; and (2) provide evidence that GA is required for seed set in sugar beet.

  15. Targeting the Microglial Signaling Pathways: New Insights in the Modulation of Neuropathic Pain

    PubMed Central

    Popiolek-Barczyk, Katarzyna; Mika, Joanna

    2016-01-01

    The microglia, once thought only to be supporting cells of the central nervous system (CNS), are now recognized to play essential roles in many pathologies. Many studies within the last decades indicated that the neuro-immune interaction underlies the generation and maintenance of neuropathic pain. Through a large number of receptors and signaling pathways, the microglial cells communicate with neurons, astrocytes and other cells, including those of the immune system. A disturbance or loss of CNS homeostasis causes rapid responses of the microglia, which undergo a multistage activation process. The activated microglia change their cell shapes and gene expression profiles, which induce proliferation, migration, and the production of pro- or antinociceptive factors. The cells release a large number of mediators that can act in a manner detrimental or beneficial to the surrounding cells and can indirectly alter the nociceptive signals. This review discusses the most important microglial intracellular signaling cascades (MAPKs, NF-κB, JAK/STAT, PI3K/Akt) that are essential for neuropathic pain development and maintenance. Our objective was to identify new molecular targets that may result in the development of powerful tools to control the signaling associated with neuropathic pain. PMID:27281131

  16. Synaptotoxicity in Alzheimer's disease: the Wnt signaling pathway as a molecular target.

    PubMed

    Inestrosa, Nibaldo C; Varela-Nallar, Lorena; Grabowski, Catalina P; Colombres, Marcela

    2007-01-01

    Recent evidence supports a role of the Wnt pathway in neurodegenerative disorders such as Alzheimer's disease (AD). A relationship between amyloid-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmatic levels of beta-catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK-3beta), a central modulator of the pathway, protects rat hippocampal neurons from Abeta-induced damage. Interestingly, during the progression of AD, it has been described that active GSK-3beta is found in neuronal cell bodies and neurites, co-localizing with pre-neurofibrillary tangles observed in disease brains. Since Abeta oligomers are associated with the post-synaptic region and we have found that the non-canonical Wnt signaling modulates PSD-95 and glutamate receptors, we propose that the synaptic target for Abeta oligomers in AD is the postsynaptic region and at the molecular level is the non-canonical Wnt signaling pathway. Altogether, our evidence suggests that a sustained loss of Wnt signaling function may be involved in the Abeta-dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD.

  17. Targeted inhibition of calcineurin signaling blocks calcium-dependent reactivation of Kaposi sarcoma-associated herpesvirus.

    PubMed

    Zoeteweij, J P; Moses, A V; Rinderknecht, A S; Davis, D A; Overwijk, W W; Yarchoan, R; Orenstein, J M; Blauvelt, A

    2001-04-15

    Kaposi sarcoma-associated herpesvirus (KSHV) is associated with KS, primary effusion lymphoma (PEL), and multicentric Castleman disease. Reactivation of KSHV in latently infected cells and subsequent plasma viremia occur before the development of KS. Intracellular signaling pathways involved in KSHV reactivation were studied. In latently infected PEL cells (BCBL-1), KSHV reactivation in single cells was determined by quantitative flow cytometry. Viral particle production was determined by electron microscope analyses and detection of minor capsid protein in culture supernatants. Agents that mobilized intracellular calcium (ionomycin, thapsigargin) induced expression of KSHV lytic cycle-associated proteins and led to increased virus production. Calcium-mediated virus reactivation was blocked by specific inhibitors of calcineurin-dependent signal transduction (cyclosporine, FK506). Similarly, calcium-mediated virus reactivation in KSHV-infected dermal microvascular endothelial cells was blocked by cyclosporine. Furthermore, retroviral transduction with plasmid DNA encoding VIVIT, a peptide specifically blocking calcineurin-NFAT interactions, inhibited calcium-dependent KSHV reactivation. By contrast, chemical induction of lytic-phase infection by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate was blocked by protein kinase C inhibitors, but not by calcineurin inhibitors. In summary, calcineurin-dependent signal transduction, an important signaling cascade in vivo, induces calcium-dependent KSHV replication, providing a possible target for the design of antiherpesvirus strategies in KSHV-infected patients.

  18. Molecular Targeting of ERKs/RSK2 Signaling Axis in Cancer Prevention

    PubMed Central

    Yoo, Sun-Mi; Cho, Sung Jun; Cho, Yong-Yeon

    2015-01-01

    RSK2 is a downstream signaling protein of ERK1 and ERK2 and plays a key role in physiological homeostasis. For this reason, RSK2 is a highly conserved protein among the p90RSK family members. In its location in the signaling pathway, RSK2 is a kinase just upstream of transcription and epigenetic factors, and a few kinases involved in cell cycle regulation and protein synthesis. Moreover, activation of RSK2 by growth factors is directly involved in cell proliferation, anchorage-independent cell transformation and cancer development. Direct evidences regarding the etiological roles of RSK2 in cancer development in humans have been published by our research group illustrating that elevated total- and phospho-RSK2 protein levels mediated by ERK1 and ERK2 are higher in skin cancer tissues compared to normal skin tissues. Notably, it has been shown that RSK2 ectopic expression in JB6 Cl41 cells induces cell proliferation and anchorage- independent cell transformation. Importantly, knockdown of RSK2 suppresses Ras-mediated foci formation and anchorage-independent colony growth of cancer cells. Kaempferol is a one of the natural compounds showing selectivity in inhibiting RSK2 activity in epidermal growth factor-induced G1/S cell cycle transition and cell transformation. Thus, ERKs/RSK2 signaling axis is an important target signaling molecule in chemoprevention. PMID:26473154

  19. [Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

    PubMed

    Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

    2015-01-01

    Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  20. Inhibition of Nod2 Signaling and Target Gene Expression by Curcumin

    PubMed Central

    Huang, Shurong; Zhao, Ling; Kim, Kihoon; Lee, Dong Seok; Hwang, Daniel H.

    2008-01-01

    Nod2 is an intracellular pattern recognition receptor that detects a conserved moiety of bacterial peptidoglycan and subsequently activates proinflammatory signaling pathways. Mutations in Nod2 have been implicated to be linked to inflammatory granulomatous disorders, such as Crohn's disease and Blau syndrome. Many phytochemicals possess anti-inflammatory properties. However, it is not known whether any of these phytochemicals might modulate Nod2-mediated immune responses and thus might be of therapeutic value for the intervention of these inflammatory diseases. In this report, we demonstrate that curcumin, a polyphenol found in the plant Curcuma longa, and parthenolide, a sesquiterpene lactone, suppress both ligand-induced and lauric acid-induced Nod2 signaling, leading to the suppression of nuclear factor-κB activation and target gene interleukin-8 expression. We provide molecular and biochemical evidence that the suppression is mediated through the inhibition of Nod2 oligomerization and subsequent inhibition of downstream signaling. These results demonstrate for the first time that curcumin and parthenolide can directly inhibit Nod2-mediated signaling pathways at the receptor level and suggest that Nod2-mediated inflammatory responses can be modulated by these phytochemicals. It remains to be determined whether these phytochemicals possess protective or therapeutic efficacy against Nod2-mediated inflammatory disorders. PMID:18413660

  1. Juvenile hormone connects larval nutrition with target of rapamycin signaling in the mosquito Aedes aegypti.

    PubMed

    Shiao, Shin-Hong; Hansen, Immo A; Zhu, Jinsong; Sieglaff, Douglas H; Raikhel, Alexander S

    2008-01-01

    Anautogenous mosquitoes require blood meals to promote egg development. If adequate nutrients are not obtained during larval development, the resulting "small" sized adult mosquitoes require multiple blood meals for egg development; markedly increasing host-vector contacts and the likelihood of disease transmission. Nutrient-sensitive target of rapamycin (TOR) signaling is a key signaling pathway that links elevated hemolymph amino acid levels derived from the blood meal to the expression of yolk protein precursors in the fat body. Here we report that the blood-meal-induced activation of the TOR-signaling pathway and subsequent egg maturation depends on the accumulation of adequate nutritional reserves during larval development. We have established well-nourished, "standard" mosquitoes and malnourished, "small" mosquitoes as models to address this nutrient sensitive pathway. This regulatory mechanism involves juvenile hormone (JH), which acts as a mediator of fat body competence, permitting the response to amino acids derived from the blood meal. We demonstrate that treatment with JH results in recovery of the TOR molecular machinery, Aedes aegypti cationic amino acid transporter 2 (AaiCAT2), TOR, and S6 kinase (S6K), in fat bodies of small mosquitoes, enabling them to complete their first gonotrophic cycle after a single blood meal. These findings establish a direct link between nutrient reserves and the establishment of TOR signaling in mosquitoes.

  2. “Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets

    PubMed Central

    TAKABE, KAZUAKI; PAUGH, STEVEN W.; MILSTIEN, SHELDON; SPIEGEL, SARAH

    2009-01-01

    Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes including proliferation, survival, and migration, as well as angiogenesis and allergic responses. S1P levels inside cells are tightly regulated by the balance between its synthesis by sphingosine kinases and degradation. S1P is interconvertible with ceramide, which is a critical mediator of apoptosis. It has been postulated that the ratio between S1P and ceramide determines cell fate. Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this “inside-out” signaling by S1P may play a role in many human diseases, including cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this review we summarize metabolism of S1P, mechanisms of sphingosine kinase activation, and S1P receptors and their downstream signaling pathways and examine relationships to multiple disease processes. In particular, we describe recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod), S1P receptor agonists, sphingosine kinase inhibitors, and anti-S1P monoclonal antibody. PMID:18552276

  3. The Role of Target of Rapamycin Signaling Networks in Plant Growth and Metabolism1

    PubMed Central

    Sheen, Jen

    2014-01-01

    The target of rapamycin (TOR) kinase, a master regulator that is evolutionarily conserved among yeasts (Saccharomyces cerevisiae), plants, animals, and humans, integrates nutrient and energy signaling to promote cell proliferation and growth. Recent breakthroughs made possible by integrating chemical, genetic, and genomic analyses have greatly increased our understanding of the molecular functions and dynamic regulation of the TOR kinase in photosynthetic plants. TOR signaling plays fundamental roles in embryogenesis, meristem activation, root and leaf growth, flowering, senescence, and life span determination. The molecular mechanisms underlying TOR-mediated ribosomal biogenesis, translation promotion, readjustment of metabolism, and autophagy inhibition are now being uncovered. Moreover, monitoring photosynthesis-derived Glc and bioenergetics relays has revealed that TOR orchestrates unprecedented transcriptional networks that wire central metabolism and biosynthesis for energy and biomass production. In addition, these networks integrate localized stem/progenitor cell proliferation through interorgan nutrient coordination to control developmental transitions and growth. PMID:24385567

  4. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer.

    PubMed

    Moossavi, Shirin; Rezaei, Nima

    2013-06-01

    Intestinal homeostasis is dependent on the proper host/microbiota interaction via pattern recognition receptors. Toll-like receptors are a specialised group of membrane receptors which detect pathogen-associated conserved structures. They are present in the intestinal tract and are required for intestinal homeostasis. Dysregulation in the Toll-like receptor signalling can conceivably result in a dysregulated immune response which could contribute to major intestinal pathologies including colorectal cancer. Evidence for the role of microbiota and toll-like receptors in colorectal cancer is emerging. In this report the evidence for the contribution of toll-like receptors to the pathogenesis of colorectal cancer; potential mechanisms affecting toll-like receptor signalling; and their therapeutic targeting in colorectal cancer are reviewed. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Targeting Notch signaling pathway to overcome drug-resistance for cancer therapy

    PubMed Central

    Wang, Zhiwei; Li, Yiwei; Ahmad, Aamir; Azmi, Asfar S; Banerjee, Sanjeev; Kong, Dejuan; Sarkar, Fazlul H

    2010-01-01

    Chemotherapy is an important therapeutic strategy for cancer treatment and remains the mainstay for the management of human malignancies; however, chemotherapy fails to eliminate all tumor cells because of intrinsic or acquired drug- resistance, which is the most common cause of tumor recurrence. Recently, emerging evidences suggest that Notch signaling pathway is one of the most important signaling pathways in drug-resistant tumor cells. Moreover, down-regulation of Notch pathway could induce drug sensitivity, leading to increased inhibition of cancer cell growth, invasion, and metastasis. This article will provide a brief overview of the published evidences in support of the roles of Notch in drug-resistance, and will further summarize how targeting Notch by “natural agents” could become a novel and safer approach for the improvement of tumor treatment by overcoming drug-resistance. PMID:20600632

  6. Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer.

    PubMed

    Miyamoto, Yuji; Suyama, Koichi; Baba, Hideo

    2017-04-02

    Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain. Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy. In the current review, we describe recent advances in anti-EGFR therapy and discuss new treatment strategies to target downstream RAS-MAPK signaling in mCRC.

  7. Pdgfrb is a direct regulatory target of TGFβ signaling in atrioventricular cushion mesenchymal cells.

    PubMed

    Peng, Yin; Yan, Shun; Chen, Dongquan; Cui, Xiangqin; Jiao, Kai

    2017-01-01

    Cushion formation is the initial step for the development of valvuloseptal structures in mammalian hearts. TGFβ signaling plays critical roles in multiple steps of cushion morphogenesis. We used a newly developed conditional immortal atrioventricular cushion mesenchymal cell line, tsA58-AVM, to identify the TGFβ regulatory target genes through microarray analysis. Expression of ~1350 genes was significantly altered by TGFβ1 treatment. Subsequent bioinformatic analysis of TGFβ activated genes revealed that PDGF-BB signaling is the top hit as the potential upstream regulator. Among the 37 target molecules, 10 genes known to be involved in valve development and hemostasis were selected for quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Our results confirmed that they are all upregulated by TGFβ1 stimulation in tsA58-AVM cells and in primary atrioventricular cushion cells. We focused on examining regulation of Pdgfrb by TGFβ1, which encodes a tyrosine kinase receptor for PDGF-BB. We found that the ~150bp Pdgfrb promoter can respond to TGFβ stimulation and that this response relies on the two SP1 binding sites within the promoter. Co-immunoprecipitation analysis confirmed SP1 interacts with SMAD2 in a TGFβ-dependent fashion. Furthermore, SMAD2 is associated with the Pdgfrb promoter and this association is diminished by knocking down expression of Sp1. Our data therefore collectively suggest that upon TGFβ stimulation, SP1 recruits SMAD2 to the promoter of Pdgfrb to up-regulate its expression and thus Pdgfrb is a direct downstream target of the TGFβ/SMAD2 signaling.

  8. Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma.

    PubMed

    Ilmer, Matthias; Garnier, Agnès; Vykoukal, Jody; Alt, Eckhard; von Schweinitz, Dietrich; Kappler, Roland; Berger, Michael

    2015-12-01

    The substance P (SP)/NK-1 receptor (NK1R) complex represents an intriguing anticancer target for a variety of tumors, including hepatoblastoma (HB). Therefore, NK1R antagonists, such as the clinical drug aprepitant, recently have been proposed as potent anticancer agents. However, very little is known regarding the molecular basis of NK1R inhibition in cancer. Using reverse phase protein array, Western blot, Super TOP/FOP, confocal microscopy, and sphere formation ability (SFA) assays, we identified the AKT and Wnt signaling pathways as the key targets of aprepitant in three human HB cell lines (HepT1, HepG2, and HuH6). Following NK1R blockage, we observed decreased phosphorylation of p70S6K and 4E-BP1/2 and inhibition of the canonical Wnt pathway with subsequent decrease of HB cell growth. This effect was dependent of high baseline Wnt activity either by mutational status of β-catenin or extrinsic Wnt activation. Wnt inhibition seemed to be strengthened by disruption of the FOXM1-β-catenin complex. Furthermore, treatment of HB cells with aprepitant led to reduced expression of (liver) stemness markers (AFP, CD13, SOX2, NANOG, and OCT4) and SFA when grown under cancer stem cell conditions. Taken together, we show for the first time that targeting the SP/NK1R signaling cascade inhibits canonical Wnt signaling in HB cells. These findings reveal important insight into the molecular mechanisms of the SP/NK1R complex as a critical component in a model of pediatric liver cancer and may support the development of novel therapeutic interventions for HB and other Wnt-activated cancers. ©2015 American Association for Cancer Research.

  9. Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation.

    PubMed

    Rahimifard, Mahban; Maqbool, Faheem; Moeini-Nodeh, Shermineh; Niaz, Kamal; Abdollahi, Mohammad; Braidy, Nady; Nabavi, Seyed Mohammad; Nabavi, Seyed Fazel

    2017-02-21

    A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to normal cellular survival. Moreover, the important role of NF-κB factors in the central nervous system (CNS) through toll-like receptor (TLR) activation has been well established. This review demonstrates recent findings regarding therapeutic aspects of polyphenolic compounds for the treatment of neuroinflammation, with the aim of regulating TLR4. Polyphenols including flavonoids, phenolic acids, phenolic alcohols, stilbenes and lignans, can target TLR4 signaling pathways in multiple ways. Toll interacting protein expression could be modulated by epigallocatechin-3-gallate. Resveratrol may also exert neuroprotective effects via the TLR4/NF-κB/STAT signaling cascade. Its role in activation of cascade via interfering with TLR4 oligomerization upon receptor stimulation has also been reported. Curcumin, another polyphenol, can suppress overexpression of inflammatory mediators via inhibiting the TLR4-MAPK/NF-κB pathway. It can also reduce neuronal apoptosis via a mechanism concerning the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages. Despite a symphony of in vivo and in vitro studies, many molecular and pharmacological aspects of neuroinflammation remain unclear. It is proposed that natural compounds targeting TLR4 may serve as important pharmacophores for the development of potent drugs for the treatment of neurological disorders.

  10. Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review).

    PubMed

    Katoh, Masaru

    2013-10-01

    Angiogenesis is a process of neovascular formation from pre-existing blood vessels, which consists of sequential steps for vascular destabilization, angiogenic sprouting, lumen formation and vascular stabilization. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin, Notch, transforming growth factor-β (TGF-β), Hedgehog and WNT signaling cascades orchestrate angiogenesis through the direct or indirect regulation of quiescence, migration and the proliferation of endothelial cells. Small-molecule compounds and human/humanized monoclonal antibodies interrupting VEGF signaling have been developed as anti-angiogenic therapeutics for cancer and neovascular age-related macular degeneration (AMD). Gene or protein therapy delivering VEGF, FGF2 or FGF4, as well as cell therapy using endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been developed as pro-angiogenic therapeutics for ischemic heart disease and peripheral vascular disease. Anti-angiogenic therapy for cancer and neovascular AMD is more successful than pro-angiogenic therapy for cardiovascular diseases, as VEGF-signal interruption is technically feasible compared with vascular re-construction. Common and rare genetic variants are detected using array-based technology and personal genome sequencing, respectively. Drug and dosage should be determined based on personal genotypes of VEGF and other genes involved in angiogenesis. As epigenetic alterations give rise to human diseases, polymer-based hydrogel film may be utilized for the delivery of drugs targeting epigenetic processes and angiogenesis as treatment modalities for cardiovascular diseases. Circulating microRNAs (miRNAs) in exosomes and microvesicles are applied as functional biomarkers for diagnostics and prognostics, while synthetic miRNAs in polymer-based nanoparticles are applicable for therapeutics. A more profound understanding of the spatio

  11. Signal Biosynthesis Inhibition with Ambuic Acid as a Strategy To Target Antibiotic-Resistant Infections.

    PubMed

    Todd, Daniel A; Parlet, Corey P; Crosby, Heidi A; Malone, Cheryl L; Heilmann, Kristopher P; Horswill, Alexander R; Cech, Nadja B

    2017-08-01

    There has been major interest by the scientific community in antivirulence approaches against bacterial infections. However, partly due to a lack of viable lead compounds, antivirulence therapeutics have yet to reach the clinic. Here we investigate the development of an antivirulence lead targeting quorum sensing signal biosynthesis, a process that is conserved in Gram-positive bacterial pathogens. Some preliminary studies suggest that the small molecule ambuic acid is a signal biosynthesis inhibitor. To confirm this, we constructed a methicillin-resistant Staphylococcus aureus (MRSA) strain that decouples autoinducing peptide (AIP) production from regulation and demonstrate that AIP production is inhibited in this mutant. Quantitative mass spectrometric measurements show that ambuic acid inhibits signal biosynthesis (50% inhibitory concentration [IC50] of 2.5 ± 0.1 μM) against a clinically relevant USA300 MRSA strain. Quantitative real-time PCR confirms that this compound selectively targets the quorum sensing regulon. We show that a 5-μg dose of ambuic acid reduces MRSA-induced abscess formation in a mouse model and verify its quorum sensing inhibitory activity in vivo Finally, we employed mass spectrometry to identify or confirm the structure of quorum sensing signaling peptides in three strains each of S. aureus and Staphylococcus epidermidis and single strains of Enterococcus faecalis, Listeria monocytogenes, Staphylococcus saprophyticus, and Staphylococcus lugdunensis By measuring AIP production by these strains, we show that ambuic acid possesses broad-spectrum efficacy against multiple Gram-positive bacterial pathogens but does not inhibit quorum sensing in some commensal bacteria. Collectively, these findings demonstrate the promise of ambuic acid as a lead for the development of antivirulence therapeutics. Copyright © 2017 American Society for Microbiology.

  12. NFAT Targets Signaling Molecules to Gene Promoters in Pancreatic β-Cells

    PubMed Central

    Borenstein-Auerbach, Nofit; McGlynn, Kathleen; Kunnathodi, Faisal; Shahbazov, Rauf; Syed, Ilham; Kanak, Mazhar; Takita, Morihito; Levy, Marlon F.; Naziruddin, Bashoo

    2015-01-01

    Nuclear factor of activated T cells (NFAT) is activated by calcineurin in response to calcium signals derived by metabolic and inflammatory stress to regulate genes in pancreatic islets. Here, we show that NFAT targets MAPKs, histone acetyltransferase p300, and histone deacetylases (HDACs) to gene promoters to differentially regulate insulin and TNF-α genes. NFAT and ERK associated with the insulin gene promoter in response to glucagon-like peptide 1, whereas NFAT formed complexes with p38 MAPK (p38) and Jun N-terminal kinase (JNK) upon promoters of the TNF-α gene in response to IL-1β. Translocation of NFAT and MAPKs to gene promoters was calcineurin/NFAT dependent, and complex stability required MAPK activity. Knocking down NFATc2 expression, eliminating NFAT DNA binding sites, or interfering with NFAT nuclear import prevented association of MAPKs with gene promoters. Inhibiting p38 and JNK activity increased NFAT-ERK association with promoters, which repressed TNF-α and enhanced insulin gene expression. Moreover, inhibiting p38 and JNK induced a switch from NFAT-p38/JNK-histone acetyltransferase p300 to NFAT-ERK-HDAC3 complex formation upon the TNF-α promoter, which resulted in gene repression. Histone acetyltransferase/HDAC exchange was reversed on the insulin gene by p38/JNK inhibition in the presence of glucagon-like peptide 1, which enhanced gene expression. Overall, these data indicate that NFAT directs signaling enzymes to gene promoters in islets, which contribute to protein-DNA complex stability and promoter regulation. Furthermore, the data suggest that TNF-α can be repressed and insulin production can be enhanced by selectively targeting signaling components of NFAT-MAPK transcriptional/signaling complex formation in pancreatic β-cells. These findings have therapeutic potential for suppressing islet inflammation while preserving islet function in diabetes and islet transplantation. PMID:25496032

  13. Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer.

    PubMed

    Chen, Wei-Ching; Chang, Yung-Sheng; Hsu, Hui-Ping; Yen, Meng-Chi; Huang, Hau-Lun; Cho, Chien-Yu; Wang, Chih-Yang; Weng, Tzu-Yang; Lai, Po-Ting; Chen, Ching-Shih; Lin, Yih-Jyh; Lai, Ming-Derg

    2015-12-15

    CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.

  14. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition.

    PubMed

    Espinoza, Ingrid; Pochampally, Radhika; Xing, Fei; Watabe, Kounosuke; Miele, Lucio

    2013-09-06

    Notch signaling is an evolutionarily conserved pathway involved in cell fate control during development, stem cell self-renewal, and postnatal tissue differentiation. Roles for Notch in carcinogenesis, the biology of cancer stem cells, tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) have been reported. This review describes the role of Notch in the "stemness" program in cancer cells and in metastases, together with a brief update on the Notch inhibitors currently under investigation in oncology. These agents may be useful in targeting cancer stem cells and to reverse the EMT process.

  15. Development of anticancer agents targeting the Wnt/β-catenin signaling

    PubMed Central

    Zhang, Xiangqian; Hao, Jijun

    2015-01-01

    Wnt/β-catenin signaling plays indispensable roles in both embryonic development and adult homeostasis. Abnormal regulation of this pathway is implicated in many types of cancer. Consequently, substantial efforts have made to develop therapeutic agents as anticancer drugs by specifically targeting the Wnt/β-catenin pathway. Here we systematically review the potential therapeutic agents that have been developed to date for inhibition of the Wnt/β-catenin cascade as well as current status of clinical trials of some of these agents. PMID:26396911

  16. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition

    PubMed Central

    Espinoza, Ingrid; Pochampally, Radhika; Xing, Fei; Watabe, Kounosuke; Miele, Lucio

    2013-01-01

    Notch signaling is an evolutionarily conserved pathway involved in cell fate control during development, stem cell self-renewal, and postnatal tissue differentiation. Roles for Notch in carcinogenesis, the biology of cancer stem cells, tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT) have been reported. This review describes the role of Notch in the “stemness” program in cancer cells and in metastases, together with a brief update on the Notch inhibitors currently under investigation in oncology. These agents may be useful in targeting cancer stem cells and to reverse the EMT process. PMID:24043949

  17. Exosomes: mobile platforms for targeted and synergistic signaling across cell boundaries.

    PubMed

    Vyas, Neha; Dhawan, Jyotsna

    2016-11-08

    Intercellular communications play a vital role during tissue patterning, tissue repair, and immune reactions, in homeostasis as well as in disease. Exosomes are cell-derived secreted vesicles, extensively studied for their role in intercellular communication. Exosomes have the intrinsic ability to package multiple classes of proteins and nucleic acids within their lumens and on their membranes. Here, we explore the hypothesis that exosomal targeting may represent a cellular strategy that has evolved to deliver specific combinations of signals to specific target cells and influence normal or pathological processes. This review aims to evaluate the available evidence for this hypothesis and to identify open questions whose answers will illuminate our understanding and applications of exosome biology.

  18. Targeting of pollen tubes to ovules is dependent on nitric oxide (NO) signaling.

    PubMed

    Prado, Ana Margarida; Colaço, Renato; Moreno, Nuno; Silva, Ana Catarina; Feijó, José A

    2008-07-01

    The guidance signals that drive pollen tube navigation inside the pistil and micropyle targeting are still, to a great extent, unknown. Previous studies in vitro showed that nitric oxide (NO) works as a negative chemotropic cue for pollen tube growth in lily (Lilium longiflorum). Furthermore, Arabidopsis thaliana Atnos1 mutant plants, which show defective NO production, have reduced fertility. Here, we focus in the role of NO in the process of pollen-pistil communication, using Arabidopsis in-vivo and lily semi-vivo assays. Cross-pollination between wild-type and Atnos1 plants shows that the mutation affects the pistil tissues in a way that is compatible with abnormal pollen tube guidance. Moreover, DAF-2DA staining for NO in kanadi floral mutants showed the presence of NO in an asymmetric restricted area around the micropyle. The pollen-pistil interaction transcriptome indicates a time-course-specific modulation of transcripts of AtNOS1 and two Nitrate Reductases (nr1 and nr2), which collectively are thought to trigger a putative NO signaling pathway. Semi-vivo assays with isolated ovules and lily pollen further showed that NO is necessary for micropyle targeting to occur. This evidence is supported by CPTIO treatment with subsequent formation of balloon tips in pollen tubes facing ovules. Activation of calcium influx in pollen tubes partially rescued normal pollen tube morphology, suggesting that this pathway is also dependent on Ca(2+) signaling. A role of NO in modulating Ca(2+) signaling was further substantiated by direct imaging the cytosolic free Ca(2+) concentration during NO-induced re-orientation, where two peaks of Ca(2+) occur-one during the slowdown/stop response, the second during re-orientation and growth resumption. Taken together, these results provide evidence for the participation of NO signaling events during pollen-pistil interaction. Of special relevance, NO seems to directly affect the targeting of pollen tubes to the ovule's micropyle by

  19. Jab1 is a target of EGFR signaling in ERα-negative breast cancer

    PubMed Central

    Wang, Jiaxu; Barnes, Rebecca O; West, Nathan R; Olson, Melanie; Chu, Jenny E; Watson, Peter H

    2008-01-01

    Introduction c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional signaling protein that previously has been shown to be a master regulator of a poor prognostic gene signature in invasive breast cancer and to mediate the action of S100A7. Since epidermal growth factor receptor (EGFR), like S100A7, is often expressed in estrogen receptor-alpha-negative (ERα-) breast cancer, we set out to investigate the role of Jab1 in mediating EGFR signaling, another facet of the ERα- phenotype. Methods MDA-MB-231 and MDA-MB-468 ERα-/EGFR+ cell lines were assessed for localization of Jab1 and levels of downstream genes by immunofluorescence and nuclear protein extract assay following treatment with epidermal growth factor (EGF) and extracellular signal-regulated kinase (ERK) pathway inhibitor. A cohort of 424 human breast tumors was also assessed by immunohistochemistry. Results EGF treatment of cell lines resulted in increased Jab1 nuclear expression. This effect was inhibited by the ERK pathway inhibitor, PD98059. EGF treatment was also associated with colocalization of pERK (phosphorylated ERK) and Jab1 as well as regulation of the Jab1 downstream target gene, p27. When Jab1 activity was knocked down, p27 levels were restored to pre-EGF treatment level. Analysis of EGFR and Jab1 expression in a cohort of invasive breast tumors by tissue microarray and immunohistochemistry confirmed a relationship between EGFR and increased nuclear Jab1 within the ERα- subset (n = 154, P = 0.019). The same association was also confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1 nuclear expression was most frequent in tumors that were positive for both EGFR and S100A7 (P = 0.004). Conclusion Jab1 is a target of EGFR signaling in ERα- cell lines and breast tumors and therefore may be a common central factor and potential therapeutic target for important cell signaling pathways in ERα- breast cancer. PMID:18534028

  20. Illuminating luminal B: QSOX1 as a subtype-specific biomarker

    PubMed Central

    2013-01-01

    Breast cancer is a complex and heterogeneous disease that affects about one out of every eight women. In the last decade, several advancements have been made that have increased our understanding of breast cancer and have allowed us to more accurately diagnose and treat this disease in a more targeted manner. For example, gene expression profiling enabled the classification of breast cancers into four main subtypes - basal-like, HER2+ (human epidermal growth factor receptor 2-positive), luminal A and luminal B - and this classification is used to direct the use of targeted therapies such as tamoxifen or trastuzumab. The luminal subtypes are generally characterized as being estrogen receptor-positive and targetable with anti-hormone therapies. However, whereas luminal A cancers have a good prognosis, luminal B cancers are associated with early relapse following endocrine therapy and a prognosis that is similar to that of the aggressive basal subtype. It is thus imperative that luminal B cancers be better characterized so that therapeutic targets and biomarkers for this disease type can be realized. In the previous issue of Breast Cancer Research, Katchman and colleagues address this need by demonstrating that quiescin sulfydryl oxidase 1 (QSOX1), a secreted enzyme involved in post-translational modifications, is associated with poor prognosis in patients with luminal B breast cancer. The authors further determined that this protein promotes breast cancer proliferation and invasion. Collectively, these studies suggest that QSOX1 is a predictive biomarker for luminal cancers and that it may be a useful target for elusive luminal B disease. PMID:23680167

  1. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

    PubMed

    McKinnon, Brett D; Kocbek, Vida; Nirgianakis, Kostantinos; Bersinger, Nick A; Mueller, Michael D

    2016-04-01

    Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment. To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; 'endometriosis', 'inflammation', 'oxidative stress', 'iron', 'kinase', 'NF kappa', 'mTOR', 'MAPK' 'p38', 'JNK', 'ERK' 'estrogen' and progesterone'. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry. The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to

  2. Reliable motion detection of small targets in video with low signal-to-clutter ratios

    NASA Astrophysics Data System (ADS)

    Nichols, Scott A.; Naylor, R. B.

    1995-09-01

    Studies show that vigilance decreases rapidly after several minutes when human operators are required to search live video for infrequent intrusion detections. Therefore, there is a need for systems which can automatically detect targets in live video and reserve the operator's attention for assessment only. Thus far, automated systems have not simultaneously provided adequate detection sensitivity, false alarm suppression, and ease of setup when used in external, unconstrained environments. This unsatisfactory performance can be exacerbated by poor video imagery with low contrast, high noise, dynamic clutter, image misregistration, and/or the presence of small, slow, or erratically moving targets. This paper describes a highly adaptive video motion detection and tracking algorithm provides good performance under stressing data and environmental conditions. Features of the algorithm include: reliable detection with negligible false alarm rate of variable velocity targets having low signal-to- clutter ratios; reliable tracking of targets that exhibit motion that is non-inertial, i.e. varies in direction and velocity; automatic adaptation to both infrared and visible imagery with variable quality; and suppression of false alarms caused by sensor flaws and/or cutouts.

  3. Regulation of Structural Dynamics within a Signal Recognition Particle Promotes Binding of Protein Targeting Substrates*

    PubMed Central

    Gao, Feng; Kight, Alicia D.; Henderson, Rory; Jayanthi, Srinivas; Patel, Parth; Murchison, Marissa; Sharma, Priyanka; Goforth, Robyn L.; Kumar, Thallapuranam Krishnaswamy Suresh; Henry, Ralph L.; Heyes, Colin D.

    2015-01-01

    Protein targeting is critical in all living organisms and involves a signal recognition particle (SRP), an SRP receptor, and a translocase. In co-translational targeting, interactions among these proteins are mediated by the ribosome. In chloroplasts, the light-harvesting chlorophyll-binding protein (LHCP) in the thylakoid membrane is targeted post-translationally without a ribosome. A multidomain chloroplast-specific subunit of the SRP, cpSRP43, is proposed to take on the role of coordinating the sequence of targeting events. Here, we demonstrate that cpSRP43 exhibits significant interdomain dynamics that are reduced upon binding its SRP binding partner, cpSRP54. We showed that the affinity of cpSRP43 for the binding motif of LHCP (L18) increases when cpSRP43 is complexed to the binding motif of cpSRP54 (cpSRP54pep). These results support the conclusion that substrate binding to the chloroplast SRP is modulated by protein structural dynamics in which a major role of cpSRP54 is to improve substrate binding efficiency to the cpSRP. PMID:25918165

  4. Nuclease-aided target recycling signal amplification strategy for ochratoxin A monitoring.

    PubMed

    Lv, Lei; Li, Donghao; Cui, Chengbi; Zhao, Yangyang; Guo, Zhijun

    2017-01-15

    Ochratoxin A (OTA), a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins worldwide. OTA mainly exerts nephrotoxicity, immunotoxicity, mutagenicity, carcinogenicity, teratogenicity, and neurotoxicity. This paper describes a simple and sensitive aptamer/single-walled carbon nanohorn (SWCNH)-based assay for OTA detection. SWCNHs can protect DNA from DNase I cleavage. However, aptamers can be detached from the surface of SWCNHs through specific target binding, exposing them to enzymatic cleavage and releases the target for a new cycle. Cycling of targets leads to significant signal amplification and low limit of detection (LOD), resulting in a nearly 20-fold reduction in LOD for OTA assay compared with non-target recycling under the same experimental parameters. This technique responded specifically to OTA without interference from other analogues (Ochratoxin B, Ochratoxin C, warfarin, and N-acetyl-l-phenylalanine). Moreover, the application of this technique in real sample has been verified using red wine samples spiked with a series of OTA concentrations. This aptasensor offers a great practical importance in food safety and can be widely extended for detection of other toxins by replacing the sequence of the recognition aptamer.

  5. Reliable motion detection of small targets in video with low signal-to-clutter ratios

    SciTech Connect

    Nichols, S.A.; Naylor, R.B.

    1995-07-01

    Studies show that vigilance decreases rapidly after several minutes when human operators are required to search live video for infrequent intrusion detections. Therefore, there is a need for systems which can automatically detect targets in live video and reserve the operator`s attention for assessment only. Thus far, automated systems have not simultaneously provided adequate detection sensitivity, false alarm suppression, and ease of setup when used in external, unconstrained environments. This unsatisfactory performance can be exacerbated by poor video imagery with low contrast, high noise, dynamic clutter, image misregistration, and/or the presence of small, slow, or erratically moving targets. This paper describes a highly adaptive video motion detection and tracking algorithm which has been developed as part of Sandia`s Advanced Exterior Sensor (AES) program. The AES is a wide-area detection and assessment system for use in unconstrained exterior security applications. The AES detection and tracking algorithm provides good performance under stressing data and environmental conditions. Features of the algorithm include: reliable detection with negligible false alarm rate of variable velocity targets having low signal-to-clutter ratios; reliable tracking of targets that exhibit motion that is non-inertial, i.e., varies in direction and velocity; automatic adaptation to both infrared and visible imagery with variable quality; and suppression of false alarms caused by sensor flaws and/or cutouts.

  6. Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

    PubMed Central

    Barrett, David; Brown, Valerie I.; Grupp, Stephan A.; Teachey, David T.

    2014-01-01

    The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin’s lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both m

  7. Real-time colorimetric detection of target DNA using isothermal target and signaling probe amplification and gold nanoparticle cross-linking assay.

    PubMed

    Jung, Cheulhee; Chung, Ji Won; Kim, Un Ok; Kim, Min Hwan; Park, Hyun Gyu

    2011-01-15

    We describe a facile gold nanoparticle (AuNP)-mediated colorimetric method for real-time detection of target DNA in conjugation with our unique isothermal target and signaling probe amplification (iTPA) method, comprising novel ICA (isothermal chain amplification) and CPT (cycling probe technology). Under isothermal conditions, the iTPA simultaneously amplifies the target and signaling probe through two displacement events induced by a combination of four specially designed primers, the strand displacement activity of DNA polymerase, and the RNA degrading activity of RNase H. The resulting target amplicons are hybridized with gold nanoparticle cross-linking assay (GCA) probes having a DNA-RNA-DNA chimeric form followed by RNA cleavage by RNase H in the CPT step. The intact GCA probes were designed to cross-link two sets of DNA-AuNPs conjugates in the absence of target DNA, inducing aggregation (blue color) of AuNPs. On the contrary, the presence of target DNA leads to cleavage of the GCA probes in proportion to the amount of amplified target DNA and the solution remains red in color without aggregation of AuNPs. Relying on this strategy, 10(2) copies of target Chlamydia trachomatis plasmid were successfully detected in a colorimetric manner. Importantly, all the procedures employed up to the final detection of the target DNA were performed under isothermal conditions without requiring any detection instruments. Therefore, this strategy would greatly benefit convenient, real-time monitoring technology of target DNA under restricted environments.

  8. Rapamycin and Glucose-Target of Rapamycin (TOR) Protein Signaling in Plants*

    PubMed Central

    Xiong, Yan; Sheen, Jen

    2012-01-01

    Target of rapamycin (TOR) kinase is an evolutionarily conserved master regulator that integrates energy, nutrients, growth factors, and stress signals to promote survival and growth in all eukaryotes. The reported land plant resistance to rapamycin and the embryo lethality of the Arabidopsis tor mutants have hindered functional dissection of TOR signaling in plants. We developed sensitive cellular and seedling assays to monitor endogenous Arabidopsis TOR activity based on its conserved S6 kinase (S6K) phosphorylation. Surprisingly, rapamycin effectively inhibits Arabidopsis TOR-S6K1 signaling and retards glucose-mediated root and leaf growth, mimicking estradiol-inducible tor mutants. Rapamycin inhibition is relieved in transgenic plants deficient in Arabidopsis FK506-binding protein 12 (FKP12), whereas FKP12 overexpression dramatically enhances rapamycin sensitivity. The role of Arabidopsis FKP12 is highly specific as overexpression of seven closely related FKP proteins fails to increase rapamycin sensitivity. Rapamycin exerts TOR inhibition by inducing direct interaction between the TOR-FRB (FKP-rapamycin binding) domain and FKP12 in plant cells. We suggest that variable endogenous FKP12 protein levels may underlie the molecular explanation for longstanding enigmatic observations on inconsistent rapamycin resistance in plants and in various mammalian cell lines or diverse animal cell types. Integrative analyses with rapamycin and conditional tor and fkp12 mutants also reveal a central role of glucose-TOR signaling in root hair formation. Our studies demonstrate the power of chemical genetic approaches in the discovery of previously unknown and pivotal functions of glucose-TOR signaling in governing the growth of cotyledons, true leaves, petioles, and primary and secondary roots and root hairs. PMID:22134914

  9. Rapamycin and glucose-target of rapamycin (TOR) protein signaling in plants.

    PubMed

    Xiong, Yan; Sheen, Jen

    2012-01-20

    Target of rapamycin (TOR) kinase is an evolutionarily conserved master regulator that integrates energy, nutrients, growth factors, and stress signals to promote survival and growth in all eukaryotes. The reported land plant resistance to rapamycin and the embryo lethality of the Arabidopsis tor mutants have hindered functional dissection of TOR signaling in plants. We developed sensitive cellular and seedling assays to monitor endogenous Arabidopsis TOR activity based on its conserved S6 kinase (S6K) phosphorylation. Surprisingly, rapamycin effectively inhibits Arabidopsis TOR-S6K1 signaling and retards glucose-mediated root and leaf growth, mimicking estradiol-inducible tor mutants. Rapamycin inhibition is relieved in transgenic plants deficient in Arabidopsis FK506-binding protein 12 (FKP12), whereas FKP12 overexpression dramatically enhances rapamycin sensitivity. The role of Arabidopsis FKP12 is highly specific as overexpression of seven closely related FKP proteins fails to increase rapamycin sensitivity. Rapamycin exerts TOR inhibition by inducing direct interaction between the TOR-FRB (FKP-rapamycin binding) domain and FKP12 in plant cells. We suggest that variable endogenous FKP12 protein levels may underlie the molecular explanation for longstanding enigmatic observations on inconsistent rapamycin resistance in plants and in various mammalian cell lines or diverse animal cell types. Integrative analyses with rapamycin and conditional tor and fkp12 mutants also reveal a central role of glucose-TOR signaling in root hair formation. Our studies demonstrate the power of chemical genetic approaches in the discovery of previously unknown and pivotal functions of glucose-TOR signaling in governing the growth of cotyledons, true leaves, petioles, and primary and secondary roots and root hairs.

  10. The evolution of regulators of G protein signalling proteins as drug targets - 20 years in the making: IUPHAR Review 21.

    PubMed

    Sjögren, B

    2017-03-01

    Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.

  11. Targeting notch signaling pathway in cancer: clinical development advances and challenges.

    PubMed

    Takebe, Naoko; Nguyen, Dat; Yang, Sherry X

    2014-02-01

    Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs.

  12. The scatter factor signaling pathways as therapeutic associated target in cancer treatment.

    PubMed

    Accornero, P; Pavone, L M; Baratta, M

    2010-01-01

    Receptor tyrosine kinases (RTKs) are key regulators of critical cellular processes such as proliferation, differentiation, neo-vascularization, and tissue repair. In addition to their importance in the regulation of normal physiology, aberrant expression of certain RTKs has also been associated to the development and progression of many types of cancer. c-Met and RON are two RTKs with closely related sequences, structural homology, and similar functional properties. Both these receptors, once activated by their respective ligands, the Hepatocyte Growth Factor/Scatter Factor (HGF/SF1) and the Macrophage Stimulating Protein/Scatter Factor 2 (MSP/SF2), can induce cell migration, invasion and proliferation. Soon after its discovery in the mid-1980s, c-Met attracted a great interest because of its role in modulating cell motility. Moreover, the causal role for c-Met activating mutations in human cancer propelled an intensive drug discovery effort throughout academic institutions and pharmaceutical companies. While c-Met is now a well-accepted target for anticancer drug design, less is known about the role of RON in cancer and less has been done to target this receptor. In this review we will discuss the biological relevance of c-Met and RON, their deregulation in human cancers and the progress, so far, in identifying c-Met and RON signaling inhibitors. Finally, we will focus on the development of therapeutic strategies and drug efficacy studies based on interfering the scatter factor signaling pathways.

  13. Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma

    PubMed Central

    Reis-Sobreiro, M; Roué, G; Moros, A; Gajate, C; de la Iglesia-Vicente, J; Colomer, D; Mollinedo, F

    2013-01-01

    Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p-PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment. PMID:23727661

  14. Haemophilus ducreyi targets Src family protein tyrosine kinases to inhibit phagocytic signaling.

    PubMed

    Mock, Jason R; Vakevainen, Merja; Deng, Kaiping; Latimer, Jo L; Young, Jennifer A; van Oers, Nicolai S C; Greenberg, Steven; Hansen, Eric J

    2005-12-01

    Haemophilus ducreyi, the etiologic agent of the sexually transmitted disease chancroid, has been shown to inhibit phagocytosis of both itself and secondary targets in vitro. Immunodepletion of LspA proteins from H. ducreyi culture supernatant fluid abolished this inhibitory effect, indicating that the LspA proteins are necessary for the inhibition of phagocytosis by H. ducreyi. Fluorescence microscopy revealed that macrophages incubated with wild-type H. ducreyi, but not with a lspA1 lspA2 mutant, were unable to complete development of the phagocytic cup around immunoglobulin G-opsonized targets. Examination of the phosphotyrosine protein profiles of these two sets of macrophages showed that those incubated with wild-type H. ducreyi had greatly reduced phosphorylation levels of proteins in the 50-to-60-kDa range. Subsequent experiments revealed reductions in the catalytic activities of both Lyn and Hck, two members of the Src family of protein tyrosine kinases that are known to be involved in the proximal signaling steps of Fcgamma receptor-mediated phagocytosis. Additional experiments confirmed reductions in the levels of both active Lyn and active Hck in three different immune cell lines, but not in HeLa cells, exposed to wild-type H. ducreyi. This is the first example of a bacterial pathogen that suppresses Src family protein tyrosine kinase activity to subvert phagocytic signaling in hostcells.

  15. Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling.

    PubMed

    Donia, Marco; Harbst, Katja; van Buuren, Marit; Kvistborg, Pia; Lindberg, Mattias F; Andersen, Rikke; Idorn, Manja; Munir Ahmad, Shamaila; Ellebæk, Eva; Mueller, Anja; Fagone, Paolo; Nicoletti, Ferdinando; Libra, Massimo; Lauss, Martin; Hadrup, Sine Reker; Schmidt, Henrik; Andersen, Mads Hald; Thor Straten, Per; Nilsson, Jonas A; Schumacher, Ton N; Seliger, Barbara; Jönsson, Göran; Svane, Inge Marie

    2017-09-01

    Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. Cancer Res; 77(17); 4562-6. ©2017 AACR. ©2017 American Association for Cancer Research.

  16. A single mechanism for both luminance and chromatic grating vernier tasks: evidence from temporal summation.

    PubMed

    Sun, Hao; Lee, Barry B

    2004-01-01

    Vernier thresholds are determined by luminance rather than chromatic contrast when both are present in vernier targets. The role of luminance and chromatic mechanisms in vernier performance under equiluminant conditions remains uncertain. Temporal summation functions for vernier thresholds with luminance and red-green equiluminant gratings were compared to those for detection thresholds with similar stimuli. Vernier thresholds showed similar temporal summation for luminance and chromatic gratings, which is consistent with a single mechanism underlying vernier performance in the two conditions. However, detection thresholds showed a shorter temporal summation duration for luminance gratings than for chromatic gratings, which suggests that two different mechanisms underlie detection thresholds. Analysis of physiological data supports the hypothesis that the frequency-doubled response of ganglion cells in the magnocellular pathway can provide accurate spatiotemporal information for vernier performance at equiluminance.

  17. Silymarin Targets β-Catenin Signaling in Blocking Migration/Invasion of Human Melanoma Cells

    PubMed Central

    Vaid, Mudit; Prasad, Ram; Sun, Qian; Katiyar, Santosh K.

    2011-01-01

    Metastatic melanoma is a leading cause of death from skin diseases, and is often associated with activation of Wnt/β-catenin signaling pathway. We have examined the inhibitory effect of silymarin, a plant flavanoid from Silybum marianum, on cell migration of metastasis-specific human melanoma cell lines (A375 and Hs294t) and assessed whether Wnt/β-catenin signaling is the target of silymarin. Using an in vitro invasion assay, we found that treatment of human melanoma cell lines with silymarin resulted in concentration-dependent inhibition of cell migration, which was associated with accumulation of cytosolic β-catenin, while reducing the nuclear accumulation of β-catenin (i.e., β-catenin inactivation) and reducing the levels of matrix metalloproteinase (MMP) -2 and MMP-9 which are the down-stream targets of β-catenin. Silymarin enhanced: (i) the levels of casein kinase 1α, glycogen synthase kinase-3β and phosphorylated-β-catenin on critical residues Ser45, Ser33/37 and Thr41, and (ii) the binding of β-transducin repeat-containing proteins (β-TrCP) with phospho forms of β-catenin in melanoma cells. These events play important roles in degradation or inactivation of β-catenin. To verify whether β-catenin is a potent molecular target of silymarin, the effect of silymarin was determined on β-catenin-activated (Mel 1241) and β-catenin-inactivated (Mel 1011) melanoma cells. Treatment of Mel 1241 cells with silymarin or FH535, an inhibitor of Wnt/β-catenin pathway, significantly inhibited cell migration of Mel 1241 cells, which was associated with the elevated levels of casein kinase 1α and glycogen synthase kinase-3β, and decreased accumulation of nuclear β-catenin and inhibition of MMP-2 and MMP-9 levels. However, this effect of silymarin and FH535 was not found in Mel 1011 melanoma cells. These results indicate for the first time that silymarin inhibits melanoma cell migration by targeting β-catenin signaling pathway. PMID:21829575

  18. Targeting FLT3-ITD signaling mediates ceramide-dependent mitophagy and attenuates drug resistance in AML.

    PubMed

    Dany, Mohammed; Gencer, Salih; Nganga, Rose; Thomas, Raquela J; Oleinik, Natalia; Baron, Kyla D; Szulc, Zdzislaw M; Ruvolo, Peter; Kornblau, Steven; Andreeff, Michael; Ogretmen, Besim

    2016-10-13

    Signaling pathways regulated by mutant Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD), which mediate resistance to acute myeloid leukemia (AML) cell death, are poorly understood. Here, we reveal that pro-cell death lipid ceramide generation is suppressed by FLT3-ITD signaling. Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively inducing mitophagy and AML cell death. Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the outer mitochondrial membrane, which then directly bound autophagy-inducing light chain 3 (LC3), involving its I35 and F52 residues, to recruit autophagosomes for execution of lethal mitophagy. Short hairpin RNA (shRNA)-mediated knockdown of LC3 prevented AML cell death in response to FLT3-ITD inhibition by crenolanib, which was restored by wild-type (WT)-LC3, but not mutants of LC3 with altered ceramide binding (I35A-LC3 or F52A-LC3). Mitochondrial ceramide accumulation and lethal mitophagy induction in response to FLT3-ITD targeting was mediated by dynamin-related protein 1 (Drp1) activation via inhibition of protein kinase A-regulated S637 phosphorylation, resulting in mitochondrial fission. Inhibition of Drp1 prevented ceramide-dependent lethal mitophagy, and reconstitution of WT-Drp1 or phospho-null S637A-Drp1 but not its inactive phospho-mimic mutant (S637D-Drp1), restored mitochondrial fission and mitophagy in response to crenolanib in FLT3-ITD(+) AML cells expressing stable shRNA against endogenous Drp1. Moreover, activating FLT3-ITD signaling in crenolanib-resistant AML cells suppressed ceramide-dependent mitophagy and prevented cell death. FLT3-ITD(+) AML drug resistance is attenuated by LCL-461, a mitochondria-targeted ceramide analog drug, in vivo, which also induced lethal mitophagy in human AML blasts with clinically relevant FLT3 mutations. Thus, these data reveal a novel mechanism which regulates AML cell death by ceramide-dependent mitophagy in response

  19. Effects of DNA probe and target flexibility on the performance of a "signal-on" electrochemical DNA sensor.

    PubMed

    Wu, Yao; Lai, Rebecca Y

    2014-09-02

    We report the effect of the length and identity of a nontarget binding spacer in both the probe and target sequences on the overall performance of a folding-based electrochemical DNA sensor. Six near-identical DNA probes were used in this study; the main differences between these probes are the length (6, 10, or 14 bases) and identity (thymine (T) or adenine (A)) of the spacer connecting the two target binding domains. Despite the differences, the signaling mechanism of these sensors remains essentially the same. The methylene blue (MB)-modified probe assumes a linear unstructured conformation in the absence of the target; upon hybridization to the target, the probe adopts a "close" conformation, resulting in an increase in the MB current. Among the six sensors, the T14 and A14 sensors showed the largest signal increase upon target hybridization, highlighting the significance of probe flexibility on sensor performance. In addition to the target without a midsequence spacer, 12 other targets, each with a different oligo-T or oligo-A spacer, were used to elucidate the effect of target flexibility on the sensors' signaling capacity. For all six sensors, hybridization to targets with a 2- or 3-base spacer resulted in the largest signal increase. Higher signal enhancement was also observed with targets with an oligo-A spacer. For this sensor design, addition of a long nontarget binding spacer to the probe sequence is advantageous, as it provides flexibility for optimal target capture. The length of the spacer in the target sequence, however, should be adequately long to enable efficient hybridization yet does not introduce undesirable electrostatic and crowding effects.

  20. Arcing and rf signal generation during target irradiation by a high-energy, pulsed neutral particle beam

    SciTech Connect

    Robiscoe, R.T.

    1988-02-01

    We present a theory describing the dynamics of arc discharges in bulk dielectric materials on board space-based vehicles. Such ''punch-through'' arcs can occur in target satellites irradiated by high-energy (250 MeV), pulsed (100 mA x 10 ms) neutral particle beams. We treat the arc as a capacitively limited avalanche current in the target dielectric material, and we find expressions for the arc duration, charge transport, currents, and discharge energy. These quantities are adjusted to be consistent with known scaling laws for the area of charge depleted by the arc. After a brief account of the statistical distribution of voltages at which the arc starts and stops, we calculate the signal strength and frequency spectrum of the electromagnetic radiation broadcast by the arc. We find that arcs from thick ()similarreverse arrowto)1 cm) targets can generate rf signals detectable up to 1000 km from the target, bu a radio receiver operating at frequency 80 MHz, bandwidth 100 kHz, and detection threshold -105 dBm. These thick-target arc signals are 10 to 20 dB above ambient noise at the receiver, and they provide target hit assessment if the signal spectrum can be sampled at several frequencies in the nominal range 30-200 MHz. Thin-target ()similarreverse arrowto)1 mm) arc signals are much weaker, but when they are detecable in conjunction with thick-target signals, target discrimination is possible by comparing the signal frequency spectra. 24 refs., 12 figs.

  1. Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants.

    PubMed

    Amani, Hamed; Ajami, Marjan; Maleki, Solmaz Nasseri; Pazoki-Toroudi, Hamidreza; Daglia, Maria; Tsetegho Sokeng, Arold Jorel; Di Lorenzo, Arianna; Nabavi, Seyed Fazel; Devi, Kasi Pandima; Nabavi, Seyed Mohammad

    2017-08-11

    Over the course of the last three decades, a large body of evidence has shown that polyphenols, the secondary metabolites occurring in plant foods and beverages, exert protective effects due to their antioxidant activity mediated through different mechanisms ranging from direct radical scavenging and metal chelating activities, to the capacity to inhibit pro-oxidant enzymes and to target specific cell-signalling pathways. In the last decade, dietary components, and polyphenols in particular have gained considerable attention as chemopreventive agents against different types of cancer. The signal transducers and activators of transcription (STAT) family is a group of cytoplasmic transcription factors which interact with specific sequences of DNA, inducing the expression of specific genes which in turn give rise to adaptive and highly specific biological responses. Growing evidence suggests that, of the seven STAT members identified, STAT3 is over-expressed in many human tumors (i.e. solid tumors and hematological malignancies) promoting the onset and development of cancer in humans by inhibiting apoptosis or by inducing cell proliferation, angiogenesis, invasion, and metastasis. This review article aims to assess the most recent studies on the role of STATs, with focus on STAT3, in oncogenesis, and the promising effects of some polyphenols on STAT expression. Moreover, the mechanisms behind the anti-inflammatory and antioxidant activities of polyphenols which have an influence on STAT expression are discussed, with a focus on their ability to target specific cell-signalling pathways. Copyright © 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.

  2. miR-204 Targets PERK and Regulates UPR Signaling and β-Cell Apoptosis.

    PubMed

    Xu, Guanlan; Chen, Junqin; Jing, Gu; Grayson, Truman B; Shalev, Anath

    2016-08-01

    Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of diabetes and the associated β-cell apoptosis. Although microRNAs (miRNAs) have been widely studied in various diseases including diabetes, the role of miRNAs in ER stress and β-cell apoptosis has only started to be elucidated. We recently showed that diabetes increases β-cell miR-204 and have now discovered that miR-204 directly targets the 3'untranslated region of protein kinase R-like ER kinase (PERK), 1 of the 3 ER transmembrane sensors and a key factor of the unfolded protein response (UPR). In addition, by using primary human islets, mouse islets, and INS-1 β-cells, we found that miR-204 decreased PERK expression as well as its downstream factors, activating transcription factor 4 and CCAAT enhancer-binding protein homologous protein, whereas it had no effect on the other 2 ER transmembrane sensors, activating transcription factor 6 and inositol-requiring enzyme-1α. Interestingly, we discovered that miR-204 also inhibited PERK signaling in the context of ER stress, and this exacerbated ER stress-induced β-cell apoptosis. This effect could be mimicked by PERK inhibitors supporting the notion that the miR-204-mediated inhibition of PERK and UPR signaling was conferring these detrimental effects on cell survival. Taken together, we have identified PERK as a novel target of miR-204 and show that miR-204 inhibits PERK signaling and increases ER stress-induced cell death, revealing for the first time a link between this miRNA and UPR.

  3. Mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction.

    PubMed

    Li, Bingshou; Li, Zhirong; Wang, Pengcheng; Huang, Qizhao; Xu, Lifan; He, Ran; Ye, Lilin; Bai, Qiang

    2017-10-01

    The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that has been shown to be essential for the differentiation and function of various immune cells. Earlier in vitro studies showed that mTOR signalling regulates B-cell biology by supporting their activation and proliferation. However, how mTOR signalling temporally regulates in vivo germinal centre B (GCB) cell development and differentiation into short-lived plasma cells, long-lived plasma cells and memory cells is still not well understood. In this study, we used a combined conditional/inducible knock-out system to investigate the temporal regulation of mTOR complex 1 (mTORC1) in the GCB cell response to acute lymphocytic choriomeningitis virus infection by deleting Raptor, a main component of mTORC1, specifically in B cells in pre- and late GC phase. Early Raptor deficiency strongly inhibited GCB cell proliferation and differentiation and plasma cell differentiation. Nevertheless, late GC Raptor deficiency caused only decreases in the size of memory B cells and long-lived plasma cells through poor maintenance of GCB cells, but it did not change their differentiation. Collectively, our data revealed that mTORC1 signalling supports GCB cell responses at both early and late GC phases during viral infection but does not regulate GCB cell differentiation into memory B cells and plasma cells at the late GC stage. © 2017 John Wiley & Sons Ltd.

  4. Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy

    PubMed Central

    Juan, Wen Chun; Hong, Wanjin

    2016-01-01

    The Hippo signaling pathway is a highly-conserved developmental pathway that plays an essential role in organ size control, tumor suppression, tissue regeneration and stem cell self-renewal. The YES-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ) are two important transcriptional co-activators that are negatively regulated by the Hippo signaling pathway. By binding to transcription factors, especially the TEA domain transcription factors (TEADs), YAP and TAZ induce the expression of growth-promoting genes, which can promote organ regeneration after injury. Therefore, controlled activation of YAP and TAZ can be useful for regenerative medicine. However, aberrant activation of YAP and TAZ due to deregulation of the Hippo pathway or overexpression of YAP/TAZ and TEADs can promote cancer development. Hence, pharmacological inhibition of YAP and TAZ may be a useful approach to treat tumors with high YAP and/or TAZ activity. In this review, we present the mechanisms regulating the Hippo pathway, the role of the Hippo pathway in tissue repair and cancer, as well as a detailed analysis of the different strategies to target the Hippo signaling pathway and the genes regulated by YAP and TAZ for regenerative medicine and cancer therapy. PMID:27589805

  5. Recent progress in fungus-derived bioactive agents for targeting of signaling machinery in cancer cells

    PubMed Central

    Lin, Xiukun; Farooqi, Ammad Ahmad; Ismail, Muhammad

    2015-01-01

    It is becoming increasingly understood that tumor cells may have different mutations and dependencies on diverse intracellular signaling cascades for survival or metastatic potential. Overexpression of oncogenes, inactivation of tumor suppressor genes, genetic/epigenetic mutations, genomic instability, and loss of apoptotic cell death are some of the mechanisms that have been widely investigated in molecular oncology. We partition this multicomponent review into the most recent evidence on the anticancer activity of fungal substances obtained from in vitro and xenografted models, and these fungal substances modulate expression of oncogenic and tumor suppressor miRNAs. There are some outstanding questions regarding fungus-derived chemical-induced modulation of intracellular signaling networks in different cancer cell lines and preclinical models. Certain hints have emerged, emphasizing mechanisms via which apoptosis can be restored in TRAIL-resistant cancer cells. Reconceptualization of the knowledge obtained from these emerging areas of research will enable us to potentially identify natural agents with notable anticancer activity and minimal off-target effects. Integration of experimentally verified evidence obtained from cancer cell line gene expression with large-scale functional screening results and pharmacological sensitivity data will be helpful in identification of therapeutics with substantial efficacy. New tools and technologies will further deepen our understanding of the signaling networks that underlie the development of cancer, metastasis, and resistance to different therapeutics at both a personal and systems-wide level. PMID:25848216

  6. Monoglyceride lipase as a drug target: At the crossroads of arachidonic acid metabolism and endocannabinoid signaling.

    PubMed

    Grabner, Gernot F; Zimmermann, Robert; Schicho, Rudolf; Taschler, Ulrike

    2017-07-01

    Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target.

    PubMed

    Islam, Md Soriful; Segars, James H; Castellucci, Mario; Ciarmela, Pasquapina

    2017-02-01

    A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions. Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal women. They may occur in more than 70% of women, and approximately 25% of women show clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid management. Moreover, surgery negatively affects women's quality of life, and its associated cost appears to be expensive. The molecular mechanism of fibroids development and growth is not fully elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3, PI3K/AKT/mTOR, ERK 1/2 and β-catenin are involved in the leiomyoma pathogenesis, indicating that they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce some potential dietary phytochemicals that could modulate those signaling pathways.

  8. Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor.

    PubMed

    Mathew, Grinu; Hannan, Abdul; Hertzler-Schaefer, Kristina; Wang, Fen; Feng, Gen-Sheng; Zhong, Jian; Zhao, Jean J; Downward, Julian; Zhang, Xin

    2016-11-15

    Deficiency in PTEN (phosphatase and tensin homolog deleted on chromosome 10) is the underlying cause of PTEN hamartoma tumor syndrome and a wide variety of human cancers. In skin epidermis, we have previously identified an autocrine FGF signaling induced by loss of Pten in keratinocytes. In this study, we demonstrate that skin hyperplasia requires FGF receptor adaptor protein Frs2α and tyrosine phosphatase Shp2, two upstream regulators of Ras signaling. Although the PI3-kinase regulatory subunits p85α and p85β are dispensable, the PI3-kinase catalytic subunit p110α requires interaction with Ras to promote hyperplasia in Pten-deficient skin, thus demonstrating an important cross-talk between Ras and PI3K pathways. Furthermore, genetic and pharmacological inhibition of Ras-MAPK pathway impeded epidermal hyperplasia in Pten animals. These results reveal a positive feedback loop connecting Pten and Ras pathways and suggest that FGF-activated Ras-MAPK pathway is an effective therapeutic target for preventing skin tumor induced by aberrant Pten signaling.

  9. Hippo signaling pathway in liver and pancreas: the potential drug target for tumor therapy.

    PubMed

    Kong, Delin; Zhao, Yicheng; Men, Tong; Teng, Chun-Bo

    2015-02-01

    Cell behaviors, including proliferation, differentiation and apoptosis, are intricately controlled during organ development and tissue regeneration. In the past 9 years, the Hippo signaling pathway has been delineated to play critical roles in organ size control, tissue regeneration and tumorigenesis through regulating cell behaviors. In mammals, the core modules of the Hippo signaling pathway include the MST1/2-LATS1/2 kinase cascade and the transcriptional co-activators YAP/TAZ. The activity of YAP/TAZ is suppressed by cytoplasmic retention due to phosphorylation in the canonical MST1/2-LATS1/2 kinase cascade-dependent manner or the non-canonical MST1/2- and/or LATS1/2-independent manner. Hippo signaling pathway, which can be activated or inactivated by cell polarity, contact inhibition, mechanical stretch and extracellular factors, has been demonstrated to be involved in development and tumorigenesis of liver and pancreas. In addition, we have summarized several small molecules currently available that can target Hippo-YAP pathway for potential treatment of hepatic and pancreatic cancers, providing clues for other YAP initiated cancers therapy as well.

  10. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis.

    PubMed

    Gao, Wei; Tang, Zhewei; Zhang, Yi-Fan; Feng, Mingqian; Qian, Min; Dimitrov, Dimiter S; Ho, Mitchell

    2015-03-11

    Glypican-3 is a cell surface glycoprotein that associates with Wnt in liver cancer. We develop two antibodies targeting glypican-3, HN3 and YP7. The first antibody recognizes a functional epitope and inhibits Wnt signalling, whereas the second antibody recognizes a C-terminal epitope but does not inhibit Wnt signalling. Both are fused to a fragment of Pseudomonas exotoxin A (PE38) to create immunotoxins. Interestingly, the immunotoxin based on HN3 (HN3-PE38) has superior antitumor activity as compared with YP7 (YP7-PE38) both in vitro and in vivo. Intravenous administration of HN3-PE38 alone, or in combination with chemotherapy, induces regression of Hep3B and HepG2 liver tumour xenografts in mice. This study establishes glypican-3 as a promising candidate for immunotoxin-based liver cancer therapy. Our results demonstrate immunotoxin-induced tumour regression via dual mechanisms: inactivation of cancer signalling via the antibody and inhibition of protein synthesis via the toxin.

  11. [Signal pathways of cell proliferation and death as targets of potential chemotherapeutics].

    PubMed

    Repický, A; Jantová, S; Milata, V

    2008-01-01

    The purpose of this paper is to review current information concerning signal transduction pathways of cell proliferation and cell death applicable in the research of antitumor compounds with a specific effect. Actually, cancer counts among the world gravest diseases. Research of the mechanisms of action of chemotherapeutics helps us to find compounds with high cytotoxic activity to tumor cells and low or no cytotoxicity to normal cells. Many present studies deal with the ability of drugs to hit the proliferation signal pathways or cell death pathways specifically. Various proliferation signal pathways have been identified, e.g. pathways of mitogen-activated proteinkinases. In original studies, cell death was considered to perform in necrotic and apoptotic forms, whereas in contrast to necrosis, apoptosis represented the programmed process. However, other forms of programmed cell death were discovered, the programmed necrosis and autophagic cell death. Similarly, beside the intrinsic, mitochondrial-mediated, and extrinsic, receptor-mediated pathways, new mechanisms of induction of apoptosis were discovered: the endoplasmic reticulum stress pathway in which calcium plays an important role, the lysosomal pathway and the ceramide-induced pathway. Current information concerning transduction of antiproliferative and death stimuli in cells allows to explain the mechanisms of action of known drugs and also brings novel therapeutical targets which can serve in treatment of such diseases as cancer.

  12. The Na/K-ATPase-mediated signal transduction as a target for new drug development.

    PubMed

    Xie, Zijian; Xie, Joe

    2005-09-01

    The Na/K-ATPase, or Na+ pump, is a member of the P-type ATPase superfamily. In addition to pumping ions, the Na/K-ATPase is a receptor that not only regulates the function of protein kinases, but also acts as a scaffold, capable of tethering different proteins into a signalplex. The signaling Na/K-ATPase resides in caveolae and forms a "binary receptor" with the tyrosine kinase Src. Endogenous cardiotonic steroids and digitalis drugs such as ouabain act as agonists and provoke this binary receptor, resulting in tyrosine phosphorylation of the proteins that are either associated with, or in close proximity to, the signaling Na/K-ATPase. Subsequently, this initiates protein kinase cascades including ERKs and PKC isozymes. It also increases mitochondrial production of reactive oxygen species (ROS) and regulates intracellular calcium concentration. Like other receptors, activation of the Na/K-ATPase/Src by ouabain induces the endocytosis of the plasma membrane Na/K-ATPase. Significantly, this newly appreciated signaling function of the Na/K-ATPase appears to play an important role in the pathogenesis of many cardiovascular diseases, therefore serving as an important target for development of novel therapeutic agents.

  13. Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials

    PubMed Central

    Subbiah, Ishwaria M.; Falchook, Gerald S.; Kaseb, Ahmed O.; Hess, Kenneth R.; Tsimberidou, Apostolia M.; Fu, Siqing; Subbiah, Vivek; Hong, David S.; Naing, Aung; Sarina, A. Piha-Paul; Akmal, Owais; Janku, Filip; Kurzrock, Razelle

    2015-01-01

    PURPOSE Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies. METHODS We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004. RESULTS Thirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013). CONCLUSIONS In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss. PMID:26164085

  14. Bacterial Effector Activates Jasmonate Signaling by Directly Targeting JAZ Transcriptional Repressors

    PubMed Central

    Jiang, Shushu; Yao, Jian; Ma, Ka-Wai; Zhou, Huanbin; Song, Jikui; He, Sheng Yang; Ma, Wenbo

    2013-01-01

    Gram-negative bacterial pathogens deliver a variety of virulence proteins through the type III secretion system (T3SS) directly into the host cytoplasm. These type III secreted effectors (T3SEs) play an essential role in bacterial infection, mainly by targeting host immunity. However, the molecular basis of their functionalities remains largely enigmatic. Here, we show that the Pseudomonas syringae T3SE HopZ1a, a member of the widely distributed YopJ effector family, directly interacts with jasmonate ZIM-domain (JAZ) proteins through the conserved Jas domain in plant hosts. JAZs are transcription repressors of jasmonate (JA)-responsive genes and major components of the jasmonate receptor complex. Upon interaction, JAZs can be acetylated by HopZ1a through a putative acetyltransferase activity. Importantly, P. syringae producing the wild-type, but not a catalytic mutant of HopZ1a, promotes the degradation of HopZ1-interacting JAZs and activates JA signaling during bacterial infection. Furthermore, HopZ1a could partially rescue the virulence defect of a P. syringae mutant that lacks the production of coronatine, a JA-mimicking phytotoxin produced by a few P. syringae strains. These results highlight a novel example by which a bacterial effector directly manipulates the core regulators of phytohormone signaling to facilitate infection. The targeting of JAZ repressors by both coronatine toxin and HopZ1 effector suggests that the JA receptor complex is potentially a major hub of host targets for bacterial pathogens. PMID:24204266

  15. An Improved Compressive Sensing and Received Signal Strength-Based Target Localization Algorithm with Unknown Target Population for Wireless Local Area Networks.

    PubMed

    Yan, Jun; Yu, Kegen; Chen, Ruizhi; Chen, Liang

    2017-05-30

    In this paper a two-phase compressive sensing (CS) and received signal strength (RSS)-based target localization approach is proposed to improve position accuracy by dealing with the unknown target population and the effect of grid dimensions on position error. In the coarse localization phase, by formulating target localization as a sparse signal recovery problem, grids with recovery vector components greater than a threshold are chosen as the candidate target grids. In the fine localization phase, by partitioning each candidate grid, the target position in a grid is iteratively refined by using the minimum residual error rule and the least-squares technique. When all the candidate target grids are iteratively partitioned and the measurement matrix is updated, the recovery vector is re-estimated. Threshold-based detection is employed again to determine the target grids and hence the target population. As a consequence, both the target population and the position estimation accuracy can be significantly improved. Simulation results demonstrate that the proposed approach achieves the best accuracy among all the algorithms compared.

  16. Dual signal amplification for highly sensitive electrochemical detection of uropathogens via enzyme-based catalytic target recycling.

    PubMed

    Su, Jiao; Zhang, Haijie; Jiang, Bingying; Zheng, Huzhi; Chai, Yaqin; Yuan, Ruo; Xiang, Yun

    2011-11-15

    We report an ultrasensitive electrochemical approach for the detection of uropathogen sequence-specific DNA target. The sensing strategy involves a dual signal amplification process, which combines the signal enhancement by the enzymatic target recycling technique with the sensitivity improvement by the quantum dot (QD) layer-by-layer (LBL) assembled labels. The enzyme-based catalytic target DNA recycling process results in the use of each target DNA sequence for multiple times and leads to direct amplification of the analytical signal. Moreover, the LBL assembled QD labels can further enhance the sensitivity of the sensing system. The coupling of these two effective signal amplification strategies thus leads to low femtomolar (5fM) detection of the target DNA sequences. The proposed strategy also shows excellent discrimination between the target DNA and the single-base mismatch sequences. The advantageous intrinsic sequence-independent property of exonuclease III over other sequence-dependent enzymes makes our new dual signal amplification system a general sensing platform for monitoring ultralow level of various types of target DNA sequences.

  17. Mitochondria death/survival signaling pathways in cardiotoxicity induced by anthracyclines and anticancer-targeted therapies.

    PubMed

    Montaigne, David; Hurt, Christopher; Neviere, Remi

    2012-01-01

    Anthracyclines remain the cornerstone of treatment in many malignancies but these agents have a cumulative dose relationship with cardiotoxicity. Development of cardiomyopathy and congestive heart failure induced by anthracyclines are typically dose-dependent, irreversible, and cumulative. Although past studies of cardiotoxicity have focused on anthracyclines, more recently interest has turned to anticancer drugs that target many proteins kinases, such as tyrosine kinases. An attractive model to explain the mechanism of this cardiotoxicity could be myocyte loss through cell death pathways. Inhibition of mitochondrial transition permeability is a valuable tool to prevent doxorubicin-induced cardiotoxicity. In response to anthracycline treatment, activation of several protein kinases, neuregulin/ErbB2 signaling, and transcriptional factors modify mitochondrial functions that determine cell death or survival through the modulation of mitochondrial membrane permeability. Cellular response to anthracyclines is also modulated by a myriad of transcriptional factors that influence cell fate. Several novel targeted chemotherapeutic agents have been associated with a small but worrying risk of left ventricular dysfunction. Agents such as trastuzumab and tyrosine kinase inhibitors can lead to cardiotoxicity that is fundamentally different from that caused by anthracyclines, whereas biological effects converge to the mitochondria as a critical target.

  18. Mitochondria Death/Survival Signaling Pathways in Cardiotoxicity Induced by Anthracyclines and Anticancer-Targeted Therapies

    PubMed Central

    Montaigne, David; Hurt, Christopher; Neviere, Remi

    2012-01-01

    Anthracyclines remain the cornerstone of treatment in many malignancies but these agents have a cumulative dose relationship with cardiotoxicity. Development of cardiomyopathy and congestive heart failure induced by anthracyclines are typically dose-dependent, irreversible, and cumulative. Although past studies of cardiotoxicity have focused on anthracyclines, more recently interest has turned to anticancer drugs that target many proteins kinases, such as tyrosine kinases. An attractive model to explain the mechanism of this cardiotoxicity could be myocyte loss through cell death pathways. Inhibition of mitochondrial transition permeability is a valuable tool to prevent doxorubicin-induced cardiotoxicity. In response to anthracycline treatment, activation of several protein kinases, neuregulin/ErbB2 signaling, and transcriptional factors modify mitochondrial functions that determine cell death or survival through the modulation of mitochondrial membrane permeability. Cellular response to anthracyclines is also modulated by a myriad of transcriptional factors that influence cell fate. Several novel targeted chemotherapeutic agents have been associated with a small but worrying risk of left ventricular dysfunction. Agents such as trastuzumab and tyrosine kinase inhibitors can lead to cardiotoxicity that is fundamentally different from that caused by anthracyclines, whereas biological effects converge to the mitochondria as a critical target. PMID:22482055

  19. Identification of a VxP targeting signal in the flagellar Na+/K+-ATPase

    PubMed Central

    Laird, Joseph G.; Pan, Yuan; Modestou, Modestos; Yamaguchi, David M.; Song, Hongman; Sokolov, Maxim; Baker, Sheila A.

    2015-01-01

    Na+/K+-ATPase (NKA) participates in setting electrochemical gradients, cardiotonic steroid signaling, and cellular adhesion. Distinct isoforms of NKA are found in different tissues and subcellular localization patterns. For example, NKA α1 is widely expressed, NKA α3 is enriched in neurons, and NKA α4 is a testes specific isoform found in sperm flagella. In some tissues, ankyrin, a key component of the membrane cytoskeleton, can regulate the trafficking of NKA. In the retina, NKA and ankyrin-B are expressed in multiple cell types and immunostaining for each is striking in the synaptic layers. Labeling for NKA is also prominent along the inner segment plasma membrane of photoreceptors. NKA co-immunoprecipitates with ankyrin-B, but on a subcellular level co-localization of these two proteins varies dependent on the cell type. We used transgenic X. laevis tadpoles to evaluate the subcellular trafficking of NKA in photoreceptors. GFP-NKA α3 and α1 localized to the inner segment plasma membrane, but α4 localized to outer segments. We identified a VxP motif responsible for the outer segment targeting by using a series of chimeric and mutant NKA constructs. This motif is similar to previously identified ciliary targeting motifs. Given the structural similarities between outer segments and flagella, our findings shed light on the subcellular targeting of this testes specific NKA isoform. PMID:26373354

  20. Targeting epidermal growth factor receptor co-dependent signaling pathways in glioblastoma.

    PubMed

    Liu, Feng; Mischel, Paul S

    2017-09-11

    The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that is critical for normal development and function. EGFR is also amplified or mutated in a variety of cancers including in nearly 60% of cases of the highly lethal brain cancer glioblastoma (GBM). EGFR amplification and mutation reprogram cellular metabolism and broadly alter gene transcription to drive tumor formation and progression, rendering EGFR as a compelling drug target. To date, brain tumor patients have yet to benefit from anti-EGFR therapy due in part to an inability to achieve sufficient intratumoral drug levels in the brain, cultivating adaptive mechanisms of resistance. Here, we review an alternative set of strategies for targeting EGFR-amplified GBMs, based on identifying and targeting tumor co-dependencies shaped both by aberrant EGFR signaling and the brain's unique biochemical environment. These approaches may include highly brain-penetrant drugs from non-cancer pipelines, expanding the pharmacopeia and providing promising new treatments. We review the molecular underpinnings of EGFR-activated co-dependencies in the brain and the promising new treatments based on this strategy. For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  1. Neuronal Target Identification Requires AHA-1-Mediated Fine-Tuning of Wnt Signaling in C. elegans

    PubMed Central

    Zhang, Jingyan; Li, Xia; Jevince, Angela R.; Guan, Liying; Wang, Jiaming; Hall, David H.; Huang, Xun; Ding, Mei

    2013-01-01

    Electrical synaptic transmission through gap junctions is a vital mode of intercellular communication in the nervous system. The mechanism by which reciprocal target cells find each other during the formation of gap junctions, however, is poorly understood. Here we show that gap junctions are formed between BDU interneurons and PLM mechanoreceptors in C. elegans and the connectivity of BDU with PLM is influenced by Wnt signaling. We further identified two PAS-bHLH family transcription factors, AHA-1 and AHR-1, which function cell-autonomously within BDU and PLM to facilitate the target identification process. aha-1 and ahr-1 act genetically upstream of cam-1. CAM-1, a membrane-bound receptor tyrosine kinase, is present on both BDU and PLM cells and likely serves as a Wnt antagonist. By binding to a cis-regulatory element in the cam-1 promoter, AHA-1 enhances cam-1 transcription. Our study reveals a Wnt-dependent fine-tuning mechanism that is crucial for mutual target cell identification during the formation of gap junction connections. PMID:23825972

  2. Targeting protein kinase-b3 (akt3) signaling in melanoma.

    PubMed

    Madhunapantula, SubbaRao V; Robertson, Gavin P

    2017-03-01

    Deregulated Akt activity leading to apoptosis inhibition, enhanced proliferation and drug resistance has been shown to be responsible for 35-70% of advanced metastatic melanomas. Of the three isoforms, the majority of melanomas have elevated Akt3 expression and activity. Hence, potent inhibitors targeting Akt are urgently required, which is possible only if (a) the factors responsible for the failure of Akt inhibitors in clinical trials is known; and (b) the information pertaining to synergistically acting targeted therapeutics is available. Areas covered: This review provides a brief introduction of the PI3K-Akt signaling pathway and its role in melanoma development. In addition, the functional role of key Akt pathway members such as PRAS40, GSK3 kinases, WEE1 kinase in melanoma development are discussed together with strategies to modulate these targets. Efficacy and safety of Akt inhibitors is also discussed. Finally, the mechanism(s) through which Akt leads to drug resistance is discussed in this expert opinion review. Expert opinion: Even though Akt play key roles in melanoma tumor progression, cell survival and drug resistance, many gaps still exist that require further understanding of Akt functions, especially in the (a) metastatic spread; (b) circulating melanoma cells survival; and (c) melanoma stem cells growth.

  3. Therapeutic microRNAs targeting the NF-kappa B Signaling Circuits of Cancers

    PubMed Central

    Tong, Lingying; Yuan, Ye; Wu, Shiyong

    2014-01-01

    MicroRNAs (miRNAs) not only directly regulate NF-κB expression, but also up- or down-regulate NF-κB activity via upstream and downstream signaling pathways of NF-κB. In many cancer cells, miRNA expressions are altered accompanied with an elevation of NF-κB, which often plays a role in promoting cancer development and progression as well as hindering the effectiveness of chemo and radiation therapies. Thus NF-κB-targeting miRNAs have been identified and characterized as potential therapeutics for cancer treatment and sensitizers of chemo and radiotherapies. However, due to cross-targeting and instability of miRNAs, some limitations of using miRNA as cancer therapeutics still exist. In this review, the mechanisms for miRNA-mediated alteration of NF-κB expression and activation in different types of cancers will be discussed. The results of therapeutic use of NF-κB-targeting miRNA for cancer treatment will be examined. Some limitations, challenges and potential strategies in future development of miRNA as cancer therapeutics are also assessed. PMID:25220353

  4. Characterising Nearby Luminous Infrared Galaxies

    NASA Astrophysics Data System (ADS)

    Ramphul, R.; Vaisanen, P.; Van der Heyden, K.

    2017-06-01

    Luminous InfraRed Galaxies (LIRGs) in the local universe are known to be highly interacting galaxies with strong star-formation in obscured environments. LIRGs have diversity in terms of morphology and mode and location of SF, while their even more energetic counterparts, the Ultra-Luminous IR galaxies, ULIRGs, (LIR ≥ 10^12 Lsol ) are normally (remnants of) gas rich major mergers with centralised starbursts and AGN. I will present ongoing work on a survey of >40 (U)LIRGs, in a distance range of 40 to 300Mpc, observed with SALT/RSS in long-slit mode. The sample of galaxies are in various stages of interaction and merging, some with strong AGN contribution. The reduction of the SALT/RSS data, was performed efficiently with our custom-built pipeline written in python/iraf/pyraf and handles error-frames propagation. We are performing a rigorous stellar populations analysis of our sample using Starlight (Cid Fernandes, 2005) which will ultimately lead to understanding the star formation history of these galaxies. We also use automatic line intensity measurements to derive chemical abundances, star formation rates, metallicity and emission line diagnostic. The talk will showcase the latest results that we just obtained for this dataset and discuss some of the future works.

  5. Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-β signalling to prevent fibrosis.

    PubMed

    Tomcik, Michal; Zerr, Pawel; Pitkowski, Jana; Palumbo-Zerr, Katrin; Avouac, Jérôme; Distler, Oliver; Becvar, Radim; Senolt, Ladislav; Schett, Georg; Distler, Jörg H

    2014-06-01

    Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-β signalling and for the treatment of fibrosis in preclinical models of SSc. Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-β receptor I (TβRI). Expression of Hsp90β was increased in SSc skin and in murine models of SSc in a TGF-β-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-β signalling and completely prevented the stimulatory effects of TGF-β on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-β signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active TβRI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses. Hsp90 is upregulated in SSc and is critical for TGF-β signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-β in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.

  6. P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration.

    PubMed

    Hernández-Negrete, Ivette; Carretero-Ortega, Jorge; Rosenfeldt, Hans; Hernández-García, Ricardo; Calderón-Salinas, J Victor; Reyes-Cruz, Guadalupe; Gutkind, J Silvio; Vázquez-Prado, José

    2007-08-10

    Polarized cell migration results from the transduction of extra-cellular cues promoting the activation of Rho GTPases with the intervention of multidomain proteins, including guanine exchange factors. P-Rex1 and P-Rex2 are Rac GEFs connecting Gbetagamma and phosphatidylinositol 3-kinase signaling to Rac activation. Their complex architecture suggests their regulation by protein-protein interactions. Novel mechanisms of activation of Rho GTPases are associated with mammalian target of rapamycin (mTOR), a serine/threonine kinase known as a central regulator of cell growth and proliferation. Recently, two independent multiprotein complexes containing mTOR have been described. mTORC1 links to the classical rapamycin-sensitive pathways relevant for protein synthesis; mTORC2 links to the activation of Rho GTPases and cytoskeletal events via undefined mechanisms. Here we demonstrate that P-Rex1 and P-Rex2 establish, through their tandem DEP domains, interactions with mTOR, suggesting their potential as effectors in the signaling of mTOR to Rac activation and cell migration. This possibility was consistent with the effect of dominant-negative constructs and short hairpin RNA-mediated knockdown of P-Rex1, which decreased mTOR-dependent leucine-induced activation of Rac and cell migration. Rapamycin, a widely used inhibitor of mTOR signaling, did not inhibit Rac activity and cell migration induced by leucine, indicating that P-Rex1, which we found associated to both mTOR complexes, is only active when in the mTORC2 complex. mTORC2 has been described as the catalytic complex that phosphorylates AKT/PKB at Ser-473 and elicits activation of Rho GTPases and cytoskeletal reorganization. Thus, P-Rex1 links mTOR signaling to Rac activation and cell migration.

  7. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling.

    PubMed Central

    Paria, B C; Das, S K; Dey, S K

    1995-01-01

    Using a reverse transcription-coupled PCR, we demonstrated that both brain and spleen type cannabinoid receptor (CB1-R and CB2-R, respectively) mRNAs are expressed in the preimplantation mouse embryo. The CB1-R mRNA expression was coincident with the activation of the embryonic genome late in the two-cell stage, whereas the CB2-R mRNA was present from the one-cell through the blastocyst stages. The major psychoactive component of marijuana (-)-delta-9-tetrahydrocannabinol [(-)-THC] inhibited forskolin-stimulated cAMP generation in the blastocyst, and this inhibition was prevented by pertussis toxin. However, the inactive cannabinoid cannabidiol (CBD) failed to influence this response. These results suggest that cannabinoid receptors in the embryo are coupled to inhibitory guanine nucleotide binding proteins. Further, the oviduct and uterus exhibited the enzymatic capacity to synthesize the putative endogenous cannabinoid ligand arachidonylethanolamide (anandamide). Synthetic and natural cannabinoid agonists [WIN 55,212-2, CP 55,940, (-)-THC, and anandamide], but not CBD or arachidonic acid, arrested the development of two-cell embryos primarily between the four-cell and eight-cell stages in vitro in a dose-dependent manner. Anandamide also interfered with the development of eight-cell embryos to blastocysts in culture. The autoradiographic studies readily detected binding of [3H]anandamide in embryos at all stages of development. Positive signals were present in one-cell embryos and all blastomeres of two-cell through four-cell embryos. However, most of the binding sites in eight-cell embryos and morulae were present in the outer cells. In the blastocyst, these signals were primarily localized in the mural trophectoderm with low levels of signals in the polar trophectoderm, while little or no signals were noted in inner cell mass cells.These results establish that the preimplantation mouse embryo is a target for cannabinoid ligands. Consequently, many of the

  8. Adult brightness vs. luminance as models of infant photometry: variability, biasability, and spectral characteristics for the two age groups favor the luminance model.

    PubMed

    Teller, Davida Y; Pereverzeva, Maria; Civan, Andrea L

    2003-01-01

    When infants fail to make chromatic discriminations, do the characteristics of their performance minima coincide more closely with the properties of adult luminance matches or heterochromatic brightness matches? In addition to their spectral properties, adult luminance matches are typically characterized by relatively small individual differences, whereas brightness matches are believed to be both more variable and more biasable. Two complementary experiments were carried out on adults and 8-week-old infant subjects. Both groups were tested with small (1.5 degrees to 4 degrees ) red and blue test fields of varying luminances, embedded in a white surround. In adults, heterochromatic brightness matches were measured. Individual differences spanned about 0.5 log units, and brightness matches could be biased by as much as 0.8 log units by varying the range of test field luminances. In infants, the locations of performance minima were measured. Individual differences spanned less than 0.1 log units, the mean performance minima coincided with predictions based on V10(lambda), and the location of the performance minimum was nearly unaffected by the range of test field luminances used. Thus by all three criteria, these data suggest that infants' performance minima are mediated by luminance rather than by brightness signals. To date there remains no evidence that the infant visual system computes a brightness signal.

  9. Potassium selectivity of frog gastric luminal membrane.

    PubMed

    Kasbekar, D K

    1986-06-01

    Transmural potential difference (PD) and resistance (R) changes after luminal or serosal instillation of K+ were determined under various conditions in chambered preparations of frog gastric mucosae. Potassium selectivity of the luminal membrane is indicated by the rapid reversal of the inverted PD of mucosae bathed in NaCl-free, choline sulfate (Ch2SO4)-Ringer on the serosal side and unbuffered hypertonic Ch2SO4 solution on the luminal side on luminal K+ instillation. The delta PD responses are significantly attenuated, however, in histamine-stimulated mucosae bathed in hypotonic or in burimamide-inhibited mucosae bathed in hyper- and hypotonic luminal media, which suggests that the K+ selectivity of the luminal membrane resides largely in the tubular cell apical membrane. Imposing a serosal-to-luminal transmucosal K+ gradient in both histamine-stimulated and omeprazole-inhibited mucosae also reversed the normal orientation of PD but not in those inhibited with burimamide. In the latter, the PD inversion was attenuated but maintained its normal orientation. These data suggest that burimamide, but not omeprazole, acts by blocking luminal membrane K+ conductance. The inverted PD in mucosae bathed in Cl-free media may thus be due partially or fully to K+ diffusion driven by the cell-to-lumen K+ gradient via the luminal K+ conductance pathway. These findings have implications for the controversy surrounding the postulated electrogenicity of the gastric proton pump.

  10. Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma

    PubMed Central

    Cucchi, Danilo; Occhione, Maria Anna; Gulino, Alberto; De Smaele, Enrico

    2012-01-01

    Basal cell carcinoma (BCC) of the skin is the most common type of cancer and accounts for up to 40% of all cancers in the US, with a growing incidence rate over recent decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutic approaches. Furthermore, patients with BCC present a high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render primary interest in the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, the critical role of the morphogenetic Hedgehog (Hh) pathway has become evident. This pathway is found altered and activated in almost all BCCs, both sporadic and inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hh components. Several Hh inhibitors have been so far identified – from the first identified natural cyclopamine to the recently Food and Drug Administration-approved synthetic vismodegib – most of which target the Hh receptor Smoothened (either its function or its translocation to the primary cilium). Other molecules await further characterization (bisamide compounds), while drugs currently approved for other diseases such as itraconazole (an antimicotic agent) and vitamin D3 have been tested on BCC with encouraging results. The outcomes of the numerous ongoing clinical trials are expected to expand the field in the very near future. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg, Gli) or to exploit combinatorial therapies (eg, with phosphatidylinositol 3-kinase inhibitors or retinoids) in order to overcome potential drug resistance. PMID:27186130

  11. Inhibition of MicroRNA-221 Alleviates Neuropathic Pain Through Targeting Suppressor of Cytokine Signaling 1.

    PubMed

    Xia, Li; Zhang, Yunlong; Dong, Tieli

    2016-07-01

    Neuropathic pain results in considerable trouble to people's physical and mental health. The pathophysiological mechanisms underlying its occurrence and development remain unclear. A large number of experiments show that microRNAs (miRNAs) play a major role in the pathogenesis of neuropathic pain and neuroinflammation resulting from nerve injury. Among various miRNAs, microRNA-221 (miR-221) overexpression has been reported in a chronic constrictive injury (CCI)-induced rat model of neuropathic pain. However, the role of miR-221 in the regulation of neuropathic pain is unknown. In this study, we investigated the potential role and underlying mechanism of miR-221 in regulating neuropathic pain. Our findings show that miR-221 is overexpressed in the spinal cord and the isolated microglia of CCI rats. Intrathecal injection of a miR-221 inhibitor attenuated CCI-induced mechanical allodynia and thermal hyperalgesia, and reduced proinflammatory cytokine expression, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in CCI rats. Using a dual-luciferase reporter assay, we show that suppressor of cytokine signaling 1 (SOCS1), an important regulator of inflammation, is a direct target of miR-221. Treatment with the miR-221 inhibitor significantly inhibited the expression of SOCS1. Furthermore, the miR-221 inhibitor markedly suppressed the activation of nuclear factor-kappa B (NF-κB) and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Knockdown of SOCS1 in CCI rats abrogated the inhibitory effect of the miR-221 inhibitor on CCI-induced neuropathic pain and the NF-κB and p38 MAPK signaling pathways. Together, these results suggest that inhibition of miR-221 alleviates neuropathic pain and neuroinflammation through increasing SOCS1 and by inhibiting the NF-κB and p38 MAPK signaling pathways, indicating that miR-221 may be a promising molecular target for the treatment of neuropathic pain.

  12. Preclinical strategies targeted at non-small-cell lung cancer signalling pathways with striking translational fallout.

    PubMed

    Favoni, Roberto E; Alama, Angela

    2013-01-01

    Over the past decades, a plethora of cytotoxic agents, administered alone or in combinations, have been prescribed for the treatment of non-small-cell lung cancer (NSCLC) but improvements regarding patient outcome remain disappointing. Therefore, additional therapeutic strategies are urgently required to increase response rate and survival. By the time researchers had begun to understand the processes involved in NSCLC development, the genetic aetiology of lung cancer had been progressively defined. The constitutive activation of receptor tyrosine kinases and their downstream signalling pathways has opened encouraging avenues of investigation for NSCLC treatment. Several new targeted compounds have evolved from preclinical to clinical settings to affect growth factor pathways of NSCLC, and their therapeutic implications will be reviewed and discussed here. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Fault diagnosis engineering in molecular signaling networks: an overview and applications in target discovery.

    PubMed

    Abdi, Ali; Emamian, Effat S

    2010-05-01

    Fault diagnosis engineering is a key component of modern industrial facilities and complex systems, and has gone through considerable developments in the past few decades. In this paper, the principles and concepts of molecular fault diagnosis engineering are reviewed. In this area, molecular intracellular networks are considered as complex systems that may fail to function, due to the presence of some faulty molecules. Dysfunction of the system due to the presence of a single or multiple molecules can ultimately lead to the transition from the normal state to the disease state. It is the goal of molecular fault diagnosis engineering to identify the critical components of molecular networks, i.e., those whose dysfunction can interrupt the function of the entire network. The results of the fault analysis of several signaling networks are discussed, and possible connections of the findings with some complex human diseases are examined. Implications of molecular fault diagnosis engineering for target discovery and drug development are outlined as well.

  14. The dynamics of Rho GTPase signaling and implications for targeting cancer and the tumor microenvironment

    PubMed Central

    Pajic, Marina; Herrmann, David; Vennin, Claire; Conway, James RW; Chin, Venessa T; Johnsson, Anna-Karin E; Welch, Heidi CE; Timpson, Paul

    2015-01-01

    Numerous large scale genomics studies have demonstrated that cancer is a molecularly heterogeneous disease, characterized by acquired changes in the structure and DNA sequence of tumor genomes. More recently, the role of the equally complex tumor microenvironment in driving the aggressiveness of this disease is increasingly being realized. Tumor cells are surrounded by activated stroma, creating a dynamic environment that promotes cancer development, metastasis and chemoresistance. The Rho family of small GTPases plays an essential role in the regulation of cell shape, cytokinesis, cell adhesion, and cell motility. Importantly, these processes need to be considered in the context of a complex 3-dimensional (3D) environment, with reciprocal feedback and cross-talk taking place between the tumor cells and host environment. Here we discuss the role of molecular networks involving Rho GTPases in cancer, and the therapeutic implications of inhibiting Rho signaling in both cancer cells and the emerging concept of targeting the surrounding stroma. PMID:26103062

  15. NF-κB signaling pathway as target for antiplatelet activity.

    PubMed

    Fuentes, Eduardo; Rojas, Armando; Palomo, Iván

    2016-07-01

    In different nucleated cells, NF-κB has long been considered a prototypical proinflammatory signaling pathway with the expression of proinflammatory genes. Although platelets lack a nucleus, a number of functional transcription factors are involved in activated platelets, such as NF-κB. In platelet activation NF-κB regulation events include IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation. Multiple pathways contribute to platelet activation and NF-κB is a common pathway in this activation. Therefore, in platelet activation the modulation of NF-κB pathway could be a potential new target in the treatment of inflammation-related vascular disease therapy (antiplatelet and antithrombotic activities).

  16. Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells.

    PubMed

    Ponnurangam, Sivapriya; Mammen, Joshua M V; Ramalingam, Satish; He, Zhiyun; Zhang, Youcheng; Umar, Shahid; Subramaniam, Dharmalingam; Anant, Shrikant

    2012-04-01

    Cancer stem cells are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon cancer stem cells to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of cancer stem cell marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1, and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, presenilin 1, nicastrin, Pen2, and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers.

  17. Molecular targets of androgen signaling that characterize skeletal muscle recovery and regeneration

    PubMed Central

    MacKrell, James G.; Yaden, Benjamin C.; Bullock, Heather; Chen, Keyue; Shetler, Pamela; Bryant, Henry U.; Krishnan, Venkatesh

    2015-01-01

    The high regenerative capacity of adult skeletal muscle relies on a self-renewing depot of adult stem cells, termed muscle satellite cells (MSCs). Androgens, known mediators of overall body composition and specifically skeletal muscle mass, have been shown to regulate MSCs. The possible overlapping function of androgen regulation of muscle growth and MSC activation has not been carefully investigated with regards to muscle regeneration.Therefore, the aim of this study was to examine coinciding androgen-mediated genetic changes in an in vitro MSC model and clinically relevant in vivo models. A gene signature was established via microarray analysis for androgen-mediated MSC engagement and highlighted several markers including follistatin (FST), IGF-1, C-X-C chemokine receptor 4 (CXCR4), hepatocyte growth factor (HGF) and glucocorticoid receptor (GR). In an in vivo muscle atrophy model, androgen re-supplementation significantly increased muscle size and expression of IGF-1, FST, and HGF, while significantly decreasing expression of GR. Biphasic gene expression profiles over the 7-day re-supplementation period identifed temporal androgen regulation of molecular targets involved in satellite cell engagement into myogenesis. In a muscle injury model, removal of androgens resulted in delayed muscle recovery and regeneration. Modifications in the androgen signaling gene signature, along with reduced Pax7 and MyoD expression, suggested that limited MSC activation and increased inflammation contributed to the delayed regeneration. However, enhanced MSC activation in the androgen-deplete mouse injury model was driven by an androgen receptor (AR) agonist. These results provide novel in vitro and in vivo evidence describing molecular targets of androgen signaling, while also increasing support for translational use of AR agonists in skeletal muscle recovery and regeneration. PMID:26457071

  18. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling.

    PubMed

    Balic, Anamaria; Sørensen, Morten Dræby; Trabulo, Sara Maria; Sainz, Bruno; Cioffi, Michele; Vieira, Catarina R; Miranda-Lorenzo, Irene; Hidalgo, Manuel; Kleeff, Joerg; Erkan, Mert; Heeschen, Christopher

    2014-07-01

    Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. ©2014 American Association for Cancer Research.

  19. Structural Insights Into the Recognition of Peroxisomal Targeting Signal 1 By Trypanosoma Brucei Peroxin 5

    SciTech Connect

    Sampathkumar, P.; Roach, C.; Michels, P.A.M.; Hol, W.G.J.

    2009-05-27

    Glycosomes are peroxisome-like organelles essential for trypanosomatid parasites. Glycosome biogenesis is mediated by proteins called 'peroxins,' which are considered to be promising drug targets in pathogenic Trypanosomatidae. The first step during protein translocation across the glycosomal membrane of peroxisomal targeting signal 1 (PTS1)-harboring proteins is signal recognition by the cytosolic receptor peroxin 5 (PEX5). The C-terminal PTS1 motifs interact with the PTS1 binding domain (P1BD) of PEX5, which is made up of seven tetratricopeptide repeats. Obtaining diffraction-quality crystals of the P1BD of Trypanosoma brucei PEX5 (TbPEX5) required surface entropy reduction mutagenesis. Each of the seven tetratricopeptide repeats appears to have a residue in the alpha(L) conformation in the loop connecting helices A and B. Five crystal structures of the P1BD of TbPEX5 were determined, each in complex with a hepta- or decapeptide corresponding to a natural or nonnatural PTS1 sequence. The PTS1 peptides are bound between the two subdomains of the P1BD. These structures indicate precise recognition of the C-terminal Leu of the PTS1 motif and important interactions between the PTS1 peptide main chain and up to five invariant Asn side chains of PEX5. The TbPEX5 structures reported here reveal a unique hydrophobic pocket in the subdomain interface that might be explored to obtain compounds that prevent relative motions of the subdomains and interfere selectively with PTS1 motif binding or release in trypanosomatids, and would therefore disrupt glycosome biogenesis and prevent parasite growth.

  20. Honokiol in combination with radiation targets Notch signaling to inhibit colon cancer stem cells

    PubMed Central

    Ponnurangam, Sivapriya; Mammen, Joshua M.V.; Ramalingam, Satish; He, Zhiyun; Zhang, Youcheng; Umar, Shahid; Subramaniam, Dharmalingam; Anant, Shrikant

    2012-01-01

    Cancer stem cells (CSCs) are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese Medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon CSCs to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of CSC marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1 and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, Presenilin 1, Nicastrin, Pen2 and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers. PMID:22319203

  1. Targeting mTOR Signaling Can Prevent the Progression of FSGS.

    PubMed

    Zschiedrich, Stefan; Bork, Tillmann; Liang, Wei; Wanner, Nicola; Eulenbruch, Kristina; Munder, Stefan; Hartleben, Björn; Kretz, Oliver; Gerber, Simon; Simons, Matias; Viau, Amandine; Burtin, Martine; Wei, Changli; Reiser, Jochen; Herbach, Nadja; Rastaldi, Maria-Pia; Cohen, Clemens D; Tharaux, Pierre-Louis; Terzi, Fabiola; Walz, Gerd; Gödel, Markus; Huber, Tobias B

    2017-07-01

    Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administer