Academic literature on the topic 'Activin signaling pathway'
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Journal articles on the topic "Activin signaling pathway"
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Olsen, Oddrun Elise, Hanne Hella, Samah Elsaadi, Carsten Jacobi, Erik Martinez-Hackert, and Toril Holien. "Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors." Biomolecules 10, no. 4 (March 29, 2020): 519. http://dx.doi.org/10.3390/biom10040519.
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Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically.
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Xie, Chen, Wenjuan Jiang, Jerome J. Lacroix, Yun Luo, and Jijun Hao. "Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling." International Journal of Molecular Sciences 21, no. 18 (September 5, 2020): 6498. http://dx.doi.org/10.3390/ijms21186498.
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Activins transduce the TGF-β pathway through a heteromeric signaling complex consisting of type I and type II receptors, and activins also inhibit bone morphogenetic protein (BMP) signaling mediated by type I receptor ALK2. Recent studies indicated that activin A cross-activates the BMP pathway through ALK2R206H, a mutation associated with Fibrodysplasia Ossificans Progressiva (FOP). How activin A inhibits ALK2WT-mediated BMP signaling but activates ALK2R206H-mediated BMP signaling is not well understood, and here we offer some insights into its molecular mechanism. We first demonstrated that among four BMP type I receptors, ALK2 is the only subtype able to mediate the activin A-induced BMP signaling upon the dissociation of FKBP12. We further showed that BMP4 does not cross-signal TGF-β pathway upon FKBP12 inhibition. In addition, although the roles of type II receptors in the ligand-independent BMP signaling activated by FOP-associated mutant ALK2 have been reported, their roles in activin A-induced BMP signaling remains unclear. We demonstrated in this study that the known type II BMP receptors contribute to activin A-induced BMP signaling through their kinase activity. Together, the current study provided important mechanistic insights at the molecular level into further understanding physiological and pathophysiological BMP signaling.
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Lebrun, Jean-Jacques, Kazuaki Takabe, Yan Chen, and Wylie Vale. "Roles of Pathway-Specific and Inhibitory Smads in Activin Receptor Signaling." Molecular Endocrinology 13, no. 1 (January 1, 1999): 15–23. http://dx.doi.org/10.1210/mend.13.1.0218.
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Abstract Activins and other members of the transforming growth factor-β-like superfamily of growth factors transduce their signals by interacting with two types of receptor serine/threonine kinases. The Smad proteins, a new family of intracellular mediators are involved in the signaling pathways of these receptors, but the initial stages of their activation as well as their specific functions remain to be defined. We report here that the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner. This complex formation is rapid but also transient. Indeed, soon after their association with the activin receptor, Smad2 and Smad3 are released into the cytoplasm where they interact with the common partner Smad4. These Smad complexes then mediate activin-induced transcription. Finally, we show that the inhibitory Smad7 can prevent the association of the two pathway-specific Smads with the activin receptor complex, thereby blocking the activin signal.
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Jung, Jae Woo, Chihoon Ahn, Sun Young Shim, Peter C. Gray, Witek Kwiatkowski, and Senyon Choe. "Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215." Journal of Endocrinology 223, no. 1 (August 6, 2014): 35–45. http://dx.doi.org/10.1530/joe-14-0317.
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Activins and bone morphogenetic proteins (BMPs) share activin type 2 signaling receptors but utilize different type 1 receptors and Smads. We designed AB215, a potent BMP2-like Activin A/BMP2 chimera incorporating the high-affinity type 2 receptor-binding epitope of Activin A. In this study, we compare the signaling properties of AB215 and BMP2 in HEK293T cells and gonadotroph LβT2 cells in which Activin A and BMP2 synergistically induce FSHβ. In HEK293T cells, AB215 is more potent than BMP2 and competitively blocks Activin A signaling, while BMP2 has a partial blocking activity. Activin A signaling is insensitive to BMP pathway antagonism in HEK293T cells but is strongly inhibited by constitutively active (CA) BMP type 1 receptors. By contrast, the potencies of AB215 and BMP2 are indistinguishable in LβT2 cells and although AB215 blocks Activin A signaling, BMP2 has no inhibitory effect. Unlike HEK293T, Activin A signaling is strongly inhibited by BMP pathway antagonism in LβT2 cells but is largely unaffected by CA BMP type 1 receptors. BMP2 increases phospho-Smad3 levels in LβT2 cells, in both the absence and the presence of Activin A treatment, and augments Activin A-induced FSHβ. AB215 has the opposite effect and sharply decreases basal phospho-Smad3 levels and blocks Smad2 phosphorylation and FSHβ induction resulting from Activin A treatment. These findings together demonstrate that while AB215 activates the BMP pathway, it has opposing effects to those of BMP2 on FSHβ induction in LβT2 cells apparently due to its ability to block Activin A signaling.
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Tang, Pei, Xueer Wang, Min Zhang, Simin Huang, Chuxi Lin, Fang Yan, Ying Deng, Lu Zhang, and Lin Zhang. "Activin B Stimulates Mouse Vibrissae Growth and Regulates Cell Proliferation and Cell Cycle Progression of Hair Matrix Cells through ERK Signaling." International Journal of Molecular Sciences 20, no. 4 (February 15, 2019): 853. http://dx.doi.org/10.3390/ijms20040853.
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Activins and their receptors play important roles in the control of hair follicle morphogenesis, but their role in vibrissae follicle growth remains unclear. To investigate the effect of Activin B on vibrissae follicles, the anagen induction assay and an in vitro vibrissae culture system were constructed. Hematoxylin and eosin staining were performed to determine the hair cycle stages. The 5-ethynyl-2′-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays were used to examine the cell proliferation. Flow cytometry was used to detect the cell cycle phase. Inhibitors and Western blot analysis were used to investigate the signaling pathway induced by Activin B. As a result, we found that the vibrissae follicle growth was accelerated by 10 ng/mL Activin B in the anagen induction assay and in an organ culture model. 10 ng/mL Activin B promoted hair matrix cell proliferation in vivo and in vitro. Moreover, Activin B modulates hair matrix cell growth through the ERK–Elk1 signaling pathway, and Activin B accelerates hair matrix cell transition from the G1/G0 phase to the S phase through the ERK–Cyclin D1 signaling pathway. Taken together, these results demonstrated that Activin B may promote mouse vibrissae growth by stimulating hair matrix cell proliferation and cell cycle progression through ERK signaling.
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Roh, Jason D., Ryan Hobson, Vinita Chaudhari, Pablo Quintero, Ashish Yeri, Mark Benson, Chunyang Xiao, et al. "Activin type II receptor signaling in cardiac aging and heart failure." Science Translational Medicine 11, no. 482 (March 6, 2019): eaau8680. http://dx.doi.org/10.1126/scitranslmed.aau8680.
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Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF.
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Qiu, Wanglong, Chia-Yu Kuo, Yu Tian, and Gloria H. Su. "Dual Roles of the Activin Signaling Pathway in Pancreatic Cancer." Biomedicines 9, no. 7 (July 14, 2021): 821. http://dx.doi.org/10.3390/biomedicines9070821.
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Activin, a member of the TGF-β superfamily, is involved in many physiological processes, such as embryonic development and follicle development, as well as in multiple human diseases including cancer. Genetic mutations in the activin signaling pathway have been reported in many cancer types, indicating that activin signaling plays a critical role in tumorigenesis. Recent evidence reveals that activin signaling may function as a tumor-suppressor in tumor initiation, and a promoter in the later progression and metastasis of tumors. This article reviews many aspects of activin, including the signaling cascade of activin, activin-related proteins, and its role in tumorigenesis, particularly in pancreatic cancer development. The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.
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Mallick, Sreeradha, Eric Kenney, and Ioannis Eleftherianos. "The Activin Branch Ligand Daw Regulates the Drosophila melanogaster Immune Response and Lipid Metabolism against the Heterorhabditis bacteriophora Serine Carboxypeptidase." International Journal of Molecular Sciences 25, no. 14 (July 21, 2024): 7970. http://dx.doi.org/10.3390/ijms25147970.
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Despite impressive advances in the broad field of innate immunity, our understanding of the molecules and signaling pathways that control the host immune response to nematode infection remains incomplete. We have shown recently that Transforming Growth Factor-β (TGF-β) signaling in the fruit fly Drosophila melanogaster is activated by nematode infection and certain TGF-β superfamily members regulate the D. melanogaster anti-nematode immune response. Here, we investigate the effect of an entomopathogenic nematode infection factor on host TGF-β pathway regulation and immune function. We find that Heterorhabditis bacteriophora serine carboxypeptidase activates the Activin branch in D. melanogaster adults and the immune deficiency pathway in Activin-deficient flies, it affects hemocyte numbers and survival in flies deficient for Activin signaling, and causes increased intestinal steatosis in Activin-deficient flies. Thus, insights into the D. melanogaster signaling pathways and metabolic processes interacting with H. bacteriophora pathogenicity factors will be applicable to entomopathogenic nematode infection of important agricultural insect pests and vectors of disease.
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LaBonne, C., and M. Whitman. "Mesoderm induction by activin requires FGF-mediated intracellular signals." Development 120, no. 2 (February 1, 1994): 463–72. http://dx.doi.org/10.1242/dev.120.2.463.
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We have examined the role of FGF signaling during activin-mediated mesoderm induction in Xenopus. Using dominant inhibitory mutants of FGF signal transducers to disrupt the FGF-signaling pathway at the plasma membrane or in the cytosol prevents animal cap blastomeres from expressing several mesodermal markers in response to exogenous activin. Dominant inhibitory mutants of the FGF receptor, c-ras or c-raf inhibit the ability of activin to induce molecular markers of both dorsal and ventral mesoderm including Xbra, Mix1 and Xnot. Some transcriptional responses to activin such as goosecoid and Xwnt8 are inhibited less effectively than others, however, suggesting that there may differing requirements for an FGF signal in the responses of mesoderm-specific genes to activin induction. Despite the requirement for this signaling pathway during activin induction, downstream components of this pathway are not activated in response to activin, suggesting that activin does not signal directly through this pathway.
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Lamba, Pankaj, Michelle M. Santos, Daniel P. Philips, and Daniel J. Bernard. "Acute regulation of murine follicle-stimulating hormone β subunit transcription by activin A." Journal of Molecular Endocrinology 36, no. 1 (February 2006): 201–20. http://dx.doi.org/10.1677/jme.1.01961.
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In rodents, activins stimulate immediate-early increases in pituitary follicle-stimulating hormone β (Fshb) subunit transcription. Here, we investigated the underlying signaling mechanisms using the mouse gonadotrope cell line, LβT2. Activin A increased mouse Fshb-luciferase reporter activity within 4 h through a Smad-dependent signaling pathway. The ligand rapidly stimulated formation of SMAD2/3/4 complexes that could interact with a consensus palindromic Smad binding element (SBE) in the proximal Fshb promoter. SMAD over-expression potently stimulated transcription, with the combination of SMADs 2, 3 and 4 producing the greatest synergistic activation. A mutation in the SBE that abolished Smad binding greatly impaired the effects of acute (4 h) activin A treatment and SMAD over-expression on promoter activity, but did not abolish the effects of chronic (24 h) activin A exposure. Within activated SMAD complexes, SMADs 3 and 4 appeared to bind the SBE simultaneously and the binding of both was required for maximal transcriptional activation. Interestingly, the human FSHB promoter, which lacks the consensus SBE, was neither rapidly stimulated by activin A nor by over-expressed SMADs, but was activated by 24 h activin A. Addition of the SBE to the human promoter increased both SMAD2/3/4-sensitivity and acute regulation by activin A, though not to levels observed in mouse. We postulate that short reproductive cycles in female rodents, particularly the brief interval between the primary and secondary FSH surges of the estrous cycle, require the Fshb promoter in these animals to be particularly sensitive to the rapid, Smad-dependent actions of activins on transcription. The human FSHB promoter, in contrast, is chronically regulated by activins seemingly through a SMAD-independent pathway.
Dissertations / Theses on the topic "Activin signaling pathway"
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Shi, Dan. "Computational analysis of transcriptional responses to the Activin signal." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/21891.
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Die Signalwege des transformierenden Wachstumsfaktors β (TGF-β) spielen eine entscheidende Rolle bei der Zellproliferation, -migration und -apoptose durch die Aktivierung von Smad-Proteinen. Untersuchungen haben gezeigt, dass die biologischen Wirkungen des TGF-β-Signalwegs stark vom Zellkontext abhängen. In dieser Arbeit ging es darum zu verstehen, wie TGF-β-Signale Zielgene unterschiedlich regulieren können, wie unterschiedliche Dynamiken der Genexpression durch TGF-β-Signale induziert werden und auf welche Weise Smad-Proteine zu unterschiedlichen Expressionsmustern von TGF- β-Zielgenen beitragen.
Der Fokus dieser Studie liegt auf den transkriptionsregulatorischen Effekten des Nodal / Activin-Liganden, der zur TGF-β-Superfamilie gehört und ein wichtiger Faktor in der frühen embryonalen Entwicklung ist. Um diese Effekte zu analysieren, habe ich kinetische Modelle entwickelt und mit den Zeitverlaufsdaten von RNA-Polymerase II (Pol II) und Smad2-Chromatin-Bindungsprofilen für die Zielgene kalibriert. Unter Verwendung des Akaike-Informationskriteriums (AIC) zur Bewertung verschiedener kinetischer Modelle stellten wir fest, dass der Nodal / Activin-Signalweg Zielgene über verschiedene Mechanismen reguliert. Im Nodal / Activin-Smad2-Signalweg spielt Smad2 für verschiedene Zielgene unterschiedliche regulatorische Rollen. Wir zeigen, wie Smad2 daran beteiligt ist, die Transkriptions- oder Abbaurate jedes Zielgens separat zu regulieren. Darüber hinaus werden eine Reihe von Merkmalen, die die Transkriptionsdynamik von Zielgenen vorhersagen können, durch logistische Regression ausgewählt.
Der hier vorgestellte Ansatz liefert quantitative Beziehungen zwischen der Dynamik des Transkriptionsfaktors und den Transkriptionsantworten. Diese Arbeit bietet auch einen allgemeinen mathematischen Rahmen für die Untersuchung der Transkriptionsregulation anderer Signalwege.Transforming growth factor-β (TGF-β) signaling pathways play a crucial role in cell proliferation, migration, and apoptosis through the activation of Smad proteins. Research has shown that the biological effects of TGF-β signaling pathway are highly cellular-context-dependent. In this thesis work, I aimed at understanding how TGF-β signaling can regulate target genes differently, how different dynamics of gene expressions are induced by TGF-β signal, and what is the role of Smad proteins in differing the profiles of target gene expression. In this study, I focused on the transcriptional responses to the Nodal/Activin ligand, which is a member of the TGF-β superfamily and a key regulator of early embryonic development. Kinetic models were developed and calibrated with the time course data of RNA polymerase II (Pol II) and Smad2 chromatin binding profiles for the target genes. Using the Akaike information criterion (AIC) to evaluate different kinetic models, we discovered that Nodal/Activin signaling regulates target genes via different mechanisms. In the Nodal/Activin-Smad2 signaling pathway, Smad2 plays different regulatory roles on different target genes. We show how Smad2 participates in regulating the transcription or degradation rate of each target gene separately. Moreover, a series of features that can predict the transcription dynamics of target genes are selected by logistic regression. The approach we present here provides quantitative relationships between transcription factor dynamics and transcriptional responses. This work also provides a general computational framework for studying the transcription regulations of other signaling pathways.
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Ibrahim, Christine. "Exploring the role of the activin A-ActRIIB pathway in sickle cell disease-associated nephropathy and sarcopenia : mechanistic insights and therapeutic potential." Electronic Thesis or Diss., Université Paris Cité, 2024. http://www.theses.fr/2024UNIP5287.
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La drépanocytose est une maladie génétique caractérisée par des crises vaso-occlusives récurrentes et des lésions multi-organes progressives, y compris des atteintes rénales et une perte musculaire, qui aggravent la morbidité et réduisent la qualité de vie des patients. Bien que les mécanismes sous-jacents de la néphropathie associée à la drépanocytose soient bien établis, les facteurs responsables de l'atrophie musculaire restent partiellement compris. Des données récentes suggèrent qu'Activine A, un membre de la superfamille TGF-β, joue un rôle significatif dans la fibrose et la progression des maladies rénales ainsi que dans l'atrophie musculaire. Cependant, son rôle dans les lésions musculaires et rénales associées à la drépanocytose reste à élucider. Cette étude explore le rôle de l'Activine A dans la perte musculaire et la néphropathie associées à la drépanocytose. Nous avons évalué la prévalence de la sarcopénie et les niveaux circulants d'Activine A chez des patients atteints de drépanocytose, et utilisé un modèle murin pour analyser la cinétique des lesions musculaire et rénale de la drépanocytose ainsi que l'implication de la voie Activine dans ces pathologies. Nos résultats confirment une prévalence importante de la sarcopénie chez les patients drépanocytaires, soulignant la nécessité de recherches ciblées sur la pathologie musculaire de la drépanocytose. Les patients et notre modèle murin ont montré des niveaux élevés d'Activine A dans la drépanocytose, soutenant l'hypothèse selon laquelle l'Activine A pourrait contribuer à la maladie rénale et à l'atrophie musculaire dans ce contexte. Chez les souris drépanocytaires, des altérations ultrastructurales, une atrophie des myofibres, une vascularisation réduite et une altération des cellules souches musculaires ont précédé les pathologies rénales détectables. L'inhibition pharmacologique de la voie de l'Activin A atténué les lésions musculaires et a montré des signes précoces d'amélioration rénale, suggérant qu'elle représente une cible thérapeutique prometteuse pour réduire les complications de la drépanocytoseSickle cell disease (SCD) is a genetic disorder marked by recurrent vaso-occlusive crises and progressive multi-organ damage, including kidney disease and muscle wasting, both of which worsen morbidity and reduce quality of life of affected patients. While the mechanisms underlying SCD-related kidney disease are well-established, the drivers of muscle atrophy remain incompletely understood. Emerging evidence suggests that Activin A, a member of the TGF-β superfamily, plays a significant role in both fibrosis and disease progression in kidney disease as well as muscle atrophy. However, its role in SCD-associated muscle and kidney damage has yet to be elucidated. This study investigates the role of Activin A in SCD-associated muscle wasting and kidney disease. We assessed sarcopenia prevalence and circulating Activin A levels in SCD patients and employed a murine model to analyse the temporal changes in muscle and kidney pathology as well as the involvement of Activin pathway in these pathologies. Our findings confirm that sarcopenia is prevalent among SCD patients, emphasizing the need for focused research on SCD muscle pathology. Both patient and murine models showed elevated Activin A levels in SCD, supporting the hypothesis that Activin A may contribute to kidney disease and muscle atrophy in this context. In SCD mice, ultrastructural alterations, myofiber atrophy, reduced vascularization, and impaired muscle stem cells preceded detectable kidney pathology. Pharmacological inhibition of Activin signalling pathway mitigated muscle damage and showed early signs of kidney improvement, suggesting it as a promising therapeutic target for SCD complications and patient outcomes enhancement
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Leon, Florian Luis Anthony. "Role of the Nodal Signaling pathway in amphioxus neural induction." Electronic Thesis or Diss., Sorbonne université, 2018. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2018SORUS151.pdf.
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L'induction neurale (IN) est le processus permettant aux cellules ectodermiques d’avoir un devenir de type neural. Chez les vertébrés, le centre organisateur produit des molécules antagonistes à BMP ainsi que d’autres signaux induisant le devenir neural. Ce processus n'est cependant pas entièrement compris chez les autres chordés. Notre équipe a démontré que l’amphioxus B. lanceolatum possède un centre organisateur fonctionnel ; que l'activation de la voie BMP induit le devenir épidermique de l'ectoderme et que son inhibition conduit à un état indifférencié, suggérant que l'inhibition de la voie BMP n'est pas suffisant à l'IN. De plus, l'inhibition de la voie FGF ne bloque pas l'IN, contrairement à ce qui est démontré chez d’autres chordés. Enfin, Nodal/Activine est capable d'activer l'IN et représente donc une signal clé dans ce processus chez l'amphioxus. Ici, nous avons identifié un groupe de régions régulatrices sensibles à l'activine par la technique d'ATAC-seq ; et trouvé des sites de liaison putatifs de facteurs de transcription dans ces régions. Nos résultats suggèrent donc que des facteurs de type « Zinc Finger », comme Klf1/2/4, peuvent avoir un rôle déterminant dans le développement neural. Ces résultats ont été confirmés par des analyses comparatives d'ARN-seq à plusieurs temps de développement et d’explants ectodermiques après activation de la voie NodalNeural induction (NI) is the process through which pluripotent ectodermal cells are committed to a neural fate. In vertebrates, the dorsal organizer produces BMP antagonists, and other signals that induce neural cell fate. However, not much was known about NI in other chordates. Our team previously shown that the cephalochordate B. lanceolatum presents a functional organizer, and that the acquisition of epidermal fate relies on BMP activation. However, deprivation of BMP signals leads to an undifferentiated state of the ectoderm, indicating that BMP inhibition is not sufficient for NI. Moreover, FGF signal inhibition does not block NI, in the contrary to what is observed in several chordate lineages, suggesting that FGF is not the key signal to induce neural fate in amphioxus. Remarkably, activation of the Nodal/Activin pathway triggers NI and represent an instructive signal in this process in amphioxus. In this work, we have identified a group of putative non-exonic regulatory regions which are Activin-sensitive, through ATAC-seq, and searched for potential transcription factors binding sites. Our results suggest that Zinc Finger-related factors, as Klf1/2/4, might be playing crucial roles in neural development. We have also confirmed these results though comparative RNA-seq analyse at several developmental time points in embryo and ectodermal explants after Nodal activation
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Saharinen, Pipsa. "Signaling through the Jak-Stat pathway : regulation of tyrosine kinase activity." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/saharinen/.
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Arngården, Linda. "Analysis of signaling pathway activity in single cells using the in situ Proximity Ligation Assay." Doctoral thesis, Uppsala universitet, Molekylära verktyg, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-281716.
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A cell that senses signals from its environment uses proteins for signal transduction via post translational modifications (PTMs) and protein- protein interactions (PPIs) from cell membrane into the nucleus where genes controlling cell proliferation, differentiation and apoptosis can be turned on or off, i.e. changing the phenotype or fate of the cell. Aberrations within such proteins are prone to cause diseases, such as cancer. Therefore, it is important so study aberrant signaling to be able to understand and treat diseases. In this thesis, signaling aberrations of PTMs and PPIs were analyzed with the use of the in situ proximity ligation assay (in situ PLA), and the thesis also contain method development of rolling circle amplification (RCA), which is the method used for signal amplification of in situ PLA reaction products. Paper I considers the integrity of RCA products. Here, the aim was to generate a smaller and more compact RCA product, for more accurate either visual or automated analysis. This was achieved with the use of an additional so called compaction oligonucleotide that during RCA was able to bind and pull segments of RCA products closer together. The compaction oligonucleotide served to increase the signal to noise ratio and decrease the number of false positive signals. The crosstalk between the Hippo and TGFβ signaling pathways were studied in paper II. Activity of the Hippo signaling pathway is regulated by cell density sensing and tissue control. We found differences in amounts and localization of interactions between the effector proteins of the two pathways depending on cell density and TGFβ stimulation. In paper III the NF-кB signaling pathway constitutively activated in chronic lymphocytic leukemia (CLL) was studied. A 4 base-pair frameshift deletion within the NFKBIE gene, which encodes the negative regulator IкBε, was found among 13 of a total 315 cases by the use of targeted deep sequencing. We found reduced levels of IкBε protein, decreased p65 inhibition, and increased phosphorylation, along with increased nuclear localization of p65 in NFKBIE deleted cases compared to healthy cases. Crosstalk between the Hippo and Wnt signaling pathway are studied within paper IV. Here, we found differences in cellular localization of TAZ/β-catenin interactions depending on colon cancer tumor stage and by further investigate Hippo/WNT crosstalk in cell line model systems we found an increase of complex formations involved in the crosstalk in sparse growing HEK293 cells compared to dense growing cells. Also, active WNT3a signaling was affected by cell density. Since cell density showed to have a big effect on Hippo/WNT crosstalk we continued to investigated the effect of E-cadherin, which has a function in cell junctions and maintenance of epithelial integrity on Hippo/WNT crosstalk. Interestingly, we found that E-cadherin is likely to regulate Hippo/WNT crosstalk.
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Montgomery, Lucy Theresa. "Investigations of ABA signalling pathways in stomatal guard cells." Thesis, Lancaster University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242895.
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Grocott, Timothy. "Regulation of Pax6 transcriptional activity by the Smad/TGF-β signalling pathway." Thesis, University of East Anglia, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436697.
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Gianella-Borradori, Matteo Luca. "The identification & optimisation of endogenous signalling pathway modulators." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:4c87de5d-24a7-4998-8edb-917c3922aae1.
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Chapter 1 Provides an overview of drug discovery with particular emphasis on library selection and hit identification methods using virtual based approaches. Chapter 2 Gives an outline of the bone morphogenetic protein (BMP) signalling pathway and literature BMP pathway modulators. The association between the regulation of BMP pathway and cardiomyogenesis is also described. Chapter 3 Describes the use of ligand based virtual screening to discover small molecule activators of the BMP signalling pathway. A robust cell based BMP responsive gene activity reporter assay was developed to test the libraries of small molecules selected. Hit molecules from the screen were synthesised to validate activity. It was found that a group of known histone deacetylase (HDAC) inhibitors displayed most promising activity. These were evaluated in a secondary assay measuring the expression of two BMP pathway regulated genes, hepcidin and Id1, using reverse transcription polymerase chain reaction (RT-PCR). 188 was discovered to increase expression of both BMP-responsive genes. Chapter 4 Provides an overview of existing cannabinoid receptor (CBR) modulating molecules and their connection to progression of atherosclerosis. Chapter 5 Outlines the identification and optimisation of selective small molecule agonists acting at the cannabinoid 2 receptor (CB2R). Ligand based virtual screen was undertaken and promising hits were synthesised to allow structure activity relationship (SAR) to be developed around the hit molecule providing further information of the functional groups tolerated at the active site. Subsequent studies led to the investigation and optimisation of physicochemical properties around 236 leading to the development of a suitable compound for in vivo testing. Finally, a CB2R selective compound with favourable physicochemical properties was evaluated in vivo in a murine inflammation model and displayed reduced recruitment of monocytes to the site of inflammation.
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Porchet, Nicolas. "Role of signaling pathays in cell-fate specification in the early mouse embryo." Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7096.
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Lors du développement précoce de l’embryon de souris, divers évènements de spécification des destins cellulaires induisent la formation du blastocyste pré-implantatoire. Ces évènements sont majoritairement contrôlés par l’action de voies de signalisation activées via la fixation de molécules signal à la membrane de la cellule. L’activité de ces voies de signalisation permet la régulation de la transcription de gènes cible responsable de l’acquisition d’une identité cellulaire et de son arrangement sous forme de tissu. Ici je m’intéresse aux rôles des voies ACTIVINE/NODAL et βCATENIN dans la spécification de ces identités cellulaires lors de la formation du blastocyste de sourisDuring the early mouse embryogenesis, cell-fate specification events result in the formation of the pre-implantation blastocyst. Those events are mainly regulated by the action of signaling cascades activated upon fixation of the signaling molecules at the cell membrane. The activity of these signaling pathways allow the transcriptional regulation of a specific pool of genes responsible for cell-fate decisions and the formation of tissues. Here, I am interested in the roles of both ACTIVIN/NODAL and βCATENIN signaling pathways in the specification of cell identities during the maturation of the mouse blastocyst
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Carlyle, Becky Catherine. "DISC1 & GSK3β modulate PDE4 activity : functional integration of psychiatric associated signalling pathways." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4823.
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Following the discovery of the DISC1 gene in 2000, subsequent research has led to DISC1 becoming one of the most promising candidate genes for psychiatric disorders. Acting as a scaffold protein, DISC1 has a large number of interacting proteins and is involved in a series of intracellular signalling pathways. Amongst these binding proteins are two enzymes, PDE4 and GSK3β, that were originally implicated in psychiatric disease by virtue of their inhibition by psychoactive drugs. PDE4 enzymes are inhibited by rolipram, which possesses anti-depressant and anti-psychotic activity, while GSK3β is one of the major targets of lithium, a potent mood stabiliser. Both these enzymes are intricately involved in the PI3K/AKT, cAMP, and MAPK signalling pathways, all of which have a number of downstream outcomes with potential relevance to psychiatric disorders. The Millar and Porteous laboratory had established that DISC1 modulates PDE4 activity, but this predated awareness of GSK3 as another DISC1 interactor whose binding site overlapped with that of PDE4. Since cAMP is a key regulator of signalling pathways in the brain, I hypothesised that not only DISC1, but also GSK3β may be involved in the regulation of PDE4 activity to control local cAMP levels and gradients. To investigate this hypothesis, I characterised SHSY5Y cells as a model for measuring PDE4 activity, and performed a series of genetic and pharmacological manipulations on this system. Inhibition of GSK3β resulted in a decrease of basal PDE4 activity that was amplified by DISC1 overexpression. Wild type cells that were treated with forskolin exhibited a significant increase in PDE4 activity, which was suppressed by GSK3β inhibition and both overexpression and knockdown of DISC1. Further experiments confirmed that none of these changes were a result of differences in PDE4 mRNA or protein expression. Thus I have provided evidence that suggests tonic activation of PDE4 by GSK3β and evidence for modulation of PDE4 activity by DISC1. I provide evidence for the localisation of PDE4B & PDE4D with key psychiatric associated receptors in structures resembling developing dendritic spines; furthermore, agonism of NMDA receptors results in a significant increase in PDE4 activity in primary neurons. These results are a simple demonstration of an emerging principle in psychiatric research: that none of the signalling pathways implicated in psychiatric disease are acting in isolation. There are likely to be multiple points of integration between these pathways, with the demonstrated DISC1-GSK3β-PDE4 interaction forming one of these points. My results add an important new element to the understanding of how the DISC1 complex may regulate intracellular signalling in response to extracellular cues.
Books on the topic "Activin signaling pathway"
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Takao, Kumazawa, Kruger Lawrence, and Mizumura Kazue, eds. The polymodal receptor: A gateway to pathological pain. Amsterdam: Elsevier, 1996.
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Fleischmann, Roy. Signalling pathway inhibitors. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0081.
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Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and SyK pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Tofacitinib is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2 while baricitinib (formerly INCB028050) predominantly inhibits JAK1/2. Many of the proinflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Fostamatinib disodium is an orally available inhibitor of spleen tyrosine kinase (SyK), which is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling may interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib has been investigated in multiple phase 2 and phase 3 trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα) and in patients who have failed TNFα inhibitors. The efficacy of fostamatinib and baricitinib has been investigated in phase 2 trials; both are in large phase 3 clinical programmes. Each of these medications has demonstrated efficacy; their safety profile has been shown to be different from each other and from currently approved biological agents. This chapter discusses what is currently known and understood about their efficacy and safety.
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D’Amato, Gaetano, Guillermo Luxán, and José Luis de la Pompa. Defining cardiac domains from the inside: NOTCH in endocardial–myocardial interactions. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0011.
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In this chapter we illustrate the signalling interactions of the endocardium with the other cardiac tissues to coordinate cardiac development. First, we describe the developmental origins of the endocardium. Then we focus on the Notch pathway because of its unique signalling activity in the endocardium, and briefly describe the elements of this signalling mechanism and the key cardiogenic processes that require endocardial Notch signalling: patterning of the early embryonic endocardium into prospective territories for valves and ventricular chambers, early valve formation, ventricular trabeculation, and compaction. Finally, we discuss how Notch dysfunction in the endocardium results in cardiac structural malformations that can lead to congenital heart disease.
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Hartman, Adam L. Amino Acids in the Treatment of Neurological Disorders. Edited by Dominic P. D’Agostino. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190497996.003.0035.
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Studies of metabolism- and diet-based therapies in epilepsy and neuroprotection have focused primarily on the quality and quantity of fat supplementation or carbohydrate restriction. However, protein is another key dietary component that has not been as thoroughly studied. A number of amino acids have been shown to stop, terminate, or prevent seizures. In addition, some have been shown to exert neuroprotective effects in other neurological disorders. Amino acids (and their metabolites) may exert their effects by acting at membrane or cytoplasmic receptors, serving as substrates for membrane transporters and as modulators of signaling pathway activity. This chapter highlights examples of each of these mechanisms of action in select nervous system disorders.
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Alves, Ines Teles, Jan Trapman, and Guido Jenster. Molecular biology of prostate cancer. Edited by James W. F. Catto. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199659579.003.0059.
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Prostate cancer is a heterogeneous disease that arises through the acquisition of key malignant hallmarks. At the molecular level, prostate tumours are dependent upon the androgen receptor pathway, which affects cell function, growth, and behaviour through downstream androgen-regulated genes. Prostate cancer requires this activity and manipulates the AR pathway to maintain signalling. For example, mutation of the AR (to bind ligands other than androgens) or amplification/duplication of the AR allows signalling to continue in the absence of testosterone. Around 50% of prostate cancers have a gene fusion between the androgen-regulated component of the TMPRSS2 gene and a transcription factor (e.g. ETS family members ERG and ETV1). This results in aberrant androgen stimulated cell growth. Current research is using molecular knowledge to identify biomarkers, such as PCA3, and new therapies, such as enzalutamide or abiraterone acetate.
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Patisaul, Heather B., and Scott M. Belcher. Receptor and Enzyme Mechanisms as Targets for Endocrine Disruptors. Oxford University Press, 2017. http://dx.doi.org/10.1093/acprof:oso/9780199935734.003.0005.
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In this chapter, the current understanding of the mechanisms of endocrine disruption on the brain and nervous system are presented. Because the overwhelming majority of mechanistic studies on EDCs have focused on the actions mediated by nuclear hormone receptors, this mechanisms is described in detail. The chapter also discusses the classic transcriptional mechanisms of steroid action and the impact of EDCs on rapid signaling (non-genomic) mechanisms. It presents an overview of the enzymes and pathways involved in the biosynthesis of steroid hormones, which are critical to proper functioning of the HPA and HPG axis, and the neuroactive steroids synthesized and active in the mammalian brain. The potential for EDCs to alter metabolic enzymes, with a focus on possible targets in the metabolic blood-brain barrier, is presented as a potential, though largely unexplored, mode of EDC action in the brain.
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Kühn, Wolfgang, and Gerd Walz. The molecular basis of ciliopathies and cyst formation. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0303.
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Abnormalities of the cilium, termed ‘ciliopathies’, are the prime suspect in the pathogenesis of renal cyst formation because the gene products of cystic disease-causing genes localize to them, or near them. However, we only partially understand how cilia maintain the geometry of kidney tubules, and how abnormal cilia lead to renal cysts, and the diverse range of diseases attributed to them. Some non-cystic diseases share pathology of the same structures. Although still incompletely understood, cilia appear to orient cells in response to extracellular cues to maintain the overall geometry of a tissue, thereby intersecting with the planar cell polarity (PCP) pathway and the actin cytoskeleton. The PCP pathway controls two morphogenetic programmes, oriented cell division (OCD) and convergent extension (CE) through cell intercalation that both seem to play a critical role in cyst formation. The two-hit theory of cystogenesis, by which loss of the second normal allele causes tubular epithelial cells to form kidney cysts, has been largely borne out. Additional hits and influences may better explain the rate of cyst formation and inter-individual differences in disease progression. Ciliary defects appear to converge on overlapping signalling modules, including mammalian target of rapamycin and cAMP pathways, which can be targeted to treat human cystic kidney disease irrespective of the underlying gene mutation.
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Lories, Rik J., and Georg Schett. Pathology: bone. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780198734444.003.0010.
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Axial spondyloarthritis is associated with different types of skeletal damage. Inflammation at the affected sites is linked with both loss of trabecular bone and new bone formation on the cortical side, potentially leading to joint or spine ankylosis. Both aspects of the disease can result in a significant burden for the patient. Bone loss is directly linked to proinflammatory cytokines and activation of osteoclasts. Control of inflammation is therefore the best strategy to prevent loss of bone. The nature of the new bone formation process is less defined. A prominent role for developmental signalling pathways has been proposed. Current therapies have limited or no impact on this process. However, emerging data suggest that early control of disease activity may be part of a window of opportunity to prevent structural damage, as biomechanical factors and instability following inflammation may also play a role.
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Noebels, Jeffrey L., Massimo Avoli, Michael A. Rogawski, Annamaria Vezzani, and Antonio V. Delgado-Escueta, eds. Jasper's Basic Mechanisms of the Epilepsies. 5th ed. Oxford University PressNew York, 2024. http://dx.doi.org/10.1093/med/9780197549469.001.0001.
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Abstract Unverricht-Lundborg disease (ULD; EPM1) is an inherited neurodegenerative disorder characterized by onset at 6–15 years, stimulus-sensitive, action-activated myoclonus, epilepsy, and progressive neurological deterioration. It is caused by biallelic pathogenic variants in the CSTB gene, encoding a cystatin B. The most common of these is an unstable expansion of a dodecamer repeat element in the promoter region of the gene, leading to marked downregulation of CSTB expression. Total loss of CSTB is associated with severe neonatal-onset encephalopathy. A cystatin B–deficient mouse models the EPM1 disease relatively well. Myoclonic seizures, preceded by microglial activation, develop at one month of age and are followed by progressive gray and white matter degeneration and motor problems. CSTB is an inhibitor of cysteine proteases of the cathepsin family showing both nuclear and cytoplasmic localization with partial co-localization with lysosomal markers. CSTB function has been linked to protecting neurons from oxidative damage through an oxidative stress-responsive cystatin B-cathepsin B signaling pathway. In the nucleus CSTB has been shown to participate in regulation of cell cycle, and histone H3 tail proteolytic cleavage. Downstream effects of CSTB dysfunction have also been implicated in apopotosis, microglial dysfunction, inflammation, neurogenesis and synapse physiology. Despite the progress made, the exact disease mechanisms in EPM1 remain elusive. This chapter discusses the clinical features of EPM1 and recent advances in understanding its pathophysiology.
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Vostral, Sharra L. Toxic Shock. NYU Press, 2018. http://dx.doi.org/10.18574/nyu/9781479877843.001.0001.
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In 1980, young, healthy women in the United States suddenly began to get sick and even die. The unexpected link to these deaths was superabsorbent tampons. Thousands of women used them during their menstrual periods, signaling the potential for a large-scale outbreak. Toxic Shock: A Social History traces the emergence of this new illness of toxic shock syndrome (TSS) and its relationship to tampon technology. This multifaceted history engages microbiology, design and innovation, journalism and mass communication, product liability, and federal policy and regulation. The broad scope captures the various approaches that contributed to defining meaning about the emergent illness. Vostral argues that tampon-related TSS was a paradigm shift in the way that illness manifests. No longer was an infection necessarily the origin of disease, or a faulty product the direct cause of injury. Together, a new pathway to an illness formed, in which a supposedly inert tampon became interactive, and a bacterium once in equilibrium grew dominant and produced toxins. Toxic Shock: A Social History makes a case for understanding tampon-related TSS as the result of biocatalytic activity between technology and bacterium. Moreover, though women were the primary consumers of tampons, the bacterium became the unintended users. This unusual disease process challenged standard approaches to public health, required women to evaluate technological risk, and currently serves as a harbinger about other internal medical devices used and worn within the human body.
Book chapters on the topic "Activin signaling pathway"
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Scheper, Gert C., Roel Van Wijk, and Adri A. M. Thomas. "Regulation of the Activity of Eukaryotic Initiation Factors in Stressed Cells." In Signaling Pathways for Translation, 39–56. Berlin, Heidelberg: Springer Berlin Heidelberg, 2001. http://dx.doi.org/10.1007/978-3-662-09889-9_2.
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Watabe, Tetsuro, Albert F. Candia, and Ken W. Y. Cho. "Activin Signaling Pathways and Their Role in Xenopus Mesoderm Formation." In Inhibin, Activin and Follistatin, 244–53. New York, NY: Springer New York, 1997. http://dx.doi.org/10.1007/978-1-4612-1874-6_23.
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Steffen, Anika, Theresia E. B. Stradal, and Klemens Rottner. "Signalling Pathways Controlling Cellular Actin Organization." In The Actin Cytoskeleton, 153–78. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/164_2016_35.
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Goldstein, Barry J., Faiyaz Ahmad, Wendi Ding, Pei-Ming Li, and Wei-Ren Zhang. "Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases." In Insulin Action, 91–99. Boston, MA: Springer US, 1998. http://dx.doi.org/10.1007/978-1-4615-5647-3_10.
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Schuller, Hildegard M. "Neurotransmitter Receptor-Mediated Signaling Pathways as Modulators of Carcinogenesis." In Neuronal Activity in Tumor Tissue, 45–63. Basel: KARGER, 2007. http://dx.doi.org/10.1159/000100045.
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Tanner, Matthew J., Elina Levina, Michael Shtutman, Mengqian Chen, Patrice Ohouo, and Ralph Buttyan. "Unique Effects of Wnt Signaling on Prostate Cancer Cells: Modulation of the Androgen Signaling Pathway by Interactions of the Androgen Receptor Gene and Protein with Key Components of the Canonical Wnt Signaling Pathway." In Androgen Action in Prostate Cancer, 569–86. New York, NY: Springer US, 2009. http://dx.doi.org/10.1007/978-0-387-69179-4_24.
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Sanders, Dale, Gethyn J. Allen, Shelagh R. Muir, and Stephen K. Roberts. "Integration of Ion Channel Activity in Calcium Signalling Pathways." In Cellular Integration of Signalling Pathways in Plant Development, 47–58. Berlin, Heidelberg: Springer Berlin Heidelberg, 1998. http://dx.doi.org/10.1007/978-3-642-72117-5_5.
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Otto, C., S. Wessler, and K. H. Fritzemeier. "Exploiting Nongenomic Estrogen Receptor-Mediated Signaling for the Development of Pathway-Selective Estrogen Receptor Ligands." In Tissue-Specific Estrogen Action, 163–81. Berlin, Heidelberg: Springer Berlin Heidelberg, 2007. http://dx.doi.org/10.1007/2789_2006_022.
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Fantus, I. George, and Evangelia Tsiani. "Multifunctional actions of vanadium compounds on insulin signaling pathways: Evidence for preferential enhancement of metabolic versus mitogenic effects." In Insulin Action, 109–19. Boston, MA: Springer US, 1998. http://dx.doi.org/10.1007/978-1-4615-5647-3_12.
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Razani, Bahram, Arash Shahangian, Beichu Guo, and Genhong Cheng. "Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity." In Cellular Signaling and Innate Immune Responses to RNA Virus Infections, 155–75. Washington, DC, USA: ASM Press, 2014. http://dx.doi.org/10.1128/9781555815561.ch11.
Full textConference papers on the topic "Activin signaling pathway"
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Qiu, Wanglong, Sophia Tang, Sohyae Lee, Andrew T. Turk, Anthony Sireci, Anne Qiu, Ralph H. Hruban, Helen E. Remotti, and Gloria H. Su. "Abstract 2735: Inactivation of activin signaling pathway accelerates the development of pancreatic intraductal papillary mucinous neoplasms in vivo." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2735.
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Parchaykina, M. V., I. D. Molchanov, E. V. Chudaikina, T. P. Kuzmenko, E. S. Revina, A. V. Zavarykina, M. A. Simakova, and V. V. Revin. "THE ROLE OF LIPID METABOLITES IN THE REGULATION OF REGENERATIVE PROCESSES IN DAMAGED SOMATIC NERVES." In XI МЕЖДУНАРОДНАЯ КОНФЕРЕНЦИЯ МОЛОДЫХ УЧЕНЫХ: БИОИНФОРМАТИКОВ, БИОТЕХНОЛОГОВ, БИОФИЗИКОВ, ВИРУСОЛОГОВ, МОЛЕКУЛЯРНЫХ БИОЛОГОВ И СПЕЦИАЛИСТОВ ФУНДАМЕНТАЛЬНОЙ МЕДИЦИНЫ. IPC NSU, 2024. https://doi.org/10.25205/978-5-4437-1691-6-266.
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Under the action of various physiologically active substances, lipid metabolites in the damaged nerve trigger key signaling cascades that are responsible for the regeneration of damaged somatic nerves. Activation of this pathway leads to the regulation of many biological processes such as cell migration, proliferation, differentiation and apoptosis.
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Dereli-Korkut, Zeynep, and Sihong Wang. "Microfluidic Cell Arrays to Mimic 3D Tissue Microenvironment." In ASME 2012 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/sbc2012-80411.
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We developed a functional high throughput 3D microfluidic living cell array (MLC) for anti-cancer drug screening and mechanism discovery. Contemporary drug screening methods suffer from low sample throughput and lack of abilities of mimicking the 3D microenvironment of mammalian tissues. The poor performance of anti-cancer drugs limits the efficacy at controlling the complex disease system like cancer. Systematic studies of apoptotic signaling pathways can be prominent approaches for searching active and effective treatments with less drug resistance. Hence, innovative bio-devices are needed to represent tumor microenvironment to understand the molecular signatures of apoptosis for testing new anticancer therapies targeting apoptosis. Our novel 3D MLC design is the prototype of a high-throughput drug screening platform targeting apoptotic signaling pathways.
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Penninger, Charles L., Andre´s Tovar, Glen L. Niebur, and John E. Renaud. "Signaling Pathways for Bone Resorption Predicted as a Hybrid Cellular Automaton Process." In ASME 2010 International Mechanical Engineering Congress and Exposition. ASMEDC, 2010. http://dx.doi.org/10.1115/imece2010-39358.
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The bone remodeling process provides for various functions such as mineral homeostasis, damage repair, and adaptation to mechanical loading. At present, a clear link between the mechanical stimulation of bones and the biochemical response is not fully understood. Computational simulations can provide a means to test hypotheses and gain insight into processes that are difficult to examine experimentally. The objective of this work is to predict the effect of damage and strain as the stimulus for regulating the cellular signaling activity of remodeling. In this study, potential signaling pathways that mediate this cellular activity were incorporated in a hybrid cellular automaton (HCA) algorithm. Biological rules were implemented in this model to control recruitment, differentiation, and activation of osteoclasts. Prominent processes for describing recruitment and inhibition of the bone cells, as reported from experimental studies, are utilized. This work focuses on the resorption of a damaged site on a trabecular strut.
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Joiner, Danese M., Bryan T. MacDonald, Xi He, Peter V. Hauschka, and Steven A. Goldstein. "Reduction of the Wnt Inhibitor Dkk1 Correlates With Improved Bone Mechanical and Morphological Properties in Mice." In ASME 2007 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2007. http://dx.doi.org/10.1115/sbc2007-175478.
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The Wnt/β-Catenin signaling pathway is a key regulator in bone development and bone homeostasis. Inactivating mutations in the Wnt co-receptor Low density lipoprotein Receptor related Protein 5 (LRP5) results in osteoporosis while “activating” mutations in LRP5 results in high bone mass. Dickkopf-1 (Dkk1) is a secreted Wnt inhibitor that binds to LRP5 and LRP6 reducing their availability to form a complex with Wnt and Frizzled and resulting in unrestrained Wnt signaling. It is expected that a decrease in Dkk1 will result in an increase in Wnt activity and ultimately a high bone mass phenotype. An allelic series of Dkk1 mutant mice were generated to examine the affects of reduced Dkk1 levels on bone density, morphology, and mechanical properties.
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Parchaykina, M. V., T. P. Kuzmenko, E. P. Popkov, A. V. Zavarykina, N. E. Arzhanov, and V. V. Revin. "STUDY OF THE EFFECT OF CLOBETASOL ON CHANGES IN THE CONTENT OF NERVE GROWTH FACTOR AND THE FUNCTIONAL ACTIVITY OF DAMAGED SOMATIC NERVES." In X Международная конференция молодых ученых: биоинформатиков, биотехнологов, биофизиков, вирусологов и молекулярных биологов — 2023. Novosibirsk State University, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-202.
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In the course of the studies, it was shown that the use of clobetasol is accompanied by an increase in the content of nerve growth factor and total protein, as well as the restoration of the conductivity of nerve fibers, which indicates its participation in the launch of regenerative signaling pathways responsible for the activation of protein synthesis and the restoration of the functional activity of injured somatic nerves.
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Parkins, Sharon, Lisa c. Green, Sarah Anthony, Adrienne R. Guarnieri, Shannon M. Shearer, Onur Kanisicak, Albert P. Owens, and Michael Tranter. "Wnt1-Inducible Signaling Pathway Protein-1 (WISP1) Modulation of Cardiac Fibroblasts Activity." In ASPET 2024 Annual Meeting Abstract. American Society for Pharmacology and Experimental Therapeutics, 2024. http://dx.doi.org/10.1124/jpet.269.989080.
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Asyakina, A. S., and K. I. Melkonyan. "THE ROLE OF THE MATRICELLULAR PROTEIN PERIOSTIN ON THE EFFICIENCY OF CULTURING MAMMALIAN CELLS." In XI МЕЖДУНАРОДНАЯ КОНФЕРЕНЦИЯ МОЛОДЫХ УЧЕНЫХ: БИОИНФОРМАТИКОВ, БИОТЕХНОЛОГОВ, БИОФИЗИКОВ, ВИРУСОЛОГОВ, МОЛЕКУЛЯРНЫХ БИОЛОГОВ И СПЕЦИАЛИСТОВ ФУНДАМЕНТАЛЬНОЙ МЕДИЦИНЫ. IPC NSU, 2024. https://doi.org/10.25205/978-5-4437-1691-6-298.
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The work presents the effect of the periostin protein on the proliferative activity of a fibroblast cell culture. The increase in cell number upon interaction with periostin suggests that the protein activates specific signaling pathways that promote cell division and increase cell viability. This is important in cell therapy, where it is necessary to obtain sufficient numbers of cells for use. Increasing the efficiency of culturing autologous cells using periostin opens up new perspective for their use in regenerative medicine.
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Erickson, Geoffrey R., and Farshid Guilak. "Osmotic Stress Initiates Intracellular Calcium Waves in Chondrocytes Through Extracellular Influx and the Inositol Phosphate Pathway." In ASME 1999 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 1999. http://dx.doi.org/10.1115/imece1999-0580.
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Abstract The biophysical environment of the chondrocytes plays an important role in the health, turnover, and homeostasis of articular cartilage. Under normal physiologic loading, chondrocytes are exposed to a complex and diverse array of biophysical signals, including mechanical and osmotic stresses, fluid flow, and fluid pressures [4]. Due to the charged and hydrated nature of the extracellular matrix, mechanical compression causes exudation of interstitial fluid in cartilage, which alters the osmotic environment of the chondrocytes. Confocal microscopy studies have shown that chondrocytes lose or gain volume in response to tissue compression [4] or changes in extracellular osmolarity [3]. The active process of volume recovery subsequent to osmotic shock has been shown to initiate intracellular signaling cascades [2], which may in turn alter cellular metabolism [6]. Although the mechanisms of intracellular signaling in response to osmotic stress are not fully understood, it has been hypothesized that intracellular transients and oscillations of calcium ion (Ca2+) are involved. The objective of this study was to examine the hypothesis that osmotic stress initiates a transient increase in the concentration of intracellular calcium ion ([Ca2+]i), and to determine the mechanisms of Ca2+ mobilization in isolated chondrocytes exposed to hypo- and hyper-osmotic stress.
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Warren, Janine S. A., Emily Norton, and John M. Lamar. "Abstract A41: Inhibition of aberrant YAP and TAZ activity to prevent metastasis formation and growth." In Abstracts: AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; May 8-11, 2019; San Diego, CA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1557-3125.hippo19-a41.
Full textReports on the topic "Activin signaling pathway"
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Yompakdee, Chulee, and Warintorn Chavasiri. An active compound Kempferia parviflora with inhibitory activity against GSK-3 kinase implicated in type II Diabetes and Alzheimer's disease. Chulalongkorn University, 2015. https://doi.org/10.58837/chula.res.2015.37.
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Calcium signaling pathways play pivotal roles in regulation of various important biological processes in eukaryotes ranging from yeast to human. Because of the high degree in gene conservation from yeast to human, the small molecule inhibitors discovered in the yeast based-drug screening system can be expected to exert their function in human as well. The immunosuppressive agents, FK506 and cyclosporine A, are an example. Our previous studies using a zds1 yeast-based assay to search for inhibitors in the calcium signaling pathway in Saccharomyces cerevisae mutant strain from the crude extract of Thai medicinal plants found the crude extract of Kaempferia parviflora as one of the strong positive candidates. Using zds1 proliferation assay to guide fractionation and purification, a compound 5-hydroxy-3,7-dimethoxyflavone (here designated as Cpd1) was obtained and showed inhibitory activity against the calcium signals in yeast. This study aimed to learn more on its biological activity related to the calcium signal inhibition. Genetic and biochemical analyses in yeast revealed that Mck1 kinase, a protein in the calcium signaling pathway was inhibited by Cpd1. Yeast MCK1 is an ortholog gene coding for GSK3β. High level of GSK3β causes several pathogenesis including type II Diabetes and Alzheimer’s disease. In addition, Cpd1 showed no cytotoxicity to the yeast cells.
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Friedman, Haya, Julia Vrebalov, and James Giovannoni. Elucidating the ripening signaling pathway in banana for improved fruit quality, shelf-life and food security. United States Department of Agriculture, October 2014. http://dx.doi.org/10.32747/2014.7594401.bard.
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Background : Banana being a monocot and having distinct peel and pulp tissues is unique among the fleshy fruits and hence can provide a more comprehensive understanding of fruit ripening. Our previous research which translated ripening discoveries from tomato, led to the identification of six banana fruit-associated MADS-box genes, and we confirmed the positive role of MaMADS1/2 in banana ripening. The overall goal was to further elucidate the banana ripening signaling pathway as mediated by MADS-boxtranscriptional regulators. Specific objectives were: 1) characterize transcriptional profiles and quality of MaMADS1/2 repressed fruit; 2) reveal the role of additional MaMADSgenes in ripening; 3) develop a model of fruit MaMADS-box mode of action; and 4) isolate new components of the banana ripening signaling pathway. Major conclusion: The functions of the banana MaMADS1-5 have been examined by complimenting the rinor the TAGL1-suppressed lines of tomato. Only MaMADS5 exhibited partial complementation of TAGL1-suppressed and rinlines, suggesting that while similar genes play corresponding roles in ripening, evolutionary divergence makes heterologous complementation studies challenging. Nevertheless, the partial complementation of tomato TAGL1-surpessed and rinlines with MaMADS5 suggests this gene is likely an important ripening regulator in banana, worthy of further study. RNA-seqtranscriptome analysis during ripening was performed on WT and MaMADS2-suppressed lines revealing additional candidate genes contributing to ripening control mechanisms. In summary, we discovered 39 MaMADS-box genes in addition to homologues of CNR, NOR and HB-1 expressed in banana fruits, and which were shown in tomato to play necessary roles in ripening. For most of these genes the expression in peel and pulp was similar. However, a number of key genes were differentially expressed between these tissues indicating that the regulatory components which are active in peel and pulp include both common and tissue-specific regulatory systems, a distinction as compared to the more uniform tomato fruit pericarp. Because plant hormones are well documented to affect fruit ripening, the expressions of genes within the auxin, gibberellin, abscisic acid, jasmonic acid, salicylic and ethylene signal transduction and synthesis pathways were targeted in our transcriptome analysis. Genes’ expression associated with these pathways generally declined during normal ripening in both peel and pulp, excluding cytokinin and ethylene, and this decline was delayed in MaMADS2-suppressed banana lines. Hence, we suggest that normal MaMADS2 activity promotes the observed downward expression within these non-ethylene pathways (especially in the pulp), thus enabling ripening progression. In contrast, the expressions of ACSand ACOof the ethylene biosynthesis pathway increase in peel and pulp during ripening and are delayed/inhibited in the transgenic bananas, explaining the reduced ethylene production of MaMADS2-suppressed lines. Inferred by the different genes’ expression in peel and pulp of the gibberellins, salicylic acid and cytokinins pathways, it is suggested that hormonal regulation in these tissues is diverse. These results provide important insights into possible avenues of ripening control in the diverse fruit tissues of banana which was not previously revealed in other ripening systems. As such, our transcriptome analysis of WT and ripening delayed banana mutants provides a starting point for further characterization of ripening. In this study we also developed novel evidence that the cytoskeleton may have a positive role in ripening as components of this pathway were down-regulated by MaMADS2 suppression. The mode of cytoskeleton involvement in fruit ripening remains unclear but presents a novel new frontier in ripening investigations. In summary, this project yielded functional understanding of the role and mode of action of MaMADS2 during ripening, pointing to both induction of ethylene and suppression of non-ethylene hormonal singling pathways. Furthermore, our data suggest important roles for cytoskeleton components and MaMADS5 in the overall banana ripening control network. Implications: The project revealed new molecular components/genes involved in banana ripening and refines our understanding of ripening responses in the peel and pulp tissues of this important species. This information is novel as compared to that derived from the more uniform carpel tissues of other highly studied ripening systems including tomato and grape. The work provides specific target genes for potential modification through genetic engineering or for exploration of useful genetic diversity in traditional breeding. The results from the project might point toward improved methods or new treatments to improve banana fruit storage and quality.
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Li, Shaoguang. A BCR-ABL Kinase Activity-Independent Signaling Pathway in Chronic Myelogenous Leukemia. Fort Belvoir, VA: Defense Technical Information Center, February 2007. http://dx.doi.org/10.21236/ada468056.
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Li, Shaoguang. A BCR-ABL Kinase Activity-Independent Signaling Pathway in Chronic Myelogenous Leukemia. Fort Belvoir, VA: Defense Technical Information Center, February 2008. http://dx.doi.org/10.21236/ada482344.
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Barash, Itamar, and Robert Rhoads. Translational Mechanisms Governing Milk Protein Levels and Composition. United States Department of Agriculture, 2006. http://dx.doi.org/10.32747/2006.7696526.bard.
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Original objectives: The long-term goal of the research is to achieve higher protein content in the milk of ruminants by modulating the translational apparatus of the mammary gland genetically, nutritionally, or pharmacologically. The short-term objectives are to obtain a better understanding of 1) the role of amino acids (AA) as regulators of translation in bovine and mouse mammary epithelial cells and 2) the mechanism responsible for the synergistic enhancement of milk-protein mRNA polyadenylation by insulin and prolactin. Background of the topic: In many cell types and tissues, individual AA affect a signaling pathway which parallels the insulin pathway to modulate rates and levels of protein synthesis. Diverse nutritional and hormonal conditions are funneled to mTOR, a multidomain serine/threonine kinase that regulates a number of components in the initiation and elongation stages of translation. The mechanism by which AA signal mTOR is largely unknown. During the current grant period, we have studied the effect of essential AA on mechanisms involved in protein synthesis in differentiated mammary epithelial cells cultured under lactogenic conditions. We also studied lactogenic hormone regulation of milk protein synthesis in differentiated mammary epithelial cells. In the first BARD grant (2000-03), we discovered a novel mechanism for mRNA-specific hormone-regulated translation, namely, that the combination of insulin plus prolactin causes cytoplasmic polyadenylation of milk protein mRNAs, which leads to their efficient translation. In the current BARD grant, we have pursued the signaling pathways of this novel hormone action. Major conclusions/solutions/achievements: The positive and negative signaling from AA to the mTOR pathway, combined with modulation of insulin sensitization, mediates the synthesis rates of total and specific milk proteins in mammary epithelial cells. The current in vitro study revealed cryptic negative effects of Lys, His, and Thr on cellular mechanisms regulating translation initiation and protein synthesis in mammary epithelial cells that could not be detected by conventional in vivo analyses. We also showed that a signaling pathway involving Jak2 and Stat5, previously shown to lead from the prolactin receptor to transcription of milk protein genes, is also used for cytoplasmic polyadenylation of milk protein mRNAs, thereby stabilizing these mRNAs and activating them for translation. Implications: In vivo, plasma AA levels are affected by nutritional and hormonal effects as well as by conditions of exercise and stress. The amplitude in plasma AA levels resembles that applied in the current in vitro study. Thus, by changing plasma AA levels in the epithelial cell microenvironment or by sensitizing the mTOR pathway to their presence, it should be possible to modulate the rate of milk protein synthesis. Furthermore, knowledge that phosphorylation of Stat5 is required for enhanced milk protein synthesis in response to lactogenic opens the possibility for pharmacologic approaches to increase the phosphorylation of Stat5 and, thereby, milk protein production.
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Yi, Ping. The Regulation of Nuclear Receptor Coactivator SRC-3 Activity Through Membrane Receptor Mediated Signaling Pathways. Fort Belvoir, VA: Defense Technical Information Center, May 2005. http://dx.doi.org/10.21236/ada460836.
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Moran, Nava, Richard Crain, and Wolf-Dieter Reiter. Regulation by Light of Plant Potassium Uptake through K Channels: Biochemical, Physiological and Biophysical Study. United States Department of Agriculture, September 1995. http://dx.doi.org/10.32747/1995.7571356.bard.
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The swelling of plant motor cells is regulated by various signals with almost unknown mediators. One of the obligatory steps in the signaling cascade is the activation of K+-influx channels -K+ channels activated by hyperpolarization (KH channels). We thus explored the regulation of these channels in our model system, motor cell protoplasts from Samanea saman, using patch-clamp in the "whole cell" configuration. (a) The most novel finding was that the activity of KH channels in situ varied with the time of the day, in positive correlation with cell swelling: in Extensor cells KH channels were active in the earlier part of the day, while in Flexor cells only during the later part of the day; (b) High internal pH promoted the activity of these channels in Extensor cells, opposite to the behavior of the equivalent channels in guard cells, but in conformity with the predicted behavior of the putative KH channel, cloned from S. saman recently; (c) HIgh external K+ concentration increased (KH channel currents in Flexor cells. BL depolarized the Flexor cells, as detected in cell-attached patch-clamp recording, using KD channels (the K+-efflux channels) as "voltage-sensing devices". Subsequent Red-Light (RL) pulse followed by Darkness, hyperpolarized the cell. We attribute these changes to the inhibition of the H+-pump by BL and its reactivation by RL, as they were abolished by an H+-pump inhibitor. BL increased also the activity KD channels, in a voltage-independent manner - in all probability by an independent signaling pathway. Blue-Light (BL), which stimulates shrinking of Flexor cells, evoked the IP3 signaling cascade (detected directly by IP3 binding assay), known to mobilize cytosolic Ca2+. Nevertheless, cytosolic Ca2+ . did not activate the KD channel in excised, inside-out patches. In this study we established a close functional similarity of the KD channels between Flexor and Extensior cells. Thus the differences in their responses must stem from different links to signaling in both cell types.
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Olszewski, Neil, and David Weiss. Role of Serine/Threonine O-GlcNAc Modifications in Signaling Networks. United States Department of Agriculture, September 2010. http://dx.doi.org/10.32747/2010.7696544.bard.
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Significant evidence suggests that serine/threonine-O-linked N-acetyl glucosamine0-(GlcNAc) modifications play a central role in the regulation of plant signaling networks. Forexample, mutations in SPINDLY,) SPY (an O-GlcNAc transferase,) OGT (promote gibberellin GA) (signal transduction and inhibit cytokinin responses. In addition, mutating both Arabidopsis OGTsSEC (and SPY) causes embryo lethality. The long-term goal of this research is to elucidate the mechanism by which Arabidopsis OGTs regulate signaling networks. This project investigated the mechanisms of O-GlcNAc regulation of cytokinin and gibberellin signaling, identified additional processes regulated by this modification and investigated the regulation of SEC activity. Although SPY is a nucleocytoplasmic protein, its site of action and targets were unknown. Severalstudies suggested that SPY acted in the nucleus where it modified nuclear components such as the DELLA proteins. Using chimeric GFP-SPY fused to a nuclear-export signal or to a nuclear-import signal, we showed that cytosolic, but not nuclear SPY, regulated cytokinin and GA signaling. We also obtained evidence suggesting that GA and SPY affect cytokinin signaling via a DELLA-independent pathway. Although SEC and SPY were believed to have overlapping functions, the role of SEC in cytokinin and GA signaling was unclear. The role of SEC in cytokinin and GA responses was investigated by partially suppressing SPY expression in secplants using a synthetic Spymicro RNA miR(SPY). The possible contribution of SEC to the regulation of GA and cytokinin signaling wastest by determining the resistance of the miR spy secplants to the GA biosynthesis inhibitor paclobutrazol and to cytokinin. We found that the transgenic plants were resistant to paclobutrazol and to cytokinin, butonlyata level similar to spy. Moreover, expressing SEC under the 35S promoter in spy mutant did not complement the spy mutation. Therefore, we believe that SEC does not act with SPY to regulate GA or cytokinin responses. The cellular targets of Spy are largely unknown. We identified the transcription factor TCP15 in a two-hybrid screen for SPY-interacting proteins and showed that both TCP15 and its closely homolog TCP14 were O-GlcNAc modified by bacterially-produced SEC. The significance of the interaction between SPY and these TCPs was examined by over-expressing the minwild-type and spy-4plants. Overexpression of TCP14 or TCP15 in wild-type background produced phenotypes typical of plants with increased cytokinin and reduced GA signaling. TCP14 overexpression phenotypes were strongly suppressed in the spy background, suggesting that TCP14 and TCP15 affect cytokinin and GA signaling and that SPY activates them. In agreement with this hypothesis, we created a tcp14tcp15 double mutant and found that it has defects similar to spyplants. In animals, O-GlcNAc modification is proposed to regulate the activity of the nuclear pore. Therefore, after discovering that SEC modified a nucleoporinNUP) (that also interacts with SPY, we performed genetic experiments exploring the relationship between NUPs and SPY nupspy double mutants exhibited phenotypes consistent with SPY and NUPs functioning in common processes and nupseeds were resistant to GA biosynthesis inhibitors. All eukaryotic OGTs have a TPR domain. Deletion studies with bacterially-expressed SEC demonstrated SEC'sTPR domain inhibits SEC enzymatic activity. Since the TPR domain interacts with other proteins, we propose that regulatory proteins regulate OGT activity by binding and modulating the inhibitory activity of the TPR domain.
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Chamovitz, A. Daniel, and Georg Jander. Genetic and biochemical analysis of glucosinolate breakdown: The effects of indole-3-carbinol on plant physiology and development. United States Department of Agriculture, January 2012. http://dx.doi.org/10.32747/2012.7597917.bard.
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Genetic and biochemical analysis of glucosinolate breakdown: The effects of indole-3-carbinol on plant physiology and development Glucosinolates are a class of defense-related secondary metabolites found in all crucifers, including important oilseed and vegetable crops in the Brassica genus and the well-studied model plant Arabidopsis thaliana. Upon tissue damage, such as that provided by insect feeding, glucosinolates are subjected to catalysis and spontaneous degradation to form a variety of breakdown products. These breakdown products typically have a deterrent effect on generalist herbivores. Glucosinolate breakdown products also contribute to the anti-carcinogenic effects of eating cabbage, broccoli and related cruciferous vegetables. Indole-3-carbinol, a breakdown product of indol-3-ylmethylglucosinolate, forms conjugates with several other plant metabolites. Although some indole-3-carbinol conjugates have known functions in defense against herbivores and pathogens, most play as yet unidentified roles in plant metabolism, and possibly also plant development. At the outset, our proposal had three main hypotheses: (1) There is a specific detoxification pathway for indole-3-carbinol; (2) Metabolites derived from indole-3-carbinol are phloem-mobile and serve as signaling molecules; and (3) Indole-3-carbinol affects plant cell cycle and cell-differentiation pathways. The experiments were designed to enable us to elucidate how indole-3-carbinol and related metabolites affect plants and their interactions with herbivorous insects. We discovered that indole-3- carbinol rapidly and reversibly inhibits root elongation in a dose-dependent manner, and that this inhibition is accompanied by a loss of auxin activity in the root meristem. A direct interaction between indole-3-carbinol and the auxin perception machinery was suggested, as application of indole-3-carbinol rescued auxin-induced root phenotypes. In vitro and yeast-based protein interaction studies showed that indole-3-carbinol perturbs the auxin-dependent interaction of TIR1 with Aux/IAA proteins, supporting the notion that indole-3-carbinol acts as an auxin antagonist. Furthermore, transcript profiling experiments revealed the influence of indole-3-carbinol on auxin signaling in root tips, and indole-3-carbinol also affected auxin transporters. Brief treatment with indole-3-carbinol led to a reduction in the amount of PIN1 and to mislocalization of PIN2. The results indicate that chemicals induced by herbivory, such as indole-3-carbinol, function not only to repel herbivores, but also as signaling molecules that directly compete with auxin to fine tune plant growth and development, which implies transport of indole-3- carbinol that we are as yet unsuccessful in detecting. Our results indicate that plant defensive metabolites also have secondary functions in regulating aspects of plant metabolism, thereby providing diversity in defense-related plant signaling pathways. Such diversity of of signaling by defensive metabolites would be beneficial for the plant, as herbivores and pathogens would be less likely to mount effective countermeasures. We propose that growth arrest can be mediated directly by the herbivory-induced chemicals, in our case, indole-3-carbinol. Thus, glucosinolate breakdown to I3C following herbivory would have two outcomes: (1) Indole-3-carbinaol would inhibit the herbivore, while (2) at the same time inducing growth arrest within the plant. Thus, our results indicate that I3C is a defensive phytohormone that modulates auxin signaling, leading to growth arrest.
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Bromberg, Michael. Targeting the Tissue Factor-Factor VIIa Signaling Pathway to Enhance Activity of mTOR Inhibitors in the Treatment of Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, September 2009. http://dx.doi.org/10.21236/ada526533.
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