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Rudin-Brown, Christina M., Darlene Roosenboom, and Clayton Finch-Field. "Railway Human Factors and Operational Issues." Transportation Research Record: Journal of the Transportation Research Board 2608, no. 1 (January 2017): 1–9. http://dx.doi.org/10.3141/2608-01.
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The widespread availability and affordability of voice and video recording systems allows researchers in all modes of transportation to observe, document, and study operator behavior. For example, naturalistic driving studies use technology to record discreetly everyday vehicle operations and driver behavior to understand the risk factors that contribute to unsafe situations. It has been proposed that similar technology could be used in locomotives to observe and evaluate the crew's use of controls and human factor issues. The joint (government–industry) Locomotive Voice and Video Recording (LVVR) project was convened to assess LVVR technology, document safety benefits, and identify best practices. An evaluation of safety-relevant human factors and operational issues was conducted to determine the adequacy of three types of recording systems (voice only, video only, and voice and video) to record and document locomotive crew behavior. All the LVVR systems that were evaluated, regardless of mode, allowed the identification of crews’ responses to train control signals. Although it was often possible to identify operators’ roles in the cab and their use of locomotive controls, evaluation of human factor issues—such as crew resource management, stress, fatigue, workload, situation awareness, and distraction—was less reliable. Recording modality and system-specific issues that limit the use of LVVR were identified. Collectively, the results indicate that LVVR systems that collect voice and video data and that are of sufficient technical quality to provide clear, unambiguous recordings are the most conducive to the assessment of crew operational and human factor issues.
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Shuldeshov, E. M., I. A. Nazarov, M. S. Ivanov, and I. N. Donskih. "DECORATIVELY FINISHING MATERIALS FOR WALL PANELS OF PASSENGER CAB AND THE CREW COCKPIT OF AIR VEHICLES (review)." Proceedings of VIAM, no. 11 (2020): 38–47. http://dx.doi.org/10.18577/2307-6046-2020-0-11-38-47.
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Questions of development of decorative and finishing materials for wall panels of passenger cab and the crew cockpit of air vehicles in the Russian Federation and abroad are considered. The structure and structure of such materials are described, examples of implementation of their different options are given. The main ways of manufacturing of materials, and also requirements to them which performance is necessary for the admission to application in aviation engineering, and the requirements providing competitive advantage of materials in comparison with analogs are provided. The main directions of development of decorative and finishing materials are evaluated.
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Zhidkova, Elena A., Ekaterina M. Gutor, Mikhail F. Vilk, Vera B. Pankova, Gennadij G. Onishchenko, and Konstantin G. Gurevich. "Influence of production and behavioral risk factors on health disorders in employees of locomotive crews." Russian Journal of Occupational Health and Industrial Ecology 60, no. 10 (November 3, 2020): 694–700. http://dx.doi.org/10.31089/1026-9428-2020-60-10-694-700.
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Preserving the working longevity of locomotive crew employees is one of the priority tasks of Russian Railways. The urgency of the problem is related to both the medical aspects of railway traffic safety and the importance of preserving human capital. The aim of study is to research the influence of occupational and behavioral risk factors on health disorders in drivers and their assistants. The study included the results of a survey of 9308 employees of locomotive crews on the presence of production and behavioral risk factors for health disorders, as well as on the presence of cases of temporary disability, hospitalization or unscheduled medical care in the previous year. Additionally, the results of clinical and laboratory studies were studied. Noise exposure is the main production factor affecting the unscheduled attendance of locomotive crew employees to the doctor, the number of cases of temporary disability and hospitalization. Only 13% of respondents have a high level of commitment to a healthy lifestyle. Among employees who are not exposed to industrial noise, the number of people who have a high commitment to a healthy lifestyle is 2 times higher than among those who complain about the presence of an acoustic factor. The main differences in adherence to a healthy lifestyle between people who have and do not have complaints about the negative impact of the sound factor are related to alcohol abuse (1.4 times more often used by people working in conditions of noise exposure), frequent use of semi-finished products and fatty foods (1.2 times more often). Among people exposed to industrial noise, a body mass index (BMI) exceeding 25 kg/m2 is 1.5 times more common than in people who do not have noise exposure. The frequency of occurrence of blood pressure is more than 130/80 mm Hg. and blood cholesterol more than 5 mmol/l, respectively, is 1.9 and 2.2 times higher in individuals with intra-cab acoustic load, compared with those without. An increase in the number of cases of temporary disability, hospitalization, and unscheduled visits to a doctor in people who report exposure to noise in the driver's cab may be associated with both occupational and behavioral factors: alcohol consumption, poor nutrition, and a high proportion of people with a BMI exceeding 25 kg/m2.
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Ahn, Sohyun, Michelle Olive, Seema Aggarwal, Dmitry Krylov, David D. Ginty, and Charles Vinson. "A Dominant-Negative Inhibitor of CREB Reveals that It Is a General Mediator of Stimulus-Dependent Transcription of c-fos." Molecular and Cellular Biology 18, no. 2 (February 1, 1998): 967–77. http://dx.doi.org/10.1128/mcb.18.2.967.
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ABSTRACT Several studies have characterized the upstream regulatory region of c-fos, and identified cis-acting elements termed the cyclic AMP (cAMP) response elements (CREs) that are critical for c-fos transcription in response to a variety of extracellular stimuli. Although several transcription factors can bind to CREs in vitro, the identity of the transcription factor(s) that activates the c-fos promoter via the CRE in vivo remains unclear. To help identify the trans-acting factors that regulate stimulus-dependent transcription of c-fos via the CREs, dominant-negative (D-N) inhibitor proteins that function by preventing DNA binding of B-ZIP proteins in a dimerization domain-dependent fashion were developed. A D-N inhibitor of CREB, termed A-CREB, was constructed by fusing a designed acidic amphipathic extension onto the N terminus of the CREB leucine zipper domain. The acidic extension of A-CREB interacts with the basic region of CREB forming a coiled-coil extension of the leucine zipper and thus prevents the basic region of wild-type CREB from binding to DNA. Other D-N inhibitors generated in a similar manner with the dimerization domains of Fos, Jun, C/EBP, ATF-2, or VBP did not block CREB DNA binding activity, nor did they inhibit transcriptional activation of a minimal promoter containing a single CRE in PC12 cells. A-CREB inhibited activation of CRE-mediated transcription evoked by three distinct stimuli: forskolin, which increases intracellular cAMP; membrane depolarization, which promotes Ca2+ influx; and nerve growth factor (NGF). A-CREB completely inhibited cAMP-mediated, but only partially inhibited Ca2+- and NGF-mediated, transcription of a reporter gene containing 750 bp of the native c-fos promoter. Moreover, glutamate induction of c-fos expression in primary cortical neurons was dependent on CREB. In contrast, induction of c-fos transcription by UV light was not inhibited by A-CREB. Lastly, A-CREB attenuated NGF induction of morphological differentiation in PC12 cells. These results suggest that CREB or its closely related family members are general mediators of stimulus-dependent transcription of c-fos and are required for at least some of the long-term actions of NGF.
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Matthews, R. P., C. R. Guthrie, L. M. Wailes, X. Zhao, A. R. Means, and G. S. McKnight. "Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression." Molecular and Cellular Biology 14, no. 9 (September 1994): 6107–16. http://dx.doi.org/10.1128/mcb.14.9.6107.
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Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-binding protein) by cAMP-dependent protein kinase (PKA) leads to the activation of many promoters containing CREs. In neurons and other cell types, CREB phosphorylation and activation of CRE-containing promoters can occur in response to elevated intracellular Ca2+. In cultured cells that normally lack this Ca2+ responsiveness, we confer Ca(2+)-mediated activation of a CRE-containing promoter by introducing an expression vector for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Activation could also be mediated directly by a constitutively active form of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induction requires the activity of CREB/ATF family members but is independent of PKA activity. In contrast, transient expression of either a constitutively active or wild-type Ca2+/calmodulin-dependent protein kinase type II (CaMKII) fails to mediate the transactivation of the same CRE-containing reporter gene. Examination of the subcellular distribution of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV enters the nucleus. Our results demonstrate that CaMKIV, which is expressed in neuronal, reproductive, and lymphoid tissues, may act as a mediator of Ca(2+)-dependent gene induction.
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Matthews, R. P., C. R. Guthrie, L. M. Wailes, X. Zhao, A. R. Means, and G. S. McKnight. "Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression." Molecular and Cellular Biology 14, no. 9 (September 1994): 6107–16. http://dx.doi.org/10.1128/mcb.14.9.6107-6116.1994.
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Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-binding protein) by cAMP-dependent protein kinase (PKA) leads to the activation of many promoters containing CREs. In neurons and other cell types, CREB phosphorylation and activation of CRE-containing promoters can occur in response to elevated intracellular Ca2+. In cultured cells that normally lack this Ca2+ responsiveness, we confer Ca(2+)-mediated activation of a CRE-containing promoter by introducing an expression vector for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Activation could also be mediated directly by a constitutively active form of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induction requires the activity of CREB/ATF family members but is independent of PKA activity. In contrast, transient expression of either a constitutively active or wild-type Ca2+/calmodulin-dependent protein kinase type II (CaMKII) fails to mediate the transactivation of the same CRE-containing reporter gene. Examination of the subcellular distribution of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV enters the nucleus. Our results demonstrate that CaMKIV, which is expressed in neuronal, reproductive, and lymphoid tissues, may act as a mediator of Ca(2+)-dependent gene induction.
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Lu, Yun-Fei, and Robert D. Hawkins. "Ryanodine Receptors Contribute to cGMP-Induced Late-Phase LTP and CREB Phosphorylation in the Hippocampus." Journal of Neurophysiology 88, no. 3 (September 1, 2002): 1270–78. http://dx.doi.org/10.1152/jn.2002.88.3.1270.
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We previously found that the nitric oxide (NO)-cGMP-cGMP-dependent protein kinase (PKG) signaling pathway acts in parallel with the cAMP-cAMP-dependent protein kinase (PKA) pathway to produce protein and RNA synthesis-dependent late-phase long-term potentiation (L-LTP) and cAMP response element-binding protein (CREB) phosphorylation in the CA1 region of mouse hippocampus. We have now investigated the possible involvement of a downstream target of PKG, ryanodine receptors. L-LTP can be induced by either multiple-train tetanization, NO or 8-Br-cGMP paired with one-train tetanization, or the cAMP activator forskolin, and all three types of potentiation are accompanied by an increase in phospho-CREB immunofluorescence in the CA1 cell body area. Both the potentiation and the increase in phospho-CREB immunofluorescence induced by multiple-train tetanization or 8-Br-cGMP paired with one-train tetanization are reduced by prolonged perfusion with ryanodine, which blocks Ca2+ release from ryanodine-sensitive Ca2+ stores. By contrast, neither the potentiation nor the increase in immunofluorescence induced by forskolin are reduced by depletion of ryanodine and inositol-1,4,5-triphosphate (IP3)-sensitive Ca2+ stores. These results suggest that NO, cGMP, and PKG cause release of Ca2+ from ryanodine-sensitive stores, which in turn causes phosphorylation of CREB in parallel with PKA during the induction of L-LTP.
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Krueger, Darcy A., Dailing Mao, Elizabeth A. Warner, and Diane R. Dowd. "Functional Analysis of the Mouse ICER (Inducible cAMP Early Repressor) Promoter: Evidence for a Protein That Blocks Calcium Responsiveness of the CAREs (cAMP Autoregulatory Elements)." Molecular Endocrinology 13, no. 7 (July 1, 1999): 1207–17. http://dx.doi.org/10.1210/mend.13.7.0319.
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Abstract Although Ca2+ and cAMP mediate their effects through distinct pathways, both signals converge upon the phosphorylation of the cAMP response element (CRE) binding protein, CREB, thereby activating transcription of CRE-regulated genes. In WEHI7.2 thymocytes, cAMP increases the expression of the inducible cAMP early repressor (ICER) gene through CRE-like elements, known as cAMP autoregulatory elements (CAREs). Because Ca2+- and cAMP-mediated transcription converge in WEHI7.2 thymocytes, we examined the effect of Ca2+ fluxes on the expression of the ICER gene in these cells. Despite the presence of multiple CAREs within its promoter, ICER gene transcription was not activated by Ca2+. Moreover, Ca2+ attenuated the stimulatory effect of cAMP on ICER expression. Transient expression of reporter constructs demonstrated that when these CAREs were placed in a different DNA promoter context, the elements became responsive to Ca2+. Detailed studies using chimeric promoter constructs to map the region responsible for blocking the transcriptional response to Ca2+ indicated that a small portion of the ICER promoter was necessary for the effect. Southwestern blot analysis identified a 83-kDa nuclear protein that bound specifically to that region. The relative binding activity of the factor to the ICER promoter and mutant promoter sequences correlated with an inhibition of Ca2+-activated gene expression in WEHI7.2 cells. These data suggest that the factor functions as a putative Ca2+-activated repressor of CREB/CRE-mediated transcription. Thus, depending on the surrounding context in which the CRE is located, CREs of individual genes can be regulated separately by Ca2+ and cAMP despite the convergence of these two signaling pathways.
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Gilmore, Brian. "Jim Crow." Callaloo 21, no. 1 (1998): 158–60. http://dx.doi.org/10.1353/cal.1998.0019.
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Abani, Christopher. "Albino Crow." Callaloo 30, no. 3 (2007): 721–29. http://dx.doi.org/10.1353/cal.2008.0004.
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Barlow, Christy A., Trisha F. Barrett, Arti Shukla, Brooke T. Mossman, and Karen M. Lounsbury. "Asbestos-mediated CREB phosphorylation is regulated by protein kinase A and extracellular signal-regulated kinases 1/2." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 6 (June 2007): L1361—L1369. http://dx.doi.org/10.1152/ajplung.00279.2006.
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Asbestos is a ubiquitous, naturally occurring fiber that has been linked to the development of malignant and fibrotic lung diseases. Asbestos exposure leads to apoptosis, followed by compensatory proliferation, yet many of the signaling cascades coupled to these outcomes are unclear. Because CREs (Ca2+/cAMP-response elements) are found in the promoters of many genes important for regulation of proliferation and apoptosis, CREB (CRE binding protein) is likely to play an important role in the development of asbestos-mediated lung injury. To explore this possibility, we tested the hypotheses that asbestos exposure leads to CREB phosphorylation in lung epithelial cells and that protein kinase A (PKA) and extracellular signal-regulated kinases 1/2 (ERK1/2) are central regulators of the CREB pathway. Persistent CREB phosphorylation was observed in lung sections from mice following inhalation of crocidolite asbestos. Exposure of C10 lung epithelial cells to crocidolite asbestos led to rapid CREB phosphorylation and apoptosis that was decreased by the inhibition of PKA or ERK1/2 using the specific inhibitors H89 and U0126, respectively. Furthermore, crocidolite asbestos selectively induced a sustained increase in MAP kinase phosphatase-1 mRNA and protein. Silencing CREB protein dramatically reduced asbestos-mediated ERK1/2 phosphorylation, yet significantly increased the number of cells undergoing asbestos-induced apoptosis. These data reveal a novel and selective role for CREB in asbestos-mediated signaling through pathways regulated by PKA and ERK1/2, further providing evidence that CREB is an important regulator of apoptosis in asbestos-induced responses of lung epithelial cells.
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Du, Qian, Xiaoyu Zhu, and Jieru Si. "Angelica polysaccharide ameliorates memory impairment in Alzheimer’s disease rat through activating BDNF/TrkB/CREB pathway." Experimental Biology and Medicine 245, no. 1 (December 17, 2019): 1–10. http://dx.doi.org/10.1177/1535370219894558.
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This study aimed to investigate the effect of Angelica sinensis polysaccharides (ASP) on Alzheimer’s disease (AD) and its underlying mechanisms. In our study, we build the AD model by injecting Aβ25–35. Morris water maze (MWM) was applied to investigate learning and memory. Moreover, neurotransmitters, free radical, and inflammatory factors were also measured. Pathological change and neuronal death in hippocampus CA1, CA3, and DG region were detected by HE staining and Nissl staining. The neuronal apoptosis was detected by TUNEL. The expressions of caspase-3, Bcl-2 and Bax were measured by immunohistochemistry and Western blot. The expressions of BDNF, TrkB, p-Akt, Akt, p-CREB, and CREB were measured by Western blot. Our results showed that ASP could ameliorate spatial learning and memory deficiency in AD rats. ASP decreased AchE level and increased the levels of Ach and chAT in AD rats. ASP could increase the activity of SOD and CAT, decrease MDA activity, and inhibit the expression levels of inflammatory factors and neurons apoptosis in AD rats. Pathological change of hippocampus CA1, CA3, and DG region was ameliorated by ASP. In addition, the effects of ASP were reversed by K252a (TrkB inhibitor). Our study demonstrated that ASP could ameliorate memory impairment in AD rat through activating BDNF/TrkB/CREB pathway. Impact statement The present study demonstrated that ASP could ameliorate memory impairment through regulation of the balance of neurotransmitters, free radical metabolism, inflammation, and neurons apoptosis. Moreover, the mechanism of ASP on memory impairment may be related to BDNF/TrkB/CREB pathway in AD. Our research provides an innovatively regulatory mechanism about the ASP in AD rat and points a new way to the treatment of AD.
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Wallace, Maurice O. (Maurice Orlando). "As the Crow Flies (review)." Callaloo 30, no. 2 (2007): 669–71. http://dx.doi.org/10.1353/cal.2007.0189.
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Rojas Borda, Camilo Andrés, and Campo Alcides Avellaneda Bautista. "Principales aspectos del ltnpuesto sobre la Renta para la Equidad CREE en Colotnbia." Vía Libre, no. 8 (June 1, 2017): 88–96. http://dx.doi.org/10.18041/2011-6705/via_libre.8.2017.3711.
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En e l siguiente artículo se puede leer de una forma clara y sencilla una introducción al impuesto sobre la renta para la equidad CREE, el cual es de mucha importancia tanto para Contadores como para empresarios que con sus empresas generen este impuesto, dado que se constituyó en el cambio estructural de mayor impacto en la reforma tributaria de la Ley 1607 del 2012. La Ley 1607 en los artículos 20 al 29 y también del 33 al 37, los cuales cabe resaltar no quedaron integrados en el Estatuto tributario (E.T) (Zuluaga, 2014), contienen todas las pautas del nuevo "Impuesto a la Renta para la Equidad", abreviado como CREE, lo que inicialmente significaba "Contribución Empresarial para la Equidad". Cabe aclarar que, según la definición y los elementos de un Impuesto, este cobro corresponde a un impuesto y no una contribución como las siglas de su nombre lo indica. Con la Ley 1607 del 2012 se disminuye la tarifa del impuesto de renta y se crea el nuevo Impuesto Sobre la Renta para la Equidad, cuya sigla es CREE. Este impuesto tiene vigencia a partir del año 2013 y al igual que el Impuesto de Renta, se deberá realizar un anticipo (Retención en la Fuente) por cada factura de venta emitida; la tarifa depende de la actividad económica principal del contribuyente, y dichas retenciones se debieron practicar a partir de los pagos o abonos en cuenta que se realizaron desde el 1 de mayo y hasta el 31 de agosto del 2013, actuando como agente de retención de acuerdo al Decreto 862 de abril del 2013, pero a partir del 1 de septiembre con la expedición del Decreto 1828 de agosto del 2013, se estableció la práctica de la auto retención para los sujetos pasivos de este nuevo impuesto.
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Gould, Rebecca. "Jim Crow in the Soviet Union." Callaloo 36, no. 1 (2013): 125–41. http://dx.doi.org/10.1353/cal.2013.0071.
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Zanassi, Patrizia, Mayra Paolillo, Antonio Feliciello, Enrico V. Avvedimento, Vittorio Gallo, and Sergio Schinelli. "cAMP-dependent Protein Kinase Induces cAMP-response Element-binding Protein Phosphorylation via an Intracellular Calcium Release/ERK-dependent Pathway in Striatal Neurons." Journal of Biological Chemistry 276, no. 15 (January 3, 2001): 11487–95. http://dx.doi.org/10.1074/jbc.m007631200.
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Activation of the cAMP-dependent protein kinase A (PKA) pathway may induce cAMP-response element-binding protein (CREB) phosphorylation either directly or via cross-talk mechanisms with other signal transduction pathways. In this study, we have investigated in striatal primary cultures the mechanism by which activation of the cAMP/PKA-dependent pathway leads to CREB phosphorylation via the extracellular signal-regulated kinase (ERK)-dependent pathway. We have found that PKA-induced CREB phosphorylation and CREB-dependent transcription are mediated by calcium (Ca2+) release from intracellular stores and are blocked by inhibitors of the protein kinase C and ERK pathways. This mechanism appears to be mediated by the small G-protein Rap1, whose activation appears to be primed by PKA-induced Ca2+release but not further induced by direct or indirect PKA- or protein kinase C-dependent phosphorylation. These results suggest that, in striatal neurons, intracellular Ca2+release, Rap1, and ERK pathway play a crucial role in the PKA-induced CREB phosphorylation and CREB-dependent transcription.
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Subedi, Krishna P., Min-Jeong Son, Bojjibabu Chidipi, Seong-Woo Kim, Jun Wang, Kyeong-Hee Kim, Sun-Hee Woo, and Joon-Chul Kim. "Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII." Cellular Physiology and Biochemistry 41, no. 1 (2017): 399–412. http://dx.doi.org/10.1159/000456422.
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Background/Aims: Endothelin-1 (ET-1) and the α<Sub>1</Sub>-adrenoceptor agonist phenylephrine (PE) activate cAMP response element binding protein (CREB), a transcription factor implicated in cardiac hypertrophy. The signaling pathway involved in CREB activation by these hypertrophic stimuli is poorly understood. We examined signaling pathways for ET-1- or PE-induced cardiac CREB activation. Methods: Western blotting was performed with pharmacological and genetic interventions in rat ventricular myocytes. Results: ET-1 and PE increased CREB phosphorylation, which was inhibited by blockade of phospholipase C, the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, protein kinase C (PKC) or Ca2+-calmodulin-dependent protein kinase II (CaMKII). Intracellular Ca2+ buffering decreased ET-1- and PE-induced CREB phosphorylation by ≥80%. Sarcoplasmic reticulum Ca2+ pump inhibitor, inositol 1,4,5-trisphosphate receptor (IP<Sub>3</Sub>R) blockers, or type 2 IP<Sub>3</Sub>R (IP<Sub>3</Sub>R2) knock-out abolished ET-1- or PE-induced CREB phosphorylation. ET-1 and PE increased phosphorylation of CaMKII and ERK1/2, which was eliminated by IP<Sub>3</Sub>R blockade/knock-out or PKC inhibition. Activation of CaMKII, but not ERK1/2, by these agonists was sensitive to Ca2+ buffering or to Gö6976, the inhibitor of Ca2+-dependent PKC and protein kinase D (PKD). Conclusion: CREB phosphorylation by ET-1 and PE may be mainly mediated by IP<Sub>3</Sub>R2/Ca2+-PKC-PKD-CaMKII signaling with a minor contribution by ERK1/2, linked to IP<Sub>3</Sub>R2 and Ca2+-independent PKC, in ventricular myocytes.
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Francis, Heather, Shannon Glaser, Sharon DeMorrow, Eugenio Gaudio, Yoshiyuki Ueno, Julie Venter, David Dostal, et al. "Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway." American Journal of Physiology-Cell Physiology 295, no. 2 (August 2008): C499—C513. http://dx.doi.org/10.1152/ajpcell.00369.2007.
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Cholangiopathies are characterized by the heterogeneous proliferation of different-sized cholangiocytes. Large cholangiocytes proliferate by a cAMP-dependent mechanism. The function of small cholangiocytes may depend on the activation of inositol trisphosphate (IP3)/Ca2+-dependent signaling pathways; however, data supporting this speculation are lacking. Four histamine receptors exist (HRH1, HRH2, HRH3, and HRH4). In several cells: 1) activation of HRH1 increases intracellular Ca2+ concentration levels; and 2) increased [Ca2+]i levels are coupled with calmodulin-dependent stimulation of calmodulin-dependent protein kinase (CaMK) and activation of cAMP-response element binding protein (CREB). HRH1 agonists modulate small cholangiocyte proliferation by activation of IP3/Ca2+-dependent CaMK/CREB. We evaluated HRH1 expression in cholangiocytes. Small and large cholangiocytes were stimulated with histamine trifluoromethyl toluidide (HTMT dimaleate; HRH1 agonist) for 24–48 h with/without terfenadine, BAPTA/AM, or W7 before measuring proliferation. Expression of CaMK I, II, and IV was evaluated in small and large cholangiocytes. We measured IP3, Ca2+ and cAMP levels, phosphorylation of CaMK I, and activation of CREB (in the absence/presence of W7) in small cholangiocytes treated with HTMT dimaleate. CaMK I knockdown was performed in small cholangiocytes stimulated with HTMT dimaleate before measurement of proliferation and CREB activity. Small and large cholangiocytes express HRH1, CaMK I, and CaMK II. Small (but not large) cholangiocytes proliferate in response to HTMT dimaleate and are blocked by terfenadine (HRH1 antagonist), BAPTA/AM, and W7. In small cholangiocytes, HTMT dimaleate increased IP3/Ca2+ levels, CaMK I phosphorylation, and CREB activity. Gene knockdown of CaMK I ablated the effects of HTMT dimaleate on small cholangiocyte proliferation and CREB activation. The IP3/Ca2+/CaMK I/CREB pathway is important in the regulation of small cholangiocyte function.
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Zhang, Shen, Carmelle V. Remillard, Ivana Fantozzi, and Jason X. J. Yuan. "ATP-induced mitogenesis is mediated by cyclic AMP response element-binding protein-enhanced TRPC4 expression and activity in human pulmonary artery smooth muscle cells." American Journal of Physiology-Cell Physiology 287, no. 5 (November 2004): C1192—C1201. http://dx.doi.org/10.1152/ajpcell.00158.2004.
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Extracellular ATP and intracellular cyclic AMP response element-binding protein (CREB, a transcription factor) promote cell proliferation in many cell types. The canonical transient receptor potential (TRPC) channels, which putatively participate in forming store- and receptor-operated Ca2+ channels, have been implicated in the pulmonary vascular remodeling processes. A link between extracellular ATP, CREB activation, and TRPC4 channel expression and activity has not been shown in human pulmonary artery smooth muscle cells (PASMC). Long-term (24–48 h) treatment of human PASMC with a low dose (100 μM) of ATP, which did not trigger a transient rise in free cytosolic Ca2+ concentration ([Ca2+]i) when applied acutely to the cells, caused marked increases in CREB phosphorylation and TRPC4 protein expression. The time course indicated that the ATP-mediated CREB phosphorylation preceded TRPC4 upregulation, whereas transfection of a nonphosphorylatable CREB mutant abolished ATP-mediated TRPC4 expression. Furthermore, treatment of human PASMC with ATP also enhanced the amplitude of capacitative Ca2+ entry (CCE) induced by passive store depletion, whereas the small interfering RNA specifically targeting TRPC4 attenuated ATP-mediated increases in TRPC4 expression and CCE amplitude and inhibited ATP-induced PASMC proliferation. These data suggest that low-dose ATP exerts part of its mitogenic effect in human PASMC via CREB-mediated upregulation of TRPC4 channel expression and activity and the subsequent increase in CCE and [Ca2+]i.
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Min, A. Young, Jae-Myung Yoo, Dai-Eun Sok, and Mee Ree Kim. "Mulberry Fruit Prevents Diabetes and Diabetic Dementia by Regulation of Blood Glucose through Upregulation of Antioxidative Activities and CREB/BDNF Pathway in Alloxan-Induced Diabetic Mice." Oxidative Medicine and Cellular Longevity 2020 (May 4, 2020): 1–13. http://dx.doi.org/10.1155/2020/1298691.
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Although mulberry fruit has various beneficial effects, its effect on diabetes-related dementia remains unknown. We investigated whether the ethyl acetate fraction of ethanolic extract of mulberry fruit (MFE) could alleviate biochemical and behavioral deficits in alloxan-induced diabetic mice. In the diabetic mice, MFE considerably abolished multiple deficits, e.g., body weight reduction; water and food intake increase; and hyperglycemia, hyperlipidemia, hypoinsulinism, and hypertrophy of the liver, kidneys, spleen, and brain. A 200 mg/kg MFE dose reduced malondialdehyde levels and improved antioxidant enzyme activity in the liver, kidney, and brain tissues. MFE attenuated hyperglycemia-induced memory impairments and acetylcholine deprivation, protected neuronal cells in CA1 and CA3 regions via p-CREB/BDNF pathway activation, and reduced amyloid-β precursor protein and p-Tau expressions in the brain tissue. In conclusion, MFE exerts antidiabetic and neuroprotective effects by upregulating antioxidative activities and p-CREB/BDNF pathway in chronic diabetes. Therefore, MFE may be used as a therapeutic agent for diabetes and diabetic neurodegenerative diseases.
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Rushin, Kate. "Instructions from the Flight Crew to a Poet of African Descent Living in a State of Emergency." Callaloo 22, no. 4 (1999): 976. http://dx.doi.org/10.1353/cal.1999.0189.
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Abdou, Houssein S., Nicholas M. Robert, and Jacques J. Tremblay. "Calcium-dependent Nr4a1 expression in mouse Leydig cells requires distinct AP1/CRE and MEF2 elements." Journal of Molecular Endocrinology 56, no. 3 (April 2016): 151–61. http://dx.doi.org/10.1530/jme-15-0202.
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The nuclear receptor NR4A1 is expressed in steroidogenic Leydig cells where it plays pivotal roles by regulating the expression of several genes involved in steroidogenesis and male sex differentiation including Star, HSD3B2, and Insl3. Activation of the cAMP and Ca2+ signaling pathways in response to LH stimulation leads to a rapid and robust activation of Nr4a1 gene expression that requires the Ca2+/CAMKI pathway. However, the downstream transcription factor(s) have yet to be characterized. To identify potential Ca2+/CaM effectors responsible for hormone-induced Nr4a1 expression, MA-10 Leydig cells were treated with forskolin to increase endogenous cAMP levels, dantrolene to inhibit endoplasmic reticulum Ca2+ release, and W7 to inhibit CaM activity. We identified Ca2+-responsive elements located in the discrete regions of the Nr4a1 promoter, which contain binding sites for several transcription factors such as AP1, CREB, and MEF2. We found that one of the three AP1/CRE sites located at –255 bp is the most responsive to the Ca2+ signaling pathway as are the two MEF2 binding sites at –315 and –285 bp. Furthermore, we found that the hormone-induced recruitment of phospho-CREB and of the co-activator p300 to the Nr4a1 promoter requires the Ca2+ pathway. Lastly, siRNA-mediated knockdown of CREB impaired NR4A1 expression and steroidogenesis. Together, our data indicate that the Ca2+ signaling pathway increases Nr4a1 expression in MA-10 Leydig cells, at least in part, by enhancing the recruitment of coactivator most likely through the MEF2, AP1, and CREB transcription factors thus demonstrating an important interplay between the Ca2+ and cAMP pathways in regulating Nr4a1 expression.
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Lobos, Pedro, Alex Córdova, Ignacio Vega-Vásquez, Omar A. Ramírez, Tatiana Adasme, Jorge Toledo, Mauricio Cerda, Steffen Härtel, Andrea Paula-Lima, and Cecilia Hidalgo. "RyR-mediated Ca2+ release elicited by neuronal activity induces nuclear Ca2+ signals, CREB phosphorylation, and Npas4/RyR2 expression." Proceedings of the National Academy of Sciences 118, no. 33 (August 13, 2021): e2102265118. http://dx.doi.org/10.1073/pnas.2102265118.
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The expression of several hippocampal genes implicated in learning and memory processes requires that Ca2+ signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca2+ in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca2+ signals to the nucleus. Here, we present evidence showing that Ca2+ release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca2+ signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons. Additionally, GBZ treatment significantly increased cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation—a key event in synaptic plasticity and hippocampal memory—and enhanced the expression of Neuronal Per Arnt Sim domain protein 4 (Npas4) and RyR2, two central regulators of these processes. Suppression of RyR-mediated Ca2+ release with ryanodine significantly reduced the increase in CREB phosphorylation and the enhanced Npas4 and RyR2 expression induced by GBZ. We propose that RyR-mediated Ca2+ release induced by neuronal activity, through its contribution to the sequential generation of nuclear Ca2+ signals, CREB phosphorylation, Npas4, and RyR2 up-regulation, plays a central role in hippocampal synaptic plasticity and memory processes.
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Dhar, Matasha, Mingyan Zhu, Soren Impey, Talley J. Lambert, Tyler Bland, Ilia N. Karatsoreos, Takanobu Nakazawa, Suzanne M. Appleyard, and Gary A. Wayman. "Leptin Induces Hippocampal Synaptogenesis via CREB-Regulated MicroRNA-132 Suppression of p250GAP." Molecular Endocrinology 28, no. 7 (July 1, 2014): 1073–87. http://dx.doi.org/10.1210/me.2013-1332.
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Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element–binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis.
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Avlani, Vimesh A., Wenting Ma, Hee-Chang Mun, Katie Leach, Leigh Delbridge, Arthur Christopoulos, and Arthur D. Conigrave. "Calcium-sensing receptor-dependent activation of CREB phosphorylation in HEK293 cells and human parathyroid cells." American Journal of Physiology-Endocrinology and Metabolism 304, no. 10 (May 15, 2013): E1097—E1104. http://dx.doi.org/10.1152/ajpendo.00054.2013.
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In addition to its acute effects on hormone secretion, epithelial transport, and shape change, the calcium-sensing receptor (CaSR) modulates the expression of genes that control cell survival, proliferation, and differentiation as well as the synthesis of peptide hormones and enzymes. In the present study, we investigated the impacts of a CaSR agonist and several CaSR modulators on phosphorylation of transcription factor CREB residue Ser133 in CaSR-expressing HEK293 (HEK-CaSR) cells and human adenomatous parathyroid cells. Elevated Ca2+o concentration had no effect on CREB phosphorylation (p-CREB) in control HEK293 cells but stimulated p-CREB in both HEK-CaSR cells and human parathyroid cells. In addition, p-CREB was stimulated by the positive modulator cinacalcet and inhibited by the negative modulator NPS 2143 in both CaSR-expressing cell types. Two positive modulators that bind in the receptor's Venus Fly Trap domain, l-phenylalanine and S-methylglutathione, had no effect on p-CREB in HEK-CaSR cells, demonstrating the existence of pronounced signaling bias. Analysis of the signaling pathways using specific inhibitors demonstrated that phosphoinositide-specific phospholipase C and conventional protein kinase C isoforms make major contributions to Ca2+o-induced p-CREB in both cell-types, suggesting key roles for Gq/11. In addition, in parathyroid cells but not HEK-CaSR cells, activation of p-CREB was dependent on Gi/o, demonstrating the existence of cell type-specific signaling.
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Hu, Wenfeng, Jingjing Wu, Ting Ye, Zhuo Chen, Jinhua Tao, Lijuan Tong, Kai Ma, Jie Wen, Hui Wang, and Chao Huang. "Farnesoid X Receptor-Mediated Cytoplasmic Translocation of CRTC2 Disrupts CREB-BDNF Signaling in Hippocampal CA1 and Leads to the Development of Depression-Like Behaviors in Mice." International Journal of Neuropsychopharmacology 23, no. 10 (May 26, 2020): 673–86. http://dx.doi.org/10.1093/ijnp/pyaa039.
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Abstract Background We recently identified neuronal expression of farnesoid X receptor (FXR), a bile acid receptor known to impair autophagy by inhibiting cyclic adenosine monophosphate response element-binding protein (CREB), a protein whose underfunctioning is linked to neuroplasticity and depression. In this study, we hypothesize that FXR may mediate depression via a CREB-dependent mechanism. Methods Depression was induced in male C57BL6/J mice via chronic unpredictable stress (CUS). Subjects underwent behavioral testing to identify depression-like behaviors. A variety of molecular biology techniques, including viral-mediated gene transfer, Western blot, co-immunoprecipitation, and immunofluorescence, were used to correlate depression-like behaviors with underlying molecular and physiological events. Results Overexpression of FXR, whose levels were upregulated by CUS in hippocampal CA1, induced or aggravated depression-like behaviors in stress-naïve and CUS-exposed mice, while FXR short hairpin RNA (shRNA) ameliorated such symptoms in CUS-exposed mice. The behavioral effects of FXR were found to be associated with changes in CREB-brain-derived neurotrophic factor (BDNF) signaling, as FXR overexpression aggravated CUS-induced reduction in BDNF levels while the use of FXR shRNA or disruption of FXR-CREB signaling reversed the CUS-induced reduction in the phosphorylated CREB and BDNF levels. Molecular analysis revealed that FXR shRNA prevented CUS-induced cytoplasmic translocation of CREB-regulated transcription coactivator 2 (CRTC2); CRTC2 overexpression and CRTC2 shRNA abrogated the regulatory effect of FXR overexpression or FXR shRNA on CUS-induced depression-like behaviors. Conclusions In stress conditions, increased FXR in the CA1 inhibits CREB by targeting CREB and driving the cytoplasmic translocation of CRTC2. Uncoupling of the FXR-CREB complex may be a novel strategy for depression treatment.
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Krajewski, W., and K. A. Lee. "A monomeric derivative of the cellular transcription factor CREB functions as a constitutive activator." Molecular and Cellular Biology 14, no. 11 (November 1994): 7204–10. http://dx.doi.org/10.1128/mcb.14.11.7204.
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The mammalian transcriptional activator CREB binds as a dimer to a broad spectrum of inducible promoters. CREB activity is modulated by several signalling agents (protein kinase A [PKA], Ca2+, and transforming growth factor beta) and via functional interactions with cell-specific transcription factors. In addition, CREB can activate transcription constitutively and repress the activity of several other transcriptional activators. The mechanisms that allow CREB to act in such a malleable manner and the role that CREB dimerization might play in this are poorly understood. To probe the latter issue, we have created monomeric forms of CREB by fusing CREB to the DNA-binding domain of a protein (B-cell specific activator protein [BSAP]) that binds to DNA as a monomer. Remarkably, monomeric CREB acts as a potent, constitutive activator under conditions in which native CREB is inducible by PKA. Thus, CREB contains constitutive activation regions that are unable to function in native CREB. Two glutamine-rich domains that are important for native, PKA-inducible CREB activity are required for the constitutive activity of monomeric CREB. In contrast, two elements within the kinase-inducible domain of CREB are dispensable for constitutive activity. We discuss our results in relation to inducible and constitutive CREB activity and the potential modes of action of other activators that directly interact with CREB.
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Krajewski, W., and K. A. Lee. "A monomeric derivative of the cellular transcription factor CREB functions as a constitutive activator." Molecular and Cellular Biology 14, no. 11 (November 1994): 7204–10. http://dx.doi.org/10.1128/mcb.14.11.7204-7210.1994.
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The mammalian transcriptional activator CREB binds as a dimer to a broad spectrum of inducible promoters. CREB activity is modulated by several signalling agents (protein kinase A [PKA], Ca2+, and transforming growth factor beta) and via functional interactions with cell-specific transcription factors. In addition, CREB can activate transcription constitutively and repress the activity of several other transcriptional activators. The mechanisms that allow CREB to act in such a malleable manner and the role that CREB dimerization might play in this are poorly understood. To probe the latter issue, we have created monomeric forms of CREB by fusing CREB to the DNA-binding domain of a protein (B-cell specific activator protein [BSAP]) that binds to DNA as a monomer. Remarkably, monomeric CREB acts as a potent, constitutive activator under conditions in which native CREB is inducible by PKA. Thus, CREB contains constitutive activation regions that are unable to function in native CREB. Two glutamine-rich domains that are important for native, PKA-inducible CREB activity are required for the constitutive activity of monomeric CREB. In contrast, two elements within the kinase-inducible domain of CREB are dispensable for constitutive activity. We discuss our results in relation to inducible and constitutive CREB activity and the potential modes of action of other activators that directly interact with CREB.
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Togo, Tatsuru, Janet M. Alderton, and Richard A. Steinhardt. "Long-Term Potentiation of Exocytosis and Cell Membrane Repair in Fibroblasts." Molecular Biology of the Cell 14, no. 1 (January 2003): 93–106. http://dx.doi.org/10.1091/mbc.e02-01-0056.
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We previously found that a microdisruption of the plasma membrane evokes Ca2+-regulated exocytosis near the wound site, which is essential for membrane resealing. We demonstrate herein that repeated membrane disruption reveals long-term potentiation of Ca2+-regulated exocytosis in 3T3 fibroblasts, which is closely correlated with faster membrane resealing rates. This potentiation of exocytosis is cAMP-dependent protein kinase A dependent in the early stages (minutes), in the intermediate term (hours) requires protein synthesis, and for long term (24 h) depends on the activation of cAMP response element-binding protein (CREB). We were able to demonstrate that wounding cells activated CREB within 3.5 h. In all three phases, the increase in the amount of exocytosis was correlated with an increase in the rate of membrane resealing. However, a brief treatment with forskolin, which is effective for short-term potentiation and which could also activate CREB, was not sufficient to induce long-term potentiation of resealing. These results imply that long-term potentiation by CREB required activation by another, cAMP-independent pathway.
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Sun, Z., P. Sassone-Corsi, and A. R. Means. "Calspermin gene transcription is regulated by two cyclic AMP response elements contained in an alternative promoter in the calmodulin kinase IV gene." Molecular and Cellular Biology 15, no. 1 (January 1995): 561–71. http://dx.doi.org/10.1128/mcb.15.1.561.
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The transcript for the high-affinity Ca2+/calmodulin-binding protein calspermin is generated from the gene encoding Ca2+/calmodulin-dependent protein kinase IV only in postmeiotic germ cells during spermatogenesis. We demonstrate that this testis-specific calspermin transcript can be produced in heterologous cells by utilization of a promoter located in an intron of the calmodulin (CaM) kinase IV gene. Critical motifs within this promoter are two cyclic AMP response element (CRE)-like sequences located about -70 and -50 bp upstream of the transcriptional initiation site. Both CRE motifs are footprinted by the authentic testis-specific transcriptional activator CREM tau or by CREM tau present in adult testis nuclear extract. Whereas a 2.1-kb DNA fragment containing the calspermin promoter is inactive when transfected into NIH 3T3 cells, activity can be restored by cotransfection of CREM tau and protein kinase A or CaM kinase IV but not CaM kinase II alpha. Restoration of activity is greatly reduced by mutation of the two CRE motifs. Since CRE-like motifs have been identified in many genes uniquely expressed in postmeiotic germ cells, which contain abundant CREM tau protein, we suggest that CREM tau may function as one transcription factor responsible for the expression of postmeiotic germ cell-specific genes.
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Hong, Yuni, Yun-Hyeok Choi, Young-Eun Han, Soo-Jin Oh, Ansoo Lee, Bonggi Lee, Rebecca Magnan, Shi Yong Ryu, Chun Whan Choi, and Min Soo Kim. "Central Administration of Ampelopsin A Isolated from Vitis vinifera Ameliorates Cognitive and Memory Function in a Scopolamine-Induced Dementia Model." Antioxidants 10, no. 6 (May 24, 2021): 835. http://dx.doi.org/10.3390/antiox10060835.
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Neurodegenerative diseases are characterized by the progressive degeneration of the function of the central nervous system or peripheral nervous system and the decline of cognition and memory abilities. The dysfunctions of the cognitive and memory battery are closely related to inhibitions of neurotrophic factor (BDNF) and brain-derived cAMP response element-binding protein (CREB) to associate with the cholinergic system and long-term potentiation. Vitis vinifera, the common grapevine, is viewed as the important dietary source of stilbenoids, particularly the widely-studied monomeric resveratrol to be used as a natural compound with wide-ranging therapeutic benefits on neurodegenerative diseases. Here we found that ampelopsin A is a major compound in V. vinifera and it has neuroprotective effects on experimental animals. Bath application of ampelopsin A (10 ng/µL) restores the long-term potentiation (LTP) impairment induced by scopolamine (100 μM) in hippocampal CA3-CA1 synapses. Based on these results, we administered the ampelopsin A (10 ng/µL, three times a week) into the third ventricle of the brain in C57BL/6 mice for a month. Chronic administration of ampelopsin A into the brain ameliorated cognitive memory-behaviors in mice given scopolamine (0.8 mg/kg, i.p.). Studies of mice’s hippocampi showed that the response of ampelopsin A was responsible for the restoration of the cholinergic deficits and molecular signal cascades via BDNF/CREB pathways. In conclusion, the central administration of ampelopsin A contributes to increasing neurocognitive and neuroprotective effects on intrinsic neuronal excitability and behaviors, partly through elevated BDNF/CREB-related signaling.
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Sivanarayanan, Anushiya. "Remembering Jim Crow: African Americans Tell About Life in the Segregated South (review)." Callaloo 26, no. 3 (2003): 901–6. http://dx.doi.org/10.1353/cal.2003.0103.
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Evans, A. "Flight deck indication of health monitoring data—a critique." Proceedings of the Institution of Mechanical Engineers, Part G: Journal of Aerospace Engineering 216, no. 5 (May 1, 2002): 249–57. http://dx.doi.org/10.1243/095441002321028766.
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In September 1995 there was an incident involving an AS332L Super Puma helicopter over the North Sea. This followed the onset of high vibration due to the fatigue failure of a tail rotor blade retaining hinge. This was the first major vibration incident involving a helicopter fitted with a health and usage monitoring system (HUMS). The UK Air Accidents Investigation Branch made a number of recommendations. One was that the UK Civil Aviation Authority (CAA) should develop the concept of providing a flight deck display of health monitoring information to the flight crew. The CAA asked the Helicopter Health Monitoring Advisory G roup (HHM AG) (an industry body that advises the CAA) to consider the issue. This paper will examine the findings of the H HMAG working group and discuss the practicality of such systems in an operational environment.
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Thommesen, Liv, Eva Hofsli, Ruth H. Paulssen, Marit W. Anthonsen, and Astrid Lægreid. "Molecular mechanisms involved in gastrin-mediated regulation of cAMP-responsive promoter elements." American Journal of Physiology-Endocrinology and Metabolism 281, no. 6 (December 1, 2001): E1316—E1325. http://dx.doi.org/10.1152/ajpendo.2001.281.6.e1316.
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In the present study, we explore the role of cAMP-responsive (CRE) promoter elements in gastrin-mediated gene activation. By using the minimal CRE promoter reporter plasmid, pCRELuc, we show that gastrin can activate CRE. This activation is blocked by H-89 and GF 109203x, which inhibit protein kinases A and C, respectively. Moreover, Ca2+-activated pathways seem to be involved, because the calmodulin inhibitor W-7 reduced gastrin-mediated activation of pCRELuc. Deletion of CRE from the c- fos promoter rendered this promoter completely unresponsive to gastrin, indicating that CRE plays a central role in c- fos transactivation. Interestingly, gastrin-induced expression of the inducible cAMP early repressor (ICER), a gene that is known to be regulated by CRE promoter elements, was not reduced by H-89, W-7, or GF 109203x. Furthermore, bandshift analyses indicated that the region of the ICER promoter containing the CRE-like elements CARE 3–4 binds transcription factors that are not members of the CRE-binding protein-CRE modulator protein-activating transcription factor, or CREB/CREM/ATF-1, family. Our results underline the significance of the CRE promoter element in gastrin-mediated gene regulation and indicate that a variety of signaling mechanisms are involved, depending on the CRE promoter context.
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König, Sarah, Sara Browne, Bernhard Doleschal, Michaela Schernthaner, Michael Poteser, Heinrich Mächler, Eric Wittchow, et al. "Inhibition of Orai1-mediated Ca2+ entry is a key mechanism of the antiproliferative action of sirolimus in human arterial smooth muscle." American Journal of Physiology-Heart and Circulatory Physiology 305, no. 11 (December 1, 2013): H1646—H1657. http://dx.doi.org/10.1152/ajpheart.00365.2013.
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Sirolimus (rapamycin) is used in drug-eluting stent strategies and proved clearly superior in this application compared with other immunomodulators such as pimecrolimus. The molecular basis of this action of sirolimus in the vascular system is still incompletely understood. Measurements of cell proliferation in human coronary artery smooth muscle cells (hCASM) demonstrated a higher antiproliferative activity of sirolimus compared with pimecrolimus. Although sirolimus lacks inhibitory effects on calcineurin, nuclear factor of activated T-cell activation in hCASM was suppressed to a similar extent by both drugs at 10 μM. Sirolimus, but not pimecrolimus, inhibited agonist-induced and store-operated Ca2+ entry as well as cAMP response element binding protein (CREB) phosphorylation in human arterial smooth muscle, suggesting the existence of an as-yet unrecognized inhibitory effect of sirolimus on Ca2+ signaling and Ca2+-dependent gene transcription. Electrophysiological experiments revealed that only sirolimus but not pimecrolimus significantly blocked the classical stromal interaction molecule/Orai-mediated, store-operated Ca2+ current reconstituted in human embryonic kidney cells (HEK293). A link between Orai function and proliferation was confirmed by dominant-negative knockout of Orai in hCASM. Analysis of the effects of sirolimus on cell proliferation and CREB activation in an in vitro model of arterial intervention using human aorta corroborated the ability of sirolimus to suppress stent implantation-induced CREB activation in human arteries. We suggest inhibition of store-operated Ca2+ entry based on Orai channels and the resulting suppression of Ca2+ transcription coupling as a key mechanism underlying the antiproliferative activity of sirolimus in human arteries. This mechanism of action is specific for sirolimus and not a general feature of drugs interacting with FK506-binding proteins.
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Wang, Oumei, Kun Cai, Shanshan Pang, Ting Wang, Dongfei Qi, Quanfeng Zhu, Zimei Ni, and Yingying Le. "Mechanisms of Glucose-Induced Expression of Pancreatic-Derived Factor in Pancreatic β-Cells." Endocrinology 149, no. 2 (November 25, 2007): 672–80. http://dx.doi.org/10.1210/en.2007-0106.
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Pancreatic-derived factor (PANDER) is a cytokine-like peptide highly expressed in pancreatic β-cells. PANDER was reported to promote apoptosis of pancreatic β-cells and secrete in response to glucose. Here we explored the effects of glucose on PANDER expression, and the underlying mechanisms in murine pancreatic β-cell line MIN6 and primary islets. Our results showed that glucose up-regulated PANDER mRNA and protein levels in a time- and dose-dependent manner in MIN6 cells and pancreatic islets. In cells expressing cAMP response element-binding protein (CREB) dominant-negative construct, glucose failed to induce PANDER gene expression and promoter activation. Treatment of the cells with calcium chelator [EGTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM)], the voltage-dependent Ca2+ channel inhibitor (nifedipine), the protein kinase A (PKA) inhibitor (H89), the protein kinase C (PKC) inhibitor (Go6976), or the MAPK kinase 1/2 inhibitor (PD98059), all significantly inhibited glucose-induced PANDER gene expression and promoter activation. Further studies showed that glucose induced CREB phosphorylation through Ca2+-PKA-ERK1/2 and Ca2+-PKC pathways. Thus, the Ca2+-PKA-ERK1/2-CREB and Ca2+-PKC-CREB signaling pathways are involved in glucose-induced PANDER gene expression. Wortmannin (phosphatidylinositol 3-kinase inhibitor), ammonium pyrrolidinedithiocarbamate (nuclear factor-κB inhibitor and nonspecific antioxidant), and N-acetylcysteine (antioxidant) were also found to inhibit glucose-induced PANDER promoter activation and gene expression. Because there is no nuclear factor-κB binding site in the promoter region of PANDER gene, these results suggest that phosphatidylinositol 3-kinase and reactive oxygen species be involved in glucose-induced PANDER gene expression. In conclusion, glucose induces PANDER gene expression in pancreatic β-cells through multiple signaling pathways. Because PANDER is expressed by pancreatic β-cells and in response to glucose in a similar way to those of insulin, PANDER may be involved in glucose homeostasis.
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Hagiwara, Masatoshi. "Ca2 + and cAMP-mduced CREB phosphorylation and transcriptional regulation." Japanese Journal of Pharmacology 67 (1995): 27. http://dx.doi.org/10.1016/s0021-5198(19)46088-5.
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Murray, Peter D., Tami J. Kingsbury, and Bruce K. Krueger. "Failure of Ca2+-activated, CREB-dependent transcription in astrocytes." Glia 57, no. 8 (June 2009): 828–34. http://dx.doi.org/10.1002/glia.20809.
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Ou, Jinying, Yuting Zhou, Chan Li, Zhijie Chen, Hancheng Li, Miao Fang, Chen Zhu, et al. "Sinomenine Protects Against Morphine Dependence through the NMDAR1/CAMKII/CREB Pathway: A Possible Role of Astrocyte-Derived Exosomes." Molecules 23, no. 9 (September 17, 2018): 2370. http://dx.doi.org/10.3390/molecules23092370.
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Sinomenine is a nonaddictive alkaloid used to prevent morphine dependence, even thoughits mechanism isnot fully understood. Astrocytes aggravate the pathological process in their neighboring cellsthrough exosomes in central nervous system diseases. However, the effect of sinomenine on astrocyte-derived exosomes for the amelioration of morphine dependence has not been reported yet. In this study, we found that sinomenine prevented the morphine-induced conditionedplace preference in mice. Sinomenine reduced the levels of cAMP and intracellular Ca2+ in morphine-treated SH-SY5Y cells. Moreover, sinomenine inhibited the expressions of p-NMDAR1/NMDAR1, p-CAMKII/CAMKII, and p-CREB/CREB in the hippocampusof morphine-dependent mice and SH-SY5Y cells. Furthermore, we found that sinomenine inhibitedthe morphine-induced activation of astrocytesin vivo and in vitro. Afterwards, exosomes were isolated from cultured primary astrocytes treated with phosphate buffer saline (PBS, ctl-exo), morphine (mor-exo), or morphine and sinomenine (Sino-exo). Subsequently, morphine-treated SH-SY5Y cells were treated with ctl-exo, mor-exo, and Sino-exo. Results showed that Sino-exo reduced the level of cAMP, intracellular Ca2+, and the expression of p-CAMKII/CAMKII and p-CREB/CREB in morphine-treated SH-SY5Y cells. In conclusion, we demonstrated that sinomenine exhibited protective effects against morphine dependencein vivo and in vitro through theNMDAR1/CAMKII/CREB pathway. Sinomenine-induced alterationof the function of astrocyte-derived exosomes may contribute to the antidependence effects of sinomenine in morphine dependence.
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Bollinger, Heidi E. "Neo-Segregation Narratives: Jim Crow in Post-Civil Rights American Literature (review)." Callaloo 35, no. 3 (2012): 812–15. http://dx.doi.org/10.1353/cal.2012.0091.
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Sayles, Jesse S. "No wilderness to plunder: Process thinking reveals Cree land-use via the goose-scape." Canadian Geographer / Le Géographe canadien 59, no. 3 (June 8, 2015): 297–303. http://dx.doi.org/10.1111/cag.12201.
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THONBERG, Håkan, J. Magnus FREDRIKSSON, Jan NEDERGAARD, and Barbara CANNON. "A novel pathway for adrenergic stimulation of cAMP-response-element-binding protein (CREB) phosphorylation: mediation via α1-adrenoceptors and protein kinase C activation." Biochemical Journal 364, no. 1 (May 8, 2002): 73–79. http://dx.doi.org/10.1042/bj3640073.
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Because of the central role of adrenergic mechanisms in the expression of crucial genes during brown adipocyte differentiation, we examined the activation (phosphorylation) of CREB (cAMP-response-element-binding protein) in mouse brown adipocytes in primary culture. We found that noradrenaline (‘norepinephrine’) stimulated CREB phosphorylation rapidly (maximum effect in ≤ 5min with slow decay) and efficiently (EC50, 6nM). The increase in CREB phosphorylation coincided with increased expression of an artificial cAMP-response-element-containing reporter construct. CREB phosphorylation was partly inhibitable, both by the β-adrenergic antagonist propranolol and by the α1-adrenergic antagonist prazosin. Adenylate cyclase hyperactivation (by forskolin) could stimulate CREB phosphorylation to the same extent as noradrenaline. The α1-adrenergic agonist cirazoline also increased CREB phosphorylation. An increase in intracellular [Ca2+] had, however, no effect, but protein kinase C activation by PMA was a potent stimulator. The cirazoline-stimulated (α1-adrenergic) CREB phosphorylation was inhibited by a desensitizing pretreatment with PMA, demonstrating that the α1-stimulation was mediated via protein kinase C activation; neither Src nor extracellular-signal-regulated kinases 1 and 2 activation was involved in the signalling process. We conclude that CREB phosphorylation in brown adipocytes is mediated not only through the classical β-adrenergic/cAMP pathway but also through a novel α1-adrenergic/protein kinase C/CREB pathway, which has not been described previously in any tissue.
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Kida, S. "Roles of CREB Signaling Pathway in Regulation of Fear Memory." European Psychiatry 24, S1 (January 2009): 1. http://dx.doi.org/10.1016/s0924-9338(09)70321-9.
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Activity-dependent gene expression through activation of Ca2+-CREB signal transduction pathways has been thought to play a central role in fear memory formation. On the other hand, retrieval of fear memory triggers two time-dependent phases of reactivated memory; reconsolidation and extinction. To understand the mechanisms for determining the fate of the reactivated fear memory, we investigated roles of CREB in reconsolidation and extinction of contextual fear memory and then analyzed the brain-regions regulating reconsolidation and extinction by identifying regions where CREB-mediated gene expression is activated and then examining the role of protein synthesis in those regions on reconsolidation and extinction. We first showed that activation of CREB-mediated transcription is required for reconsolidation and long-term extinction of contextual fear memory. Using immunocytochemical analyses, we demonstrated that CREB is activated in the hippocampus/amygdala and amygdala/medial prefrontal cortex (mPFC) in the reconsolidation and extinction phases, respectively. Similar results were observed by analyzing the expression of a CREB-dependent gene, Arc. We finally showed that reconsolidation and long-term extinction of the contextual fear memory depended on new gene expression in the hippocampus/amygdala and amygdala/mPFC, respectively. Thus reactivated contextual fear memory is reconsolidated or extinguished through distinct CREB-mediated gene expression regulation in the hippocampus, amygdala and mPFC.
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Nashat, Amir H., and Robert Langer. "Temporal Characteristics of Activation, Deactivation, and Restimulation of Signal Transduction following Depolarization in the Pheochromocytoma Cell Line PC12." Molecular and Cellular Biology 23, no. 14 (July 15, 2003): 4788–95. http://dx.doi.org/10.1128/mcb.23.14.4788-4795.2003.
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ABSTRACT This study focuses on the transient and dynamic activation of intracellular signal transduction following different protocols of depolarization. During chronic depolarization, phosphorylation of extracellular signal-regulated kinases (ERKs) was observed to peak and subsequently fall to low levels within 10 min of depolarization. Short periods of depolarization, from 1 to 5 min in duration, also led to phosphorylation of ERK, and the rate of ERK dephosphorylation was not affected by the duration of depolarization. Phosphorylation of the cyclic AMP response element binding protein (CREB) also peaked as a result of chronic depolarization but decreased to intermediate levels that were maintained for more than 1 h. Pulsatile depolarization was explored as a means to circumvent the deactivation of intracellular signaling activity during chronic depolarization. Both ERK and CREB were rephosphorylated by a second period of depolarization that followed a recovery period of 10 min or more. The effects of the durations of depolarization and interpulse recovery on reactivation of ERK and CREB were characterized. Measurements of free cytoplasmic Ca2+ confirmed the transient rise in the intracellular calcium concentration ([Ca2+]i) during chronic depolarization and the pulsatile increase in [Ca2+]i that can be achieved with short periods of depolarization. This study characterizes the dynamic activities of signal transduction following depolarization. Electrical stimulation of neurons induces many cellular changes that unfold over time, and the influx of Ca2+ ions that mediate these events is transient. This study suggests that pulsatile activity may be a means of maintaining signaling activity over long periods of time.
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Ding, Guopeng, Dandan Li, Yingjie Sun, Keyan Chen, and Dandan Song. "κ-Opioid Receptor Agonist Ameliorates Postoperative Neurocognitive Disorder by Activating the Ca2+/CaMKII/CREB Pathway." Journal of Healthcare Engineering 2021 (September 24, 2021): 1–11. http://dx.doi.org/10.1155/2021/3401654.
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Objective. Cardiopulmonary bypass (CPB) is an important cardiac operation and also a high-risk procedure, leading to postoperative neurocognitive disorder. However, there are few effective drugs to treat the aftermath of CPB. Therefore, we observe the effect of kappa opioid receptor (KOR) agonist on cognitive disorders of rats after cardiopulmonary bypass (CPB) and investigate the mechanism of the Ca2+/calmodulin-dependent protein kinase (CaMKII)/cAMP responsive element-binding protein (CREB) pathway. Methods. A total of 40 Sprague Dawley rats were randomly divided into the sham operation group (sham group, n = 10), CPB model group (CPB group, n = 10), CPB + KOR agonist U50488H group (UH group, n = 10), and CPB + specific CaMKII antagonist + U50488H group (CKU group, n = 10). The changes in the rats’ cognitive function were evaluated using the Morris water maze, the hippocampal histopathological changes were observed via hematoxylin-eosin (H&E) staining, and the apoptosis rate of neuronal cells was detected through terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Moreover, enzyme-linked immunosorbent assay (ELISA) was applied to examine the changes in brain injury markers, inflammatory factors, and oxidative stress factors. The hippocampal variations in Ca2+ concentration and oxidative stress index (ROS) levels were measured by immunofluorescence staining, and western blotting was performed to determine the expression changes in the Ca2+/CaMKII/CREB pathway. Results. The KOR agonist could shorten latency, increase the swimming distance and residence time in the target quadrant, and ameliorate postoperative neurocognitive disorder (PND). Meanwhile, the KOR agonist relieved CPB-induced hippocampal and oxidative stress injuries, reduced NSE and S-100β expression, decreased the apoptosis rate, and repressed the inflammatory response, which alleviated the brain injury. In addition, U50488H was able to decrease Ca2+ influx and glutamate (Glu) level, inhibit N-methyl-D-aspartate receptor (NMDAR) expression, upregulate CaMKII expression, promote CREB phosphorylation, and increase the brain-derived neurotrophic factor (BDNF) level in CPB rats. However, the protective effects of KORs against PND were suppressed following the application of the CaMKII-specific antagonist. Conclusion. The KOR agonist activates the Ca2+/CaMKII/CREB pathway, which improves the brain injury and relieves PND in CPB rats.
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Xu, Xiangyang, Wenzheng Zhang, and Bruce C. Kone. "CREB trans-activates the murine H+-K+-ATPase α2-subunit gene." American Journal of Physiology-Cell Physiology 287, no. 4 (October 2004): C903—C911. http://dx.doi.org/10.1152/ajpcell.00065.2004.
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Despite its key role in potassium homeostasis, transcriptional control of the H+-K+-ATPase α2-subunit (HKα2) gene in the collecting duct remains poorly characterized. cAMP increases H+-K+-ATPase activity in the collecting duct, but its role in activating HKα2 transcription has not been explored. Previously, we demonstrated that the proximal 177 bp of the HKα2 promoter confers basal collecting duct-selective expression. This region contains several potential cAMP/Ca2+-responsive elements (CRE). Accordingly, we examined the participation of CRE-binding protein (CREB) in HKα2 transcriptional control in murine inner medullary collecting duct (mIMCD)-3 cells. Forskolin and vasopressin induced HKα2 mRNA levels, and CREB overexpression stimulated the activity of HKα2 promoter-luciferase constructs. Serial deletion analysis revealed that CREB inducibility was retained in a construct containing the proximal 100 bp of the HKα2 promoter. In contrast, expression of a dominant negative inhibitor (A-CREB) resulted in 60% lower HKα2 promoter-luciferase activity, suggesting that constitutive CREB participates in basal HKα2 transcriptional activity. A constitutively active CREB mutant (CREB-VP16) strongly induced HKα2 promoter-luciferase activity, whereas overexpression of CREBdLZ-VP16, which lacks the CREB DNA-binding domain, abolished this activation. In vitro DNase I footprinting and gel shift/supershift analysis of the proximal promoter with recombinant glutathione S-transferase (GST)-CREB-1 and mIMCD-3 cell nuclear extracts revealed sequence-specific DNA-CREB-1 complexes at −86/−60. Mutation at three CRE-like sequences within this region abolished CREB-1 DNA-binding activity and abrogated CREB-VP16 trans-activation of the HKα2 promoter. In contrast, mutation of the neighboring −104/−94 κβ element did not alter CREB-VP16 trans-activation of the HKα2 promoter. Thus CREB-1, binding to one or more CRE-like elements in the −86/−60 region, trans-activates the HKα2 gene and may represent an important link between rapid and delayed effects of cAMP on HKα2 activity.
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Martin, Chanté Baker. "Writing through Jane Crow: Race and Gender Politics in African American Literature by Ayesha K. Hardison." CLA Journal 61, no. 1-2 (2017): 128–30. http://dx.doi.org/10.1353/caj.2017.0027.
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Ledo, F. "Ca2+-dependent block of CREB-CBP transcription by repressor DREAM." EMBO Journal 21, no. 17 (September 2, 2002): 4583–92. http://dx.doi.org/10.1093/emboj/cdf440.
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Porte, Y., P. Trifilieff, M. Wolff, J. Micheau, M. C. Buhot, and N. Mons. "Extinction of spatial memory alters CREB phosphorylation in hippocampal CA1." Hippocampus 21, no. 11 (September 16, 2010): 1169–79. http://dx.doi.org/10.1002/hipo.20844.
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Song, Shanshan, Ramon J. Ayon, Aya Yamamura, Hisao Yamamura, Swetaleena Dash, Aleksandra Babicheva, Haiyang Tang, et al. "Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH." American Journal of Physiology-Lung Cellular and Molecular Physiology 312, no. 3 (March 1, 2017): L309—L325. http://dx.doi.org/10.1152/ajplung.00357.2016.
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Capsaicin is an active component of chili pepper and a pain relief drug. Capsaicin can activate transient receptor potential vanilloid 1 (TRPV1) channels to increase cytosolic Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. In this study, we observed that a capsaicin-induced increase in [Ca2+]cyt was significantly enhanced in PASMCs from patients with idiopathic pulmonary arterial hypertension (IPAH) compared with normal PASMCs from healthy donors. In addition, the protein expression level of TRPV1 in IPAH PASMCs was greater than in normal PASMCs. Increasing the temperature from 23 to 43°C, or decreasing the extracellular pH value from 7.4 to 5.9 enhanced capsaicin-induced increases in [Ca2+]cyt; the acidity (pH 5.9)- and heat (43°C)-mediated enhancement of capsaicin-induced [Ca2+]cyt increases were greater in IPAH PASMCs than in normal PASMCs. Decreasing the extracellular osmotic pressure from 310 to 200 mOsmol/l also increased [Ca2+]cyt, and the hypo-osmolarity-induced rise in [Ca2+]cyt was greater in IPAH PASMCs than in healthy PASMCs. Inhibition of TRPV1 (with 5′-IRTX or capsazepine) or knockdown of TRPV1 (with short hairpin RNA) attenuated capsaicin-, acidity-, and osmotic stretch-mediated [Ca2+]cyt increases in IPAH PASMCs. Capsaicin induced phosphorylation of CREB by raising [Ca2+]cyt, and capsaicin-induced CREB phosphorylation were significantly enhanced in IPAH PASMCs compared with normal PASMCs. Pharmacological inhibition and knockdown of TRPV1 attenuated IPAH PASMC proliferation. Taken together, the capsaicin-mediated [Ca2+]cyt increase due to upregulated TRPV1 may be a critical pathogenic mechanism that contributes to augmented Ca2+ influx and excessive PASMC proliferation in patients with IPAH.