The Experts below are selected from a list of 10917 Experts worldwide ranked by ideXlab platform
Gaynor E. Spencer - One of the best experts on this subject based on the ideXlab platform.
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Retinoid Receptor based signaling plays a role in voltage dependent inhibition of invertebrate voltage gated ca2 channels
Journal of Biological Chemistry, 2019Co-Authors: Eric De Hoog, Mark K Lukewich, Gaynor E. SpencerAbstract:The retinoic acid Receptor (RAR) and Retinoid X Receptor (RXR) mediate the cellular effects of Retinoids (derivatives of vitamin A). Both RAR and RXR signaling events are implicated in hippocampal synaptic plasticity. Furthermore, Retinoids can interact with calcium signaling during homeostatic plasticity. We recently provided evidence that Retinoids attenuate calcium current (ICa) through neuronal voltage-gated calcium channels (VGCCs). We now examined the possibility that constitutive activity of neuronal RXR and/or RAR alters calcium influx via the VGCCs. We found that in neurons of the mollusk Lymnaea stagnalis, two different RXR antagonists (PA452 and HX531) had independent and opposing effects on ICa that were also time-dependent; whereas the RXR pan-antagonist PA452 enhanced ICa, HX531 reduced ICa Interestingly, this effect of HX531 occurred through voltage-dependent inhibition of VGCCs, a phenomenon known to influence neurotransmitter release from neurons. This inhibition appeared to be independent of G proteins and was largely restricted to Cav2 Ca2+ channels. Of note, an RAR pan-antagonist, LE540, also inhibited ICa but produced G protein-dependent, voltage-dependent inhibition of VGCCs. These findings provide evidence that Retinoid Receptors interact with G proteins in neurons and suggest mechanisms by which Retinoids might affect synaptic calcium signaling.
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Extending the duration of long-term memories: Interactions between environmental darkness and Retinoid signaling.
Neurobiology of Learning and Memory, 2016Co-Authors: Sevanne Carpenter, Cailin M. Rothwell, Michelle L. Wright, Eric De Hoog, Sarah E. Walker, Emma Hudson, Gaynor E. SpencerAbstract:Retinoid signaling plays an important role in hippocampal-dependent vertebrate memories. However, we have previously demonstrated that Retinoids are also involved in the formation of long-term implicit memory following operant conditioning of the invertebrate mollusc Lymnaea stagnalis. Furthermore, we have discovered an interaction between environmental light/dark conditions and Retinoid signaling and the ability of both to convert intermediate-term memory into long-term memory. In this study, we extend these findings to show that Retinoid Receptor agonists and environmental darkness can both also extend the duration of long-term memory. Interestingly, exposure to constant environmental darkness significantly increased the expression of Retinoid Receptors in the adult central nervous system, as well as induced specific changes in a key neuron mediating the conditioned behaviour. These studies not only shed more light on how Retinoids influence memory formation, but also further link environmental light conditions to the Retinoid signaling pathway.
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Retinoid signaling is necessary for, and promotes long-term memory formation following operant conditioning
Neurobiology of Learning and Memory, 2014Co-Authors: Cailin M. Rothwell, Gaynor E. SpencerAbstract:Retinoic acid, a metabolite of vitamin A, is proposed to play an important role in vertebrate learning and memory, as well as hippocampal-dependent synaptic plasticity. However, it has not yet been determined whether retinoic acid plays a similar role in learning and memory in invertebrates. In this study, we report that Retinoid signaling in the mollusc Lymnaea stagnalis, is required for long-term memory formation following operant conditioning of its aerial respiratory behaviour. Animals were exposed to inhibitors of the RALDH enzyme (which synthesizes retinoic acid), or various Retinoid Receptor antagonists. Following exposure to these inhibitors, neither learning nor intermediate-term memory (lasting 2 h) was affected, but long-term memory formation (tested at either 24 or 72 h) was inhibited. We next demonstrated that various Retinoid Receptor agonists promoted long-term memory formation. Using a training paradigm shown only to produce intermediate-term memory (lasting 2 h, but not 24 h) we found that exposure of animals to synthetic Retinoids promoted memory formation that lasted up to 30 h. These findings suggest that the role of Retinoids in memory formation is ancient in origin, and that Retinoid signaling is also important for the formation of implicit memories, in addition to its previously demonstrated role in hippocampal-dependent memories.
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Novel interactive effects of darkness and Retinoid signaling in the ability to form long-term memory following aversive operant conditioning
Neurobiology of Learning and Memory, 2014Co-Authors: Cailin M. Rothwell, Jason Simmons, Grace Peters, Gaynor E. SpencerAbstract:The vitamin A metabolite, retinoic acid, is important for memory formation and hippocampal synaptic plasticity in vertebrate species. In our studies in the mollusc Lymnaea stagnalis, we have shown that retinoic acid plays a role in memory formation following operant conditioning of the aerial respiratory behaviour. Inhibition of either retinaldehyde dehydrogenase (RALDH) or the Retinoid Receptors prevents long-term memory (LTM) formation, whereas synthetic Retinoid Receptor agonists promote memory formation by converting intermediate-term memory (ITM) into LTM. In this study, animals were exposed to constant darkness in order to test whether light-sensitive retinoic acid would promote memory formation. However, we found that exposure to constant darkness alone (in the absence of retinoic acid) enhanced memory formation. To determine whether the memory-promoting effects of darkness could override the memory-inhibiting effects of the Retinoid signaling inhibitors, we exposed snails to RALDH inhibitors or a Retinoid Receptor antagonist in constant darkness. We found that darkness overcame the inhibitory effects of RALDH inhibition, but did not overcome the inhibitory effects of the Retinoid Receptor antagonist. We also tested whether constant darkness and training affected the mRNA levels of the Retinoid metabolic enzymes RALDH and Cyp26, or the mRNA levels of the Retinoid Receptors, but found no significant effect. Overall, these data demonstrate an interaction between environmental light conditions and the Retinoid signaling pathway, which influence long-term memory formation in a mollusc.
Pierre Chambon - One of the best experts on this subject based on the ideXlab platform.
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Modular patterning of structure and function of the striatum by Retinoid Receptor signaling.
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Wen-lin Liao, Hsiu-chao Tsai, Hsiao-fang Wang, Josephine Chang, Yi-chao Lee, Ting-fen Tsai, Hiroshi Takahashi, Michael Wagner, Norbert B Ghyselinck, Pierre ChambonAbstract:Retinoid signaling plays a crucial role in patterning rhombomeres in the hindbrain and motor neurons in the spinal cord during development. A fundamentally interesting question is whether Retinoids can pattern functional organization in the forebrain that generates a high order of cognitive behavior. The striatum contains a compartmental structure of striosome (or "patch") and intervening matrix. How this highly complex mosaic design is patterned by the genetic programs during development remains elusive. We report a developmental mechanism by which Retinoid Receptor signaling controls compartmental formation in the striatum. We analyzed RARbeta(-/-) mutant mice and found a selective loss of striosomal compartmentalization in the rostral mutant striatum. The loss of RARbeta signaling in the mutant mice resulted in reduction of cyclin E2, a cell cycle protein regulating transition from G(1) to S phase, and also reduction of the proneural gene Mash1, which led to defective neurogenesis of late-born striosomal cells. Importantly, during striatal neurogenesis, endogenous levels of retinoic acid were spatiotemporally regulated such that transduction of high levels of retinoic acid through RARbeta selectively expanded the population of late-born striosomal progenitors, which evolved into a highly elaborate compartment in the rostral striatum. RARbeta(-/-) mutant mice, which lacked such enlarged compartment, displayed complex alternations of dopamine agonist-induced stereotypic motor behavior, including exaggeration of head bobbing movement and reduction of rearing activity. RARbeta signaling thus plays a crucial role in setting up striatal compartments that may engage in neural circuits of psychomotor control.
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modular patterning of structure and function of the striatum by Retinoid Receptor signaling
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Wen-lin Liao, Hsiu-chao Tsai, Hsiao-fang Wang, Josephine Chang, Yi-chao Lee, Ting-fen Tsai, Hiroshi Takahashi, Michael Wagner, Norbert B Ghyselinck, Pierre ChambonAbstract:Retinoid signaling plays a crucial role in patterning rhombomeres in the hindbrain and motor neurons in the spinal cord during development. A fundamentally interesting question is whether Retinoids can pattern functional organization in the forebrain that generates a high order of cognitive behavior. The striatum contains a compartmental structure of striosome (or “patch”) and intervening matrix. How this highly complex mosaic design is patterned by the genetic programs during development remains elusive. We report a developmental mechanism by which Retinoid Receptor signaling controls compartmental formation in the striatum. We analyzed RARβ−/− mutant mice and found a selective loss of striosomal compartmentalization in the rostral mutant striatum. The loss of RARβ signaling in the mutant mice resulted in reduction of cyclin E2, a cell cycle protein regulating transition from G1 to S phase, and also reduction of the proneural gene Mash1, which led to defective neurogenesis of late-born striosomal cells. Importantly, during striatal neurogenesis, endogenous levels of retinoic acid were spatiotemporally regulated such that transduction of high levels of retinoic acid through RARβ selectively expanded the population of late-born striosomal progenitors, which evolved into a highly elaborate compartment in the rostral striatum. RARβ−/− mutant mice, which lacked such enlarged compartment, displayed complex alternations of dopamine agonist-induced stereotypic motor behavior, including exaggeration of head bobbing movement and reduction of rearing activity. RARβ signaling thus plays a crucial role in setting up striatal compartments that may engage in neural circuits of psychomotor control.
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Contribution of targeted conditional somatic mutagenesis to deciphering Retinoid X Receptor functions and to generating mouse models of human diseases.
Handb Exp Pharmacol, 2007Co-Authors: Daniel Metzger, Pierre ChambonAbstract:The last decade has witnessed an enormous rise in the interest for Retinoid signalling and its cognate Receptors, because of their central role in the coordination of development and homeostasis, through their ability to orchestrate the expression of numerous target genes. These Receptors include six nuclear Receptor (NR) family members, the retinoic acid Receptor (RAR) alpha, beta and gamma, and the Retinoid X Receptor (RXR) alpha, beta and gamma, which are expressed in many cell types in mammals. Analysis of the development of mouse embryos bearing Retinoid Receptor null mutations demonstrated that these Receptors transduce the effects of retinoic acid (RA, the active derivative of vitamin A) in vivo, and revealed impressive complexity. However, frequent redundancy in Receptor functions and lethality of compound RAR-null mutants, as well as of RXRalpha-null mutants, precluded the characterisation of the functions of these Receptors during late development and postnatally. We illustrate here how recent developments of conditional targeted somatic mutagenesis have opened new avenues in analysing the physiological functions of Retinoid X Receptor signalling in a variety of tissues and cell types, as well as in exploring the pathophysiological consequences of their alteration that led to novel mouse models of human diseases.
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Targeted somatic mutagenesis in the mouse epidermis.
Methods in Molecular Biology, 2005Co-Authors: Daniel Metzger, Pierre ChambonAbstract:The efficient introduction of somatic mutations in a given gene at a given time and in specific cell types of the skin will greatly facilitate the studies of a number of genes expressed in the skin and the production of animal models for skin diseases. We describe here strategies and techniques to create spatiotemporally controlled somatic mutations of target genes in the skin using a conditional Cre/LoxP system. They are based on cell-specific expression of the chimeric Cre recombinase Cre-ERT2, whose activity is induced by antiestrogens such as Tamoxifen (Tam), and which is obtained by fusing the Cre recombinase with a mutated ligand binding domain of the human estrogen Receptor ERalpha. As an example, we present ablation of the Retinoid Receptor RXRalpha in epidermal basal keratinocytes of adult mice.
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Impaired Locomotion and Dopamine Signaling in Retinoid Receptor Mutant Mice
Science (New York N.Y.), 1998Co-Authors: Norbert B Ghyselinck, Tarek A. Samad, Valérie Dupé, Philippe Kastner, Emiliana Borrelli, Pierre ChambonAbstract:In the adult mouse, single and compound null mutations in the genes for retinoic acid Receptor beta and Retinoid X Receptors beta and gamma resulted in locomotor defects related to dysfunction of the mesolimbic dopamine signaling pathway. Expression of the D1 and D2 Receptors for dopamine was reduced in the ventral striatum of mutant mice, and the response of double null mutant mice to cocaine, which affects dopamine signaling in the mesolimbic system, was blunted. Thus, Retinoid Receptors are involved in the regulation of brain functions, and retinoic acid signaling defects may contribute to pathologies such as Parkinson's disease and schizophrenia.
Reuben Lotan - One of the best experts on this subject based on the ideXlab platform.
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Decreased expression of Retinoid Receptors in melanoma : Entailment in tumorigenesis and prognosis
Clinical cancer research : an official journal of the American Association for Cancer Research, 2007Co-Authors: Nitin Chakravarti, Reuben Lotan, Abdul H. Diwan, Carla L. Warneke, Marcella M. Johnson, Victor G. PrietoAbstract:Purpose: Retinoids inhibit proliferation and induce differentiation in melanoma cells. Retinoic acid Receptors (RAR) and Retinoid X Receptors (RXR) mediate the various modulatory effects of Retinoids in cells. We have studied the in situ expression of each RAR and RXR protein (α, β, γ) in a large series of melanocytic lesions and correlated the expression with clinicopathologic features and prognosis of the patients. Experimental Design: Tissue microarray blocks of 226 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic and nuclear expression of RAR and RXR protein (α, β, γ). Results: A significant decrease of RARβ protein ( P P P P = 0.048) and RXRα ( P = 0.001) was observed in the lesions showing vertical growth pattern. In addition, in patients with concomitant loss of cytoplasmic staining for RARα and RXRα, the probability of overall survival (log-rank test, P = 0.002) and disease-specific survival (log-rank test, P = 0.014) was significantly lower. Conclusions: Aberrant expression of Retinoid Receptors seems to be a frequent event in melanoma and suggests an impairment of the Retinoid pathway in this cancer. Our data indicate the loss of Retinoid Receptor expression with melanoma progression and suggest a possible prognostic significance of the analysis of Retinoid Receptors in melanoma.
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Expression of Retinoid Receptors in sebaceous cell carcinoma.
Journal of cutaneous pathology, 2006Co-Authors: Nitin Chakravarti, H.g. Saadati, Adel K. El-naggar, Reuben Lotan, Roxanna E. Diba, Abdul H. Diwan, Victor G. Prieto, James Anderson, Bita EsmaeliAbstract:PURPOSE: The aim of this study is to investigate whether there are any abnormalities in the in vivo expression of Retinoid acid Receptors (RAR-alpha, RAR-beta and RAR-gamma) and Retinoid X Receptors (RXR-alpha, RXR-beta and RXR-gamma) in sebaceous cell carcinoma. METHODS: Expression of Retinoid Receptors in paired specimens of cancerous tissues (n = 10) and adjacent normal tissues (n = 10) from 10 patients with sebaceous cell carcinoma was studied immunohistochemically by using anti-Retinoid Receptor antibodies. RESULTS: In eight of the 10 normal tissue samples, all six Receptors were expressed. In the other two samples, all Receptors were expressed except RAR-gamma (one sample) or RXR-gamma (two samples). Five tumours (50%) lacked RAR-alpha; RAR-alpha expression was lower in tumours than in normal tissues in eight of 10 cases. RAR-beta was expressed in the cytoplasm of nine of 10 tumours; RAR-beta expression was at least as high in tumours as in normal tissue in eight of 10 cases. Two tumours lacked RAR-gamma; three tumours had lower RAR-gamma expression than paired normal epithelium; four had the same RAR-gamma expression, and one had higher RAR-gamma expression. RXR-alpha expression was strong in all normal tissues and tumour samples. Ten tumours lacked RXR-beta and all 10 tumours lacked RXR-gamma expression. CONCLUSIONS: Diminished RXR-beta and RXR-gamma expression might be related to the development of sebaceous cell carcinoma. Additional studies are required to establish whether the defects in RAR expression in sebaceous cell carcinoma might affect the potential response of this tumour to treatment with Retinoids.
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Retinoid Receptor Subtypes in Sebaceous Cell Carcinoma of the Eyelid
Ophthalmic plastic and reconstructive surgery, 2005Co-Authors: Nitin Chakravarti, H.g. Saadati, Adel K. El-naggar, Reuben Lotan, Roxanna E. Diba, Bita EsmaeliAbstract:PURPOSE To study Retinoid Receptor expression in sebaceous cell carcinoma of the eyelid. METHODS Expression of Retinoid Receptors (RAR alpha, beta, and gamma and RXR alpha, beta, and gamma) in tumor specimens from 10 patients with sebaceous cell carcinoma of the eyelid and in 3 normal incidental tarsus specimens from healthy adults without cancer was studied immunohistochemically by using antiRetinoid Receptor antibodies. RESULTS In all 3 specimens of normal tarsus, all 6 Retinoid Receptors were expressed. RARalpha expression was absent in 3 tumors and was decreased in 3 tumors compared with expression in the control tissues. RARbeta expression in carcinomas was primarily perinuclear; 6 tumors showed increased RARbeta expression compared with controls. RARgamma expression was absent in 4 tumors and was decreased in 2 tumors compared with controls. RXRalpha nuclear expression was decreased compared with controls in 5 tumors. RXRbeta expression was low in 7 tumors. RXRgamma expression was absent in 6 tumors. CONCLUSIONS Aberrant expression of Retinoid Receptors in sebaceous cell carcinoma of the eyelid might play a role in the pathogenesis and progression of this carcinoma.
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Retinoid Receptor-Dependent and Independent Biological Activities of Novel Fenretinide Analogues and Metabolites
Clinical cancer research : an official journal of the American Association for Cancer Research, 2003Co-Authors: Anita L. Sabichi, Susan M. Fischer, Reuben Lotan, Changchan Zou, Xiulan Yang, Vernon E. Steele, Gary J. Kelloff, John L. CliffordAbstract:Fenretinide (4-HPR) is a Retinoid analogue with antitumor and chemopreventive activities. In addition to 4-HPR, there are several other new phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal phenylamine ring [N-(2-hydroxyphenyl)retinamide (2-HPR), N-(3-hydroxyphenyl)retinamide, N-(2-carboxyphenyl)retinamide, N-(3-carboxyphenyl)retinamide, N-(4-carboxyphenyl)retinamide, and N-(4-methoxyphenyl)retinamide (4-MPR) ]. It is hypothesized that these agents can act independent of the nuclear Retinoid Receptor pathway. To test this hypothesis directly, we have analyzed the activity of these phenylretinamides in vitro on a panel of F9 murine embryonal carcinoma cell lines, which includes wild-type (F9-WT) and mutant cells that have disrupted genes for both Retinoid X Receptor alpha and retinoic acid Receptor gamma Retinoid Receptors (F9-KO). The F9-KO cells lack almost all measurable response to all-trans-retinoic acid, the primary biologically active Retinoid. Two distinct effects of retinamides were identified. The first is a rapid, dose-dependent induction of cell growth inhibition (reduced cell viability), and the second is a slower induction of differentiation and accumulation of cells in the G(1) phase of the cell cycle that was observed with a concentration of 1 micro M, for only those phenylretinamides bearing charged (hydroxyl or carboxyl) groups on the terminal phenylamine ring. The induction of differentiation and G(1) accumulation was only observed in the F9-WT cells, indicating that this effect is Receptor-dependent. 4-MPR, a major metabolite of 4-HPR, lacks a charged group on the terminal phenylamine ring and did not induce Retinoid Receptor-dependent effects, but did induce cell growth inhibition. Thus, 4-MPR may play a role in the clinical activity of 4-HPR. This study further reveals the mechanism of action of these novel phenylretinamides and supports continued investigation into their development as chemopreventive drugs.
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cyclooxygenase 2 overexpression is a marker of poor prognosis in stage i non small cell lung cancer
Clinical Cancer Research, 2001Co-Authors: Fadlo R Khuri, Reuben Lotan, Waun Ki Hong, Hong Wu, Bonnie L Kemp, Scott M Lippman, Lei Feng, Xiao Chun XuAbstract:Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins, is overexpressed in a variety of different tumors, including those of the colon, pancreas, lung, and head and neck. We used in situ hybridization with a digoxgenin-labeled COX-2 antisense riboprobe to assess the presence of strong or intermediate versus weak or absent COX-2 expression in specimens from 160 patients with stage I non-small cell lung cancer (NSCLC). Of these, 3 specimens had strong expression, 69 had intermediate expression of COX-2, 24 had weak expression, and 64 had no detectable COX-2. The strength of COX-2 expression was associated with a worse overall survival rate (P = 0.001) and a worse disease-free survival rate (P = 0.022). The median survival times for the strong, intermediate or weak, and null COX-2 expressors were 1.04, 5.50, and 8.54 years, respectively. Interestingly, all three specimens with strong COX-2 expression came from patients who died within 18 months. Retinoic acid Receptor β (RAR-β) is a nuclear Retinoid Receptor whose expression is frequently lost in aerodigestive tract carcinogenesis. We previously demonstrated that expression of RAR-β in stage I NSCLC indicates a poor prognosis. Retinoids have been shown to prevent induction of COX-2 by mitogens and tumor promoters. Expression of COX-2 correlated with RAR-β expression (P = 0.053), but not with k-ras mutational status, vascular endothelial growth factor, basic fibroblast growth factor, interleukin 8 levels, or other markers of angiogenesis, invasion, and metastases. Thus, like RAR-β positivity, COX-2 overexpression appears to portend a shorter survival among patients with early stage non-small cell lung cancer. Future studies of RAR-β and COX-2 regulation in NSCLC should further the development of prevention and therapy interventions with Retinoids and/or COX-2 antagonists in this patient population.
Xiaodong Zhang - One of the best experts on this subject based on the ideXlab platform.
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long noncoding rna hulc modulates abnormal lipid metabolism in hepatoma cells through an mir 9 mediated rxra signaling pathway
Cancer Research, 2015Co-Authors: Ming Cui, Zelin Xiao, Yue Wang, Minying Zheng, Tianqiang Song, Xiaoli Cai, Baodi Sun, Xiaodong ZhangAbstract:HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo. Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the Retinoid Receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling.
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long noncoding rna hulc modulates abnormal lipid metabolism in hepatoma cells through an mir 9 mediated rxra signaling pathway
Cancer Research, 2015Co-Authors: Zelin Xiao, Yue Wang, Minying Zheng, Tianqiang Song, Lihong Ye, Xiaodong ZhangAbstract:HULC is a long noncoding RNA overexpressed in hepatocellular carcinoma (HCC), but its functional contributions in this setting have not been determined. In this study, we explored the hypothesis that HULC contributes to malignant development by supporting abnormal lipid metabolism in hepatoma cells. HULC modulated the deregulation of lipid metabolism in HCC by activating the acyl-CoA synthetase subunit ACSL1. Immunohistochemical analysis of tissue microarrays revealed that approximately 77% (180/233) of HCC tissues were positive for ACSL1. Moreover, HULC mRNA levels correlated positively with ACSL1 levels in 60 HCC cases according to real-time PCR analysis. Mechanistic investigations showed that HULC upregulated the transcriptional factor PPARA, which activated the ACSL1 promoter in hepatoma cells. HULC also suppressed miR-9 targeting of PPARA mRNA by eliciting methylation of CpG islands in the miR-9 promoter. We documented the ability of HULC to promote lipogenesis, thereby stimulating accumulation of intracellular triglycerides and cholesterol in vitro and in vivo . Strikingly, ACSL1 overexpression that generates cholesterol was sufficient to enhance the proliferation of hepatoma cells. Further, cholesterol addition was sufficient to upregulate HULC expression through a positive feedback loop involving the Retinoid Receptor RXRA, which activated the HULC promoter. Overall, we concluded that HULC functions as an oncogene in hepatoma cells, acting mechanistically by deregulating lipid metabolism through a signaling pathway involving miR-9, PPARA, and ACSL1 that is reinforced by a feed-forward pathway involving cholesterol and RXRA to drive HULC signaling. Cancer Res; 75(5); 846–57. ©2015 AACR .
Cailin M. Rothwell - One of the best experts on this subject based on the ideXlab platform.
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Extending the duration of long-term memories: Interactions between environmental darkness and Retinoid signaling.
Neurobiology of Learning and Memory, 2016Co-Authors: Sevanne Carpenter, Cailin M. Rothwell, Michelle L. Wright, Eric De Hoog, Sarah E. Walker, Emma Hudson, Gaynor E. SpencerAbstract:Retinoid signaling plays an important role in hippocampal-dependent vertebrate memories. However, we have previously demonstrated that Retinoids are also involved in the formation of long-term implicit memory following operant conditioning of the invertebrate mollusc Lymnaea stagnalis. Furthermore, we have discovered an interaction between environmental light/dark conditions and Retinoid signaling and the ability of both to convert intermediate-term memory into long-term memory. In this study, we extend these findings to show that Retinoid Receptor agonists and environmental darkness can both also extend the duration of long-term memory. Interestingly, exposure to constant environmental darkness significantly increased the expression of Retinoid Receptors in the adult central nervous system, as well as induced specific changes in a key neuron mediating the conditioned behaviour. These studies not only shed more light on how Retinoids influence memory formation, but also further link environmental light conditions to the Retinoid signaling pathway.
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Retinoid signaling is necessary for, and promotes long-term memory formation following operant conditioning
Neurobiology of Learning and Memory, 2014Co-Authors: Cailin M. Rothwell, Gaynor E. SpencerAbstract:Retinoic acid, a metabolite of vitamin A, is proposed to play an important role in vertebrate learning and memory, as well as hippocampal-dependent synaptic plasticity. However, it has not yet been determined whether retinoic acid plays a similar role in learning and memory in invertebrates. In this study, we report that Retinoid signaling in the mollusc Lymnaea stagnalis, is required for long-term memory formation following operant conditioning of its aerial respiratory behaviour. Animals were exposed to inhibitors of the RALDH enzyme (which synthesizes retinoic acid), or various Retinoid Receptor antagonists. Following exposure to these inhibitors, neither learning nor intermediate-term memory (lasting 2 h) was affected, but long-term memory formation (tested at either 24 or 72 h) was inhibited. We next demonstrated that various Retinoid Receptor agonists promoted long-term memory formation. Using a training paradigm shown only to produce intermediate-term memory (lasting 2 h, but not 24 h) we found that exposure of animals to synthetic Retinoids promoted memory formation that lasted up to 30 h. These findings suggest that the role of Retinoids in memory formation is ancient in origin, and that Retinoid signaling is also important for the formation of implicit memories, in addition to its previously demonstrated role in hippocampal-dependent memories.
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Novel interactive effects of darkness and Retinoid signaling in the ability to form long-term memory following aversive operant conditioning
Neurobiology of Learning and Memory, 2014Co-Authors: Cailin M. Rothwell, Jason Simmons, Grace Peters, Gaynor E. SpencerAbstract:The vitamin A metabolite, retinoic acid, is important for memory formation and hippocampal synaptic plasticity in vertebrate species. In our studies in the mollusc Lymnaea stagnalis, we have shown that retinoic acid plays a role in memory formation following operant conditioning of the aerial respiratory behaviour. Inhibition of either retinaldehyde dehydrogenase (RALDH) or the Retinoid Receptors prevents long-term memory (LTM) formation, whereas synthetic Retinoid Receptor agonists promote memory formation by converting intermediate-term memory (ITM) into LTM. In this study, animals were exposed to constant darkness in order to test whether light-sensitive retinoic acid would promote memory formation. However, we found that exposure to constant darkness alone (in the absence of retinoic acid) enhanced memory formation. To determine whether the memory-promoting effects of darkness could override the memory-inhibiting effects of the Retinoid signaling inhibitors, we exposed snails to RALDH inhibitors or a Retinoid Receptor antagonist in constant darkness. We found that darkness overcame the inhibitory effects of RALDH inhibition, but did not overcome the inhibitory effects of the Retinoid Receptor antagonist. We also tested whether constant darkness and training affected the mRNA levels of the Retinoid metabolic enzymes RALDH and Cyp26, or the mRNA levels of the Retinoid Receptors, but found no significant effect. Overall, these data demonstrate an interaction between environmental light conditions and the Retinoid signaling pathway, which influence long-term memory formation in a mollusc.