INTERNATIONAL ECONOMIC REVIEW, Issue 3 2007
Sanghoon Lee
American students study harder in college than in high school, whereas East Asian students study harder in high school than in college. This article proposes a signaling explanation. Signaling may occur over time both in high school and in college, and societies may differ in the timing of signaling. Students work harder in the signaling stage determined by the society as a whole. A testable implication is that high ability workers in East Asia are more concentrated among a few colleges than their U.S. counterparts. This implication is confirmed by top CEO education profile data in the United States and Korea. [source]

CELL RECEPTOR-LIGAND INTERACTION, SIGNALING AND ACTIVATION

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2006
Article first published online: 6 JUL 200
No abstract is available for this article. [source]

IDENTIFICATION AND COMPARATIVE GENOMIC ANALYSIS OF SIGNALING AND REGULATORY COMPONENTS IN THE DIATOM THALASSIOSIRA PSEUDONANA,

JOURNAL OF PHYCOLOGY, Issue 3 2007
Anton Montsant
Diatoms are unicellular brown algae that likely arose from the endocytobiosis of a red alga into a single-celled heterotroph and that constitute an algal class of major importance in phytoplankton communities around the globe. The first whole-genome sequence from a diatom species, Thalassiosira pseudonana Hasle et Heimdal, was recently reported, and features that are central to diatom physiology and ecology, such as silicon and nitrogen metabolism, iron uptake, and carbon concentration mechanisms, were described. Following this initial study, the basic cellular systems controlling cell signaling, gene expression, cytoskeletal structures, and response to stress have been cataloged in an attempt to obtain a global view of the molecular foundations that sustain such an ecologically successful group of organisms. Comparative analysis with several microbial, plant, and metazoan complete genome sequences allowed the identification of putative membrane receptors, signaling proteins, and other components of central interest to diatom ecophysiology and evolution. Thalassiosira pseudonana likely perceives light through a novel phytochrome and several cryptochrome photoreceptors; it may lack the conserved RHO small-GTPase subfamily of cell-polarity regulators, despite undergoing polarized cell-wall synthesis; and it possesses an unusually large number of heat-shock transcription factors, which may indicate the central importance of transcriptional responses to environmental stress. The availability of the complete gene repertoire will permit a detailed biochemical and genetic analysis of how diatoms prosper in aquatic environments and will contribute to the understanding of eukaryotic evolution. [source]

BLOCKADE OF P38 ALPHA MAPK SIGNALING AMELIORATES RENAL INJURY IN ACUTE RAT ANTI-GBM GLOMERULONEPHRITIS

NEPHROLOGY, Issue 1 2002
C Stambe
[source]

MULTIDIMENSIONAL SIGNALING IN THE LABOR MARKET

THE MANCHESTER SCHOOL, Issue 2007
JEONG-YOO KIM
I consider a two-dimensional job market signaling model in which firms care about a worker's personal network as well as his technical productivity, and a worker can choose both academic activity and social activity to signal his ability. In a simple model where the social activity forming a social network does not require special ability, I show that the Cho,Kreps intuitive criterion singles out Spence's outcome of signaling high academic ability by high education. I also demonstrate the possibility that a worker with high academic ability may underinvest in education when the social ability is correlated with the academic ability. [source]

Signaling and Election Motivations in a Voting Model with Common Values and Responsive Candidates

ECONOMETRICA, Issue 4 2003
Ronny Razin
In this paper we focus on strategic voting behavior when both an election and a signaling motivation affect voters' behavior. We analyze a model of elections with two candidates competing on a one-dimensional policy space. Voters are privately and imperfectly informed about a common shock affecting the electorate's preferences. Candidates are assumed to choose policy in response to information gleaned from election results and according to exogenous factors that may lead to polarization in candidates' policy choices. We analyze a subset of symmetric equilibria in which strategies are symmetric to candidates' names and private signals (CSS equilibria). We show that signaling and election motivations pull voters to vote in different directions. We provide conditions that show the relation between the amount of information aggregated in the election and the motivation that influences voting behavior the most. Finally, we show that when candidates are responsive and polarized, all CSS equilibria are inefficient in the limit. [source]

Interleukin-4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010
Angela M. Crawley
Abstract Signaling via the IL-7 receptor complex (IL-7R,/CD127 and IL-2R,/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2R,-sharing (,C) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8+ T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL-4 is a potential contributor to impaired CD8+ T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated. [source]

Specific Ca2+ Fluorescent Sensor: Signaling by Conformationally Induced PET Suppression in a Bichromophoric Acridinedione

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 34 2009
Pichandi Ashokkumar
Abstract A series of acridinedione-based bichromophoric podand systems 1a,c were synthesized and characterized. Among these, bichromophore 1c shows specific binding of Ca2+ in the presence of other biologically important metal ions like Na+, K+, Mg2+, and Zn2+. The selective complexation was proved by steady-state emission, time-resolved emission, and 1H NMR titration. Signaling of the binding event was achieved by Ca2+ -induced folding of the bichromophore, resulting in PET suppression in the acridinedione chromophore. Involvement of a PET process in the optical signaling was confirmed by comparing bichromophores 1a,c with non-PET compound 2 and monochromophore model compound 3. Non-PET compound 2 failed to give optical response upon Ca2+ binding as a result of the absence of a PET process in the Ca2+ -bound complex. Monochromophore 3 shows a similar optical response, which is the same as that in 1c. Titration of the metal-ion-bound complex of 1c with EDTA released the metal ion from the complex, thereby regaining the original photophysical properties of the bichromophore.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source]

Signaling, solidarity, and the sacred: The evolution of religious behavior

EVOLUTIONARY ANTHROPOLOGY, Issue 6 2003
Richard Sosis
Abstract Anthropologists have repeatedly noted that there has been little theoretical progress in the anthropology of religion over the past fifty years.1,7 By the 1960s, Geertz2 had pronounced the field dead. Recently, however, evolutionary researchers have turned their attention toward understanding the selective pressures that have shaped the human capacity for religious thoughts and behaviors, and appear to be resurrecting this long-dormant but important area of research.8,19 This work, which focuses on ultimate evolutionary explanations, is being complemented by advances in neuropsychology and a growing interest among neuroscientists in how ritual, trance, meditation, and other altered states affect brain functioning and development.20,26 This latter research is providing critical insights into the evolution of the proximate mechanisms responsible for religious behavior. Here we review these literatures and examine both the proximate mechanisms and ultimate evolutionary processes essential for developing a comprehensive evolutionary explanation of religion. [source]

Signaling, Free Cash Flow and "Nonmonotonic" Dividends

FINANCIAL REVIEW, Issue 1 2010
Kathleen Fuller
G35 Abstract Many argue that dividends signal future earnings or dispose of excess cash. Empirical support is inconclusive, potentially because no model combines both rationales. This paper does. Higher quality firms pay dividends to eliminate the free cash-flow problem, while firms that outsiders perceive as lower quality pay dividends to signal future earnings and reduce the free cash-flow problem. In equilibrium, dividends are nonmonotonic with respect to the signal observed by outsiders; the highest quality firms pay smaller dividends than lower perceived quality firms. The model reconciles the existing literature and generates new empirical predictions that are tested and supported. [source]

Neuron,Glia Signaling in Trigeminal Ganglion: Implications for Migraine Pathology

HEADACHE, Issue 7 2007
Srikanth Thalakoti BS
Objective.,The goal of this study was to investigate neuronal,glial cell signaling in trigeminal ganglia under basal and inflammatory conditions using an in vivo model of trigeminal nerve activation. Background.,Activation of trigeminal ganglion nerves and release of calcitonin gene-related peptide (CGRP) are implicated in the pathology of migraine. Cell bodies of trigeminal neurons reside in the ganglion in close association with glial cells. Neuron,glia interactions are involved in all stages of inflammation and pain associated with several central nervous system (CNS) diseases. However, the role of neuron,glia interactions within the trigeminal ganglion under normal and inflammatory conditions is not known. Methods.,Sprague,Dawley rats were utilized to study neuron,glia signaling in the trigeminal ganglion. Initially, True Blue was used as a retrograde tracer to localize neuronal cell bodies in the ganglion by fluorescent microscopy and multiple image alignment. Dye-coupling studies were conducted under basal conditions and in response to capsaicin injection into the TMJ capsule. S100B and p38 expression in neurons and glia were determined by immunohistochemistry following chemical stimulation. CGRP levels in the ganglion were measured by radioimmunoassay in response to capsaicin. In addition, the effect of CGRP on the release of 19 different cytokines from cultured glial cells was investigated by protein microarray analysis. Results.,In unstimulated control animals, True Blue was detected primarily in neuronal cell bodies localized in clusters within the ganglion corresponding to the V3 region (TMJ capsule), V2 region (whisker pad), or V1 region (eyebrow and eye). However, True Blue was detected in both neuronal cell bodies and adjacent glia in the V3 region of the ganglion obtained from animals injected with capsaicin. Dye movement into the surrounding glia correlated with the time after capsaicin injection. Chemical stimulation of V3 trigeminal nerves was found to increase the expression of the inflammatory proteins S100B and p38 in both neurons and glia within the V3 region. Unexpectedly, increased levels of these proteins were also observed in the V2 and V1 regions of the ganglion. CGRP and the vesicle docking protein SNAP-25 were colocalized in many neuronal cell bodies and processes. Decreased CGRP levels in the ganglion were observed 2 hours following capsaicin stimulation. Using protein microarray analysis, CGRP was shown to differentially regulate cytokine secretion from cultured trigeminal ganglion glia. Conclusions.,We demonstrated that activation of trigeminal neurons leads to changes in adjacent glia that involve communication through gap junctions and paracrine signaling. This is the first evidence, to our knowledge, of neuron,glia signaling via gap junctions within the trigeminal ganglion. Based on our findings, it is likely that neuronal,glial communication via gap junctions and paracrine signaling are involved in the development of peripheral sensitization within the trigeminal ganglion and, thus, are likely to play an important role in the initiation of migraine. Furthermore, we propose that propagation of inflammatory signals within the ganglion may help to explain commonly reported symptoms of comorbid conditions associated with migraine. [source]

Translating Electronic Currents to Precise Acetylcholine,Induced Neuronal Signaling Using an Organic Electrophoretic Delivery Device

ADVANCED MATERIALS, Issue 44 2009
Klas Tybrandt
A miniaturized organic electronic ion pump (OEIP) based on conjugated polymers is developed for delivery of positively charged biomolecules. Characterization shows that applied voltage can precisely modulate the delivery rate of the neurotransmitter acetylcholine. The capability of the device is demonstrated by convection-free, spatiotemporally resolved delivery of acetylcholine via a 10 µm channel for dynamic stimulation of single neuronal cells. [source]

THE TIMING OF SIGNALING: TO STUDY IN HIGH SCHOOL OR IN COLLEGE?,

RANKing Intracellular Signaling in Osteoclasts

IUBMB LIFE, Issue 6 2005
Xu Feng
Abstract RANKL plays a pivotal role in the differentiation, function and survival of osteoclasts, the principal bone-resorbing cells. RANKL exerts the effects by binding RANK, the receptor activator of NF-,B, in osteoclasts and its precursors. Upon binding RANKL, RANK activates six major signaling pathways: NFATc1, NF-,B, Akt/PKB, JNK, ERK and p38, which play distinct roles in osteoclast differentiation, function and survival. Recent studies have not only provided more insights into RANK signaling but have also revealed that several factors, including INF-,, IFN-,, and ITAM-activated costimulatory signals, regulate osteoclastogenesis via direct crosstalk with RANK signaling. It was recently shown that RANK contains three functional motifs capable of mediating osteoclastogenesis. Moreover, although both IFN-, and IFN-, inhibit osteoclastogenesis, they exert the inhibitory effects by distinct mechanisms. Whereas IFN-, has been shown to block osteoclastogenesis by promoting degradation of TRAF6, IFN-, inhibits osteoclastogenesis by down-regulating c-fos expression. In contrast, the ITAM-activated costimulatory signals positively regulate osteoclastogenesis by mediating the activation of NFATc1 through two ITAM-harboring adaptors: FcR, and DAP12. This review is focused on discussing the current understanding of RANK signaling and signaling crosstalk between RANK and the various factors in osteoclasts. IUBMB Life, 57: 389-395, 2005 [source]

FHA Domains as Phospho-Threonine Binding Modules in Cell Signaling

IUBMB LIFE, Issue 1 2003
Andrew Hammet
Abstract Forkhead-associated (FHA) domains are present in <200 diverse proteins in all phyla from bacteria to mammals and seem to be particularly prevalent in proteins with cell cycle control functions. Recent work from several laboratories has considerably improved our understanding of the structure and function of these domains that were virtually unknown a few years ago, and the first disease associations of FHA domains have now emerged. FHA domains form 11-stranded beta-sandwiches that contain some 100-180 amino acid residues with a high degree of sequence diversity. FHA domains act as phosphorylation-dependent protein-protein interaction modules that preferentially bind to phospho-threonine residues in their targets. Interestingly, point mutations in the human CHK2 gene that lead to single-residue amino acid substitutions in the FHA domain of this cell cycle checkpoint kinase have been found to cause a subset of cases of the Li-Fraumeni multi-cancer syndrome. IUBMB Life, 55: 23-27, 2003 [source]

Cell Compartmentalization in Redox Signaling

IUBMB LIFE, Issue 1 2001
Giovambattista Pani
Abstract From a growing body of evidence on the role of Reactive Oxygen Species as intracellular signaling molecules, the concept starts to emerge that cell responses to redox changes are function of the intracellular site where oxidants are produced and/or meet their molecular targets. In particular,a major distinction between oxidative events in the cytosolic versus the mitochondrial compartment appears to exist in terms of physiological stimuli, signaling mechanisms and functional consequences. Experimental data supporting this view are reviewed here, and the potential implications of this new perspective in redox signaling are discussed. [source]

Mitogenic and Apoptotic Signaling by Carotenoids: Involvement of a Redox Mechanism

IUBMB LIFE, Issue 1 2001
Paola Palozza
Abstract The potential for carotenoids to modulate tumor growth is currently under investigation. Although epidemiological studies evidence that a high intake of vegetables, rich in carotenoids, decreases cancer incidence and mortality, clinical trials demonstrate that supplementation of ,-carotene to chronic smokers or to asbestos workers increases the risk for lung cancer. These contradictory findings have renewed interest in elucidating the mechanism of action of carotenoids in biological systems. In this review, we show evidence for mitogenic and apoptotic effects of carotenoids and we support the hypothesis that these molecules may act as anticarcinogens or as procarcinogens through a redox mechanism. In particular, we report demonstrations for the anti-oxidant or pro-oxidant effects of carotenoids in vitro and in vivo, focusing our attention on the relationship existing between cell growth and redox status. [source]

Sequestosome 1 Mutations in Paget's Disease of Bone in Australia: Prevalence, Genotype/Phenotype Correlation, and a Novel Non-UBA Domain Mutation (P364S) Associated With Increased NF-,B Signaling Without Loss of Ubiquitin Binding,,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2009
Sarah L Rea
Abstract Previously reported Sequestosome 1(SQSTM1)/p62 gene mutations associated with Paget's disease of bone (PDB) cluster in, or cause deletion of, the ubiquitin-associated (UBA) domain. The aims of this study were to examine the prevalence of SQSTM1 mutations in Australian patients, genotype/phenotype correlations and the functional consequences of a novel point mutation (P364S) located upstream of the UBA. Mutation screening of the SQSTM1 gene was conducted on 49 kindreds with PDB. In addition, 194 subjects with apparently sporadic PDB were screened for the common P392L mutation by restriction enzyme digestion. HEK293 cells stably expressing RANK were co-transfected with expression plasmids for SQSTM1 (wildtype or mutant) or empty vector and a NF-,B luciferase reporter gene. GST-SQSTM1 (wildtype and mutant) proteins were used in pull-down assays to compare monoubiquitin-binding ability. We identified SQSTM1 mutations in 12 of 49 families screened (24.5%), comprising 9 families with the P392L mutation and 1 family each with the following mutations: K378X, 390X, and a novel P364S mutation in exon 7, upstream of the UBA. The P392L mutation was found in 9 of 194 (4.6%) patients with sporadic disease. Subjects with SQSTM1 mutations had more extensive disease, but not earlier onset, compared with subjects without mutations. In functional studies, the P364S mutation increased NF-,B activation compared with wildtype SQSTM1 but did not reduce ubiquitin binding. This suggests that increased NF-,B signaling, but not the impairment of ubiquitin binding, may be essential in the pathogenesis of PDB associated with SQSTM1 mutations. [source]

Sustained BMP Signaling in Osteoblasts Stimulates Bone Formation by Promoting Angiogenesis and Osteoblast Differentiation,,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2009
Fengjie Zhang
Abstract Angiogenesis and bone formation are tightly coupled during the formation of the skeleton. Bone morphogenetic protein (BMP) signaling is required for both bone development and angiogenesis. We recently identified endosome-associated FYVE-domain protein (endofin) as a Smad anchor for BMP receptor activation. Endofin contains a protein-phosphatase pp1c binding domain, which negatively modulates BMP signals through dephosphorylation of the BMP type I receptor. A single point mutation of endofin (F872A) disrupts interaction between the catalytic subunit pp1c and sensitizes BMP signaling in vitro. To study the functional impact of this mutation in vivo, we targeted expression of an endofin (F872A) transgene to osteoblasts. Mice expressing this mutant transgene had increased levels of phosphorylated Smad1 in osteoblasts and showed increased bone formation. Trabecular bone volume was significantly increased in the transgenic mice compared with the wildtype littermates with corresponding increases in trabecular bone thickness and number. Interestingly, the transgenic mice also had a pronounced increase in the density of the bone vasculature measured using contrast-enhanced ,CT imaging of Microfil-perfused bones. The vessel surface and volume were both increased in association with elevated levels of vascular endothelial growth factor (VEGF) in osteoblasts. Endothelial sprouting from the endofin (F872A) mutant embryonic metatarsals cultured ex vivo was increased compared with controls and was abolished by an addition of a VEGF neutralizing antibody. In conclusion, osteoblast targeted expression of a mutant endofin protein lacking the pp1c binding activity results in sustained signaling of the BMP type I receptor, which increases bone formation and skeletal angiogenesis. [source]

Dysregulated BMP Signaling and Enhanced Osteogenic Differentiation of Connective Tissue Progenitor Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP),

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2008
Paul C Billings
Abstract The study of FOP, a disabling genetic disorder of progressive heterotopic ossification, is hampered by the lack of readily available connective tissue progenitor cells. We isolated such cells from discarded primary teeth of patients with FOP and controls and discovered dysregulation of BMP signaling and rapid osteoblast differentiation in FOP cells compared with control cells. Introduction: Fibrodysplasia ossificans progressiva (FOP), the most disabling condition of progressive heterotopic ossification in humans, is caused by a recurrent heterozygous missense mutation in activin receptor IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor, in all classically affected individuals. A comprehensive understanding of FOP has been limited, in part, by a lack of readily available connective tissue progenitor cells in which to study the molecular pathology of this disorder. Materials and Methods: We derived connective tissue progenitor cells from discarded primary teeth (SHED cells) of patients with FOP and controls and examined BMP signaling and osteogenic differentiation in these cells. Results: SHED cells transmitted BMP signals through both the SMAD and p38 mitogen-activated protein kinase (MAPK) pathways and responded to BMP4 treatment by inducing BMP responsive genes. FOP cells showed ligand-independent BMP signaling and ligand-dependent hyper-responsiveness to BMP stimulation. Furthermore, FOP cells showed more rapid differentiation to an osteogenic phenotype than control cells. Conclusions: This is the first study of BMP signaling and osteogenic differentiation in connective tissue progenitor cells from patients with FOP. Our data strongly support both basal and ligand-stimulated dysregulation of BMP signaling consistent with in silico studies of the mutant ACVR1 receptor in this condition. This study substantially extends our understanding of dysregulated BMP signaling in a progenitor cell population relevant to the pathogenesis of this catastrophic disorder of progressive ectopic ossification. [source]

Enhanced Chondrogenesis and Wnt Signaling in PTH-Treated Fractures,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2007
Sanjeev Kakar
Abstract Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. Introduction: Since FDA approval of PTH [PTH(1,34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. Materials and Methods: Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 ,g/kg PTH(1,34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. Results: Quantitative ,CT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized ,-catenin protein, a central feature of canonical Wnt signaling. Conclusions: These results showed that the PTH-mediated enhancement of fracture repair is primarily associated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways. [source]

Bone Regeneration Is Regulated by Wnt Signaling,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2007
Jae-Beom Kim
Abstract Tissue regeneration is increasingly viewed as reactivation of a developmental process that, when misappropriated, can lead to malignant growth. Therefore, understanding the molecular and cellular pathways that govern tissue regeneration provides a glimpse into normal development as well as insights into pathological conditions such as cancer. Herein, we studied the role of Wnt signaling in skeletal tissue regeneration. Introduction: Some adult tissues have the ability to regenerate, and among these, bone is one of the most remarkable. Bone exhibits a persistent, lifelong capacity to reform after injury, and continual bone regeneration is a prerequisite to maintaining bone mass and density. Even slight perturbations in bone regeneration can have profound consequences, as exemplified by conditions such as osteoporosis and delayed skeletal repair. Here, our goal was to determine the role of Wnts in adult bone regeneration. Materials and Methods: Using TOPgal reporter mice, we found that damage to the skeleton instigated Wnt reporter activity, specifically at the site of injury. We used a skeletal injury model to show that Wnt inhibition, achieved through adenoviral expression of Dkk1 in the adult skeleton, prevented the differentiation of osteoprogenitor cells. Results: As a result, injury-induced bone regeneration was reduced by 84% compared with controls. Constitutive activation of the Wnt pathway resulting from a mutation in the Lrp5 Wnt co-receptor results in high bone mass, but our experiments showed that this same point mutation caused a delay in bone regeneration. In these transgenic mice, osteoprogenitor cells in the injury site were maintained in a proliferative state and differentiation into osteoblasts was delayed. Conclusions: When considered together, these data provide a framework for understanding the roles of Wnt signaling in adult bone regeneration and suggest a feasible approach to treating clinical conditions where enhanced bone formation is desired. [source]

Expression of Acid-Sensing Ion Channel 3 (ASIC3) in Nucleus Pulposus Cells of the Intervertebral Disc Is Regulated by p75NTR and ERK Signaling,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2007
Yoshiyasu Uchiyama
Abstract Although a recent study has shown that skeletal tissues express ASICs, their function is unknown. We show that intervertebral disc cells express ASIC3; moreover, expression is uniquely regulated and needed for survival in a low pH and hypoeromsotic medium. These findings suggest that ASIC3 may adapt disc cells to their hydrodynamically stressed microenvironment. Introduction: The nucleus pulposus is an avascular, hydrated tissue that permits the intervertebral disc to resist compressive loads to the spine. Because the tissue is hyperosmotic and avascular, the pH of the nucleus pulposus is low. To determine the mechanisms by which the disc cells accommodate to the low pH and hypertonicity, the expression and regulation of the acid sensing ion channel (ASIC)3 was examined. Materials and Methods: Expression of ASICs in cells of the intervertebral disc was analyzed. To study its regulation, we cloned the 2.8-kb rat ASIC3 promoter and performed luciferase reporter assays. The effect of pharmacological inhibition of ASICs on disc cell survival was studied by measuring MTT and caspase-3 activities. Results: ASIC3 was expressed in discal tissues and cultured disc cells in vitro. Because studies of neuronal cells have shown that ASIC3 expression and promoter activity is induced by nerve growth factor (NGF), we examined the effect of NGF on nucleus pulposus cells. Surprisingly, ASIC3 promoter activity did not increase after NGF treatment. The absence of induction was linked to nonexpression of tropomyosin-related kinase A (TrkA), a high-affinity NGF receptor, although a modest expression of p75NTR was seen. When treated with p75NTR antibody or transfected with dominant negative-p75NTR plasmid, there was significant suppression of ASIC3 basal promoter activity. To further explore the downstream mechanism of control of ASIC3 basal promoter activity, we blocked p75NTR and measured phospho extracellular matrix regulated kinase (pERK) levels. We found that DN-p75NTR suppressed NGF mediated transient ERK activation. Moreover, inhibition of ERK activity by dominant negative-mitogen activated protein kinase kinase (DN-MEK) resulted in a dose-dependent suppression of ASIC3 basal promoter activity, whereas overexpression of constitutively active MEK1 caused an increase in ASIC3 promoter activity. Finally, to gain insight in the functional importance of ASIC3, we suppressed ASIC activity in nucleus pulposus cells. Noteworthy, under both hyperosmotic and acidic conditions, ASIC3 served to promote cell survival and lower the activity of the pro-apoptosis protein, caspase-3. Conclusions: Results of this study indicate that NGF serves to maintain the basal expression of ASIC3 through p75NTR and ERK signaling in discal cells. We suggest that ASIC3 is needed for adaptation of the nucleus pulposus and annulus fibrosus cells to the acidic and hyperosmotic microenvironment of the intervertebral disc. [source]

Smad3-Deficient Chondrocytes Have Enhanced BMP Signaling and Accelerated Differentiation,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2006
Tian-Fang Li
Abstract Smad3 deficiency accelerates chondrocyte maturation and leads to osteoarthritis. Primary chondrocytes without Smad3 lack compensatory increases of TGF-, signaling factors, but BMP-related gene expression is increased. Smad2 or Smad3 overexpression and BMP blockade abrogate accelerated maturation in Smad3,/, chondrocytes. BMP signaling is increased in TGF-, deficiency and is required for accelerated chondrocyte maturation. Introduction: Disruption of TGF-, signaling results in accelerated chondrocyte maturation and leads to postnatal dwarfism and premature osteoarthritis. The mechanisms involved in this process were studied using in vitro murine chondrocyte cultures. Materials and Methods: Primary chondrocytes were isolated from the sterna of neonatal wildtype and Smad3,/, mice. Expressions of maturational markers, as well as genes involved in TGF-, and BMP signaling were examined. Chondrocytes were treated with TGF-, and BMP-2, and effects on maturation-related genes and BMP/TGF-, responsive reporters were examined. Recombinant noggin or retroviral vectors expressing Smad2 or Smad3 were added to the cultures. Results: Expression of colX and other maturational markers was markedly increased in Smad3,/, chondrocytes. Smad3,/, chondrocytes lacked compensatory increases in Smad2, Smad4, TGFRII, Sno, or Smurf2 and had reduced expression of TGF - ,1 and TGFRI. In contrast, Smad1, Smad5, BMP2, and BMP6 expression was increased, suggesting a shift from TGF-, toward BMP signaling. In Smad3,/, chondrocytes, alternative TGF-, signaling pathways remained responsive, as shown by luciferase assays. These non-Smad3-dependent TGF-, pathways reduced colX expression and alkaline phosphatase activity in TGF-,-treated Smad3,/, cultures, but only partially. In contrast, Smad3,/, chondrocytes were more responsive to BMP-2 treatment and had increased colX expression, phosphoSmads 1, 5, and 8 levels, and luciferase reporter activity. Overexpression of both Smad2 and Smad3 blocked spontaneous maturation in Smad3-deficient chondrocytes. Maturation was also abrogated by the addition of noggin, an extracellular BMP inhibitor. Conclusions: These findings show a key role for BMP signaling during the chondrocyte maturation, occurring with loss of TGF-, signaling with important implications for osteoarthritis and cartilage diseases. [source]

LRP5 and Wnt Signaling: A Union Made for Bone,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2004
Mark L Johnson PhD
First page of article [source]

In Vivo RANK Signaling Blockade Using the Receptor Activator of NF-,B:Fc Effectively Prevents and Ameliorates Wear Debris-Induced Osteolysis via Osteoclast Depletion Without Inhibiting Osteogenesis

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2002
Lisa M. Childs
Abstract Prosthesis failure due to wear debris-induced osteolysis remains a major clinical problem and the greatest limitation for total joint arthroplasty. Based on our knowledge of osteoclast involvement in this process and the requirements of receptor activator of NF-,B (RANK) signaling in osteoclastogenesis and bone resorption, we investigated the efficacy of RANK blockade in preventing and ameliorating titanium (Ti)-induced osteolysis in a mouse calvaria model. Compared with placebo controls we found that all doses of RANK:Fc above 1 mg/kg intraperitoneally (ip) per 48 h significantly inhibited osteoclastogenesis and bone resorption in response to Ti implanted locally. Complete inhibition occurred at 10 mg/kg ip per 48 h, yielding results that were statistically equivalent to data obtained with Ti-treated RANK,/, mice. We also evaluated the effects of a single injection of RANK:Fc on day 5 on established osteolysis and found that Ti-treated were still depleted for multinucleated tartrate-resistant acid phosphatase-positive (TRAP+) cells 16 days later. More importantly, this osteoclast depletion did not affect bone formation because the bone lost from the osteolysis on day 5 was restored by day 21. An assessment of the quantity and quality of the newly formed bone in these calvariae by calcein labeling and infrared (IR) microscopy, respectively, showed no significant negative effect of RANK:Fc treatment. These studies indicate that osteoclast depletion via RANK blockade is an effective method to prevent and reverse wear debris-induced osteolysis without jeopardizing osteogenesis. [source]

JNK signaling in insulin-producing cells is required for adaptive responses to stress in Drosophila

AGING CELL, Issue 3 2009
Jason Karpac
Summary Adaptation to environmental challenges is critical for the survival of an organism. Repression of Insulin/IGF Signaling (IIS) by stress-responsive Jun-N-terminal Kinase (JNK) signaling is emerging as a conserved mechanism that allows reallocating resources from anabolic to repair processes under stress conditions. JNK activation in Insulin-producing cells (IPCs) is sufficient to repress Insulin and Insulin-like peptide (ILP) expression in rats and flies, but the significance of this interaction for adaptive responses to stress is unclear. In this study, it is shown that JNK activity in IPCs of flies is required for oxidative stress-induced repression of the Drosophila ILP2. It is found that this repression is required for growth adaptation to heat stress as well as adult oxidative stress tolerance, and that induction of stress response genes in the periphery is in part dependent on IPC-specific JNK activity. Endocrine control of IIS by JNK in IPCs is thus critical for systemic adaptation to stress. [source]

AKIN,1 is Involved in the Regulation of Nitrogen Metabolism and Sugar Signaling in Arabidopsis

JOURNAL OF INTEGRATIVE PLANT BIOLOGY, Issue 5 2009
Xiao-Fang Li
Abstract Sucrose non-fermenting-1-related protein kinase 1 (SnRK1) has been located at the heart of the control of metabolism and development in plants. The active SnRK1 form is usually a heterotrimeric complex. Subcellular localization and specific target of the SnRK1 kinase are regulated by specific beta subunits. In Arabidopsis, there are at least seven genes encoding beta subunits, of which the regulatory functions are not yet clear. Here, we tried to study the function of one beta subunit, AKIN,1. It showed that AKIN,1 expression was dramatically induced by ammonia nitrate but not potassium nitrate, and the investigation of AKIN,1 transgenic Arabidopsis and T-DNA insertion lines showed that AKIN,1 negatively regulated the activity of nitrate ruductase and was positively involved in sugar repression in early seedling development. Meanwhile AKIN,1 expression was reduced upon sugar treatment (including mannitol) and did not affect the activity of sucrose phosphate synthase. The results indicate that AKIN,1 is involved in the regulation of nitrogen metabolism and sugar signaling. [source]

Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders

JOURNAL OF NEUROCHEMISTRY, Issue 2 2010
William M. Armstead
J. Neurochem. (2010) 113, 303,312. Abstract Stroke is a leading cause of morbidity and mortality. While tissue-type plasminogen activator (tPA) remains the only FDA-approved treatment for ischemic stroke, clinical use of tPA has been constrained to roughly 3% of eligible patients because of the danger of intracranial hemorrhage and a narrow 3 h time window for safe administration. Basic science studies indicate that tPA enhances excitotoxic neuronal cell death. In this review, the beneficial and deleterious effects of tPA in ischemic brain are discussed along with emphasis on development of new approaches toward treatment of patients with acute ischemic stroke. In particular, roles of tPA-induced signaling and a novel delivery system for tPA administration based on tPA coupling to carrier red blood cells will be considered as therapeutic modalities for increasing tPA benefit/risk ratio. The concept of the neurovascular unit will be discussed in the context of dynamic relationships between tPA-induced changes in cerebral hemodynamics and histopathologic outcome of CNS ischemia. Additionally, the role of age will be considered since thrombolytic therapy is being increasingly used in the pediatric population, but there are few basic science studies of CNS injury in pediatric animals. [source]

Regulators of G Protein Signaling

JOURNAL OF NEUROCHEMISTRY, Issue 4 2000
A Bestiary of Modular Protein Binding Domains
Abstract: Members of the newly discovered regulator of G protein signaling (RGS) families of proteins have a common RGS domain. This RGS domain is necessary for conferring upon RGS proteins the capacity to regulate negatively a variety of G, protein subunits. However, RGS proteins are more than simply negative regulators of signaling. RGS proteins can function as effector antagonists, and recent evidence suggests that RGS proteins can have positive effects on signaling as well. Many RGS proteins possess additional C- and N-terminal modular protein-binding domains and motifs. The presence of these additional modules within the RGS proteins provides for multiple novel regulatory interactions performed by these molecules. These regions are involved in conferring regulatory selectivity to specific G,-coupled signaling pathways, enhancing the efficacy of the RGS domain, and the translocation or targeting of RGS proteins to intracellular membranes. In other instances, these domains are involved in cross-talk between different G,-coupled signaling pathways and, in some cases, likely serve to integrate small GTPases with these G protein signaling pathways. This review discusses these C- and N-terminal domains and their roles in the biology of the brain-enriched RGS proteins. Methods that can be used to investigate the function of these domains are also discussed. [source]