The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Anthony P. H. Wright - One of the best experts on this subject based on the ideXlab platform.
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Recruitment of Gcn5-containing complexes during c-Myc-dependent Gene Activation. Structure and function aspects.
The Journal of biological chemistry, 2002Co-Authors: Elizabeth M. Flinn, Annika E. Wallberg, Stefan Hermann, Patrick A. Grant, Jerry L. Workman, Anthony P. H. WrightAbstract:The N-terminal domain of c-Myc plays a key role in cellular transformation and is involved in both Activation and repression of target Genes as well as in modulated proteolysis of c-Myc via the proteasome. Given this functional complexity, it has been difficult to clarify the structures within the N terminus that contribute to these different processes as well as the mechanisms by which they function. We have used a simplified yeast model system to identify the primary determinants within the N terminus for (i) chromatin remodeling of a promoter, (ii) Gene Activation from a chromatin template in vivo, and (iii) interaction with highly purified Gcn5 complexes as well as other chromatin-remodeling complexes in vitro. The results identify two regions that contain autonomous chromatin opening and Gene Activation activity, but both regions are required for efficient interaction with chromatin-remodeling complexes in vitro. The conserved Myc boxes do not play a direct role in Gene Activation, and Myc box II is not Generally required for in vitro interactions with remodeling complexes. The yeast SAGA complex, which is orthologous to the human GCN5-TRRAP complex that interacts with Myc in human cells, plays a role in Myc-mediated chromatin opening at the promoter but may also be involved in later steps of Gene Activation.
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Recruitment of chromatin remodelling factors during Gene Activation via the glucocorticoid receptor N-terminal domain.
Biochemical Society transactions, 2000Co-Authors: A. E. Wallberg, E. M. Flinn, Jan-ake Gustafsson, Anthony P. H. WrightAbstract:We have shown that yeast mutants with defects in the Ada adaptor proteins are defective in hormone-dependent Gene Activation by ectopically expressed human glucocorticoid receptor (GR). Others have shown that the Ada2 protein is required for physical interactions between some Activation domains and TBP (TATA-binding protein), whereas the Gcn5 (Ada4) protein has a histone acetyltransferase (HAT) activity. Although all HAT enzymes are able to acetylate histone substrates, some also acetylate non-histone proteins. Taken together, these observations suggest that the Ada proteins have the ability to effect different steps in the process of Gene Activation. It has recently been shown that the Ada proteins are present in two distinct protein complexes, the Ada complex and a larger SAGA complex. Our recent work has focused on determining (1) which of the Ada-containing complexes mediates Gene Activation by GR, (2) whether the HAT activity encoded by GCN5 is required for GR-dependent Gene Activation, (3) whether the Ada proteins contribute to GR-mediated Activation at the level of chromatin remodelling and (4) how the role of these HAT complexes is integrated with other chromatin remodelling activities during GR-mediated Gene Activation. Our results suggest a model in which GR recruits the SAGA complex and that this contributes to chromatin remodelling via a mechanism involving the acetylation of histones. Furthermore, recruitment of the SWI/SNF remodelling complex also has a role in GR-mediated Activation that is independent of the role of SAGA. These complexes are similar to analogous mammalian complexes and therefore these results are likely to be relevant to the human system.
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Role of the Ada adaptor complex in Gene Activation by the glucocorticoid receptor.
Molecular and cellular biology, 1997Co-Authors: Annika Henriksson, Jan-ake Gustafsson, Tova Almlöf, Jacqueline Ford, Iain J. Mcewan, Anthony P. H. WrightAbstract:We have shown that the Ada adaptor complex is important for the Gene Activation capacity of the glucocorticoid receptor in yeast. The recently isolated human Ada2 protein also increases the potency of the receptor protein in mammalian cells. The Ada pathway is of key significance for the tau1 core transActivation domain (tau1c) of the receptor, which requires Ada for activity in vivo and in vitro. Ada2 can be precipitated from nuclear extracts by a glutathione S-transferase-tau1 fusion protein coupled to agarose beads, and a direct interaction between Ada2 and tau1c can be shown by using purified proteins. This interaction is strongly reduced by a mutation in tau1c that reduces transActivation activity. Mutations affecting the Ada complex do not reverse transcriptional squelching by the tau1 domain, as they do for the VP16 transActivation domain, and thus these powerful acidic activators differ in at least some important aspects of Gene Activation. Mutations that reduce the activity of the tau1c domain in wild-type yeast strains cause similar reductions in ada mutants that contain little or no Ada activity. Thus, Gene Activation mechanisms, in addition to the Ada pathway, are involved in the activity of the tau1c domain.
Pal Maliga - One of the best experts on this subject based on the ideXlab platform.
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Gene Activation in plastids by the CRE site-specific recombinase.
Plant molecular biology, 2006Co-Authors: Tarinee Tungsuchat, Hiroshi Kuroda, Jarunya Narangajavana, Pal MaligaAbstract:We developed a novel system for Gene Activation in plastids that uses the CRE/loxP site-specific recombination system to create a translatable reading frame by excision of a blocking sequence. To test the system, we introduced an inactive gfp* Gene into the tobacco plastid genome downstream of the selectable spectinomcyin resistance (aadA) marker Gene. The aadA Gene is the blocking sequence, and is flanked by directly oriented loxP sites for excision by the CRE. In the non-activated state, gfp* is transcribed from the aadA promoter, but the mRNA is not translated due to the lack of an AUG translation initiation codon. Green Fluorescent Protein (GFP) expression is activated by excision of the aadA coding segment to link up the gfp* coding region with the translation initiation codon of aadA. Tobacco plants that carry the inactive gfp* Gene do not contain detectable levels of GFP. However, Activation of gfp* resulted in GFP accumulation, proving the utility of CRE-induced protein expression in tobacco chloroplasts. The Gene Activation system described here will be useful to probe plastid Gene function and for the production of recombinant proteins in chloroplasts.
Pauli V. Luoma - One of the best experts on this subject based on the ideXlab platform.
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Gene Activation regresses atherosclerosis, promotes health, and enhances longevity
Lipids in health and disease, 2010Co-Authors: Pauli V. LuomaAbstract:Background Lifestyle factors and pharmacological compounds activate Genetic mechanisms that influence the development of atherosclerotic and other diseases. This article reviews studies on natural and pharmacological Gene Activation that promotes health and enhances longevity.
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Gene Activation regresses atherosclerosis, promotes health, and enhances longevity
Lipids in Health and Disease, 2010Co-Authors: Pauli V. LuomaAbstract:Background Lifestyle factors and pharmacological compounds activate Genetic mechanisms that influence the development of atherosclerotic and other diseases. This article reviews studies on natural and pharmacological Gene Activation that promotes health and enhances longevity. Results Living habits including healthy diet and regular physical activity, and pharmacotherapy, upregulate Genes encoding enzymes and apolipoprotein and ATP-binding cassette transporters, acting in metabolic processes that promote health and increase survival. Cytochrome P450-enzymes, physiological factors in maintaining cholesterol homeostasis, Generate oxysterols for the elimination of surplus cholesterol. Hepatic CTP:phosphocholine cytidylyltransferase-α is an important regulator of plasma HDL-C level. Gene-activators produce plasma lipoprotein profile, high HDL-C, HDL_2-C and HDL-C/cholesterol ratio, which is typical of low risk of atherosclerotic disease, and also of exceptional longevity together with reduced prevalence of cardiovascular, metabolic and other diseases. High HDL contributes to protection against inflammation, oxidation and thrombosis, and associates with good cognitive function in very old people. Avoiding unhealthy stress and managing it properly promotes health and increases life expectancy. Conclusions Healthy living habits and Gene-activating xenobiotics upregulate mechanisms that produce lipoprotein pattern typical of very old people and enhance longevity. Lipoprotein metabolism and large HDL_2 associate with the process of living a very long life. Major future goals for health promotion are the improving of commitment to both wise lifestyle choices and drug therapy, and further the developing of new and more effective and well tolerated drugs and treatments.
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Cytochrome P450 and Gene Activation—from pharmacology to cholesterol elimination and regression of atherosclerosis
European Journal of Clinical Pharmacology, 2008Co-Authors: Pauli V. LuomaAbstract:Background Lipoproteins are closely associated with the atherosclerotic vascular process. Elevated levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) in plasma indicate a low probability of coronary heart disease (CHD) together with enhanced longevity, and elevated levels of low-density lipoprotein-cholesterol (LDL-C) and apo B indicate an increased risk of CHD and death. Studies linking Gene Activation and the induction of cytochrome P450 with elevated plasma levels of apo AI and HDL-C and lowered plasma levels of LDL-C presented a new potential approach to prevent and treat atherosclerotic disease. Objective and methods This is a review aimed at clarifying the effects of P450-enzymes and Gene Activation on cholesterol homeostasis, the atherosclerotic vascular process, prevention and regression of atherosclerosis and the manifestation of atherosclerotic disease, particularly CHD, the leading cause of death in the world. Results P450-enzymes maintain cellular cholesterol homeostasis. They respond to cholesterol accumulation by enhancing the Generation of hydroxycholesterols (oxysterols) and activating cholesterol-eliminating mechanisms. The CYP7A1, CYP27A1, CYP46A1 and CYP3A4 enzymes Generate major oxysterols that enter the circulation. The oxysterols activate—via nuclear receptors—ATP-binding cassette (ABC) A1 and other Genes, leading to the elimination of excess cholesterol and protecting arteries from atherosclerosis. Several drugs and nonpharmacologic compounds are ligands for the liver X receptor, pregnane X receptor and other receptors, activate P450 and other Genes involved in cholesterol elimination, prevent or regress atherosclerosis and reduce cardiovascular events. Conclusions P450-enzymes are essential in the physiological maintenance of cholesterol balance. They activate mechanisms which eliminate excess cholesterol and counteract the atherosclerotic process. Several drugs and nonpharmacologic compounds induce P450 and other Genes, prevent or regress atherosclerosis and reduce the occurrence of non-fatal and fatal CHD and other atherosclerotic diseases.
Howard M. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Steroid-like signalling by interferons: making sense of specific Gene Activation by cytokines
The Biochemical journal, 2012Co-Authors: Howard M. Johnson, Ezra N. Noon-song, Kaisa M. Kemppainen, Chulbul M. AhmedAbstract:Many cytokines, hormones and growth factors use the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway for cell signalling and specific Gene Activation. In the classical model, ligand is said to interact solely with the receptor extracellular domain, which triggers JAK Activation of STATs at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific Gene Activation. Given the limited number of STATs (seven) and the Activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on IFNγ (interferon γ), we have shown that ligand, receptor and activated JAKs are involved in nuclear events that are associated with specific Gene Activation, where the receptor subunit IFNGR1 (IFNγ receptor 1) functions as a transcription/co-transcription factor and the JAKs are involved in key epiGenetic events. RTKs (receptor tyrosine kinases) such as EGFR [EGF (epidermal growth factor) receptor] and FGFR [FGF (fibroblast growth factor) receptor] also undergo nuclear translocation in association with their respective ligands. EGFR and FGFR, like IFNGR1, have been shown to function as transcription/co-transcription factors. The RTKs also regulate other kinases that have epiGenetic effects. Our IFNγ model, as well as the RTKs EGFR and FGFR, have similarities to that of steroid receptor signalling. These systems consist of ligand–receptor–co-activator complexes at the Genes that they activate. The co-activators consist of transcription factors and kinases, of which the latter play an important role in the associated epiGenetics. It is our view that signalling by cytokines such as IFNγ is but a variation of specific Gene Activation by steroid hormones.
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Controlling Nuclear Jaks and Stats for Specific Gene Activation by Ifn γ and Other Cytokines: A Possible Steroid-like Connection
Journal of clinical & cellular immunology, 2011Co-Authors: Howard M. Johnson, Ezra N. Noon-song, Chulbul M. AhmedAbstract:The mechanism of specific Gene Activation by cytokines that use JAK/STAT signalling pathway is unknown. There are four different types of JAKs and seven different types of STATs. In the classical model of signaling, ligand interacts solely with the receptor extracellular domain, which triggers JAK Activation at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific Gene Activation, including associated epiGenetic changes that cause heterochromatin destabilization. Ligand, receptor, and JAKs play no further role in the classical model. Given the limited number of STATs and the Activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on gamma interferon (IFNγ), we have shown that ligand, receptor, and activated JAKs are involved in nuclear events that are associated with specific Gene Activation. In this model, receptor subunit IFNGR1 functions as a transcription/cotranscription factor and the JAKs are involved in key epiGenetic events that are required for specific Gene Activation. The model has implications for Gene Activation in cancer as well as stem cell differentiation.
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Controlling nuclear JAKs and STATs for specific Gene Activation by IFNγ.
Biochemical and biophysical research communications, 2011Co-Authors: Ezra N. Noon-song, Chulbul M. I. Ahmed, Rea Dabelic, Johnathan Canton, Howard M. JohnsonAbstract:We previously showed that gamma interferon (IFNγ) and its receptor subunit, IFNGR1, interacted with the promoter region of IFNγ-activated Genes along with transcription factor STAT1α. Recent studies have suggested that activated Janus kinases pJAK2 and pJAK1 also played a role in Gene Activation by phosphorylation of histone H3 on tyrosine 41. This study addresses the question of the role of activated JAKs in specific Gene Activation by IFNγ. We carried out chromatin immunoprecipitation (ChIP) followed by PCR in IFNγ treated WISH cells and showed association of pJAK1, pJAK2, IFNGR1, and STAT1 on the same DNA sequence of the IRF-1 Gene promoter. The β-actin Gene, which is not activated by IFNγ, did not show this association. The movement of activated JAK to the nucleus and the IRF-1 promoter was confirmed by the combination of nuclear fractionation, confocal microscopy and DNA precipitation analysis using the biotinylated GAS promoter. Activated JAKs in the nucleus was associated with phosphorylated tyrosine 41 on histone H3 in the region of the GAS promoter. Unphosphorylated JAK2 was found to be constitutively present in the nucleus and was capable of undergoing Activation in IFNγ treated cells, most likely via nuclear IFNGR1. Association of pJAK2 and IFNGR1 with histone H3 in IFNγ treated cells was demonstrated by histone H3 immunoprecipitation. Unphosphorylated STAT1 protein was associated with histone H3 of untreated cells. IFNγ treatment resulted in its disassociation and then re-association as pSTAT1. The results suggest a novel role for activated JAKs in epiGenetic events for specific Gene Activation.
Chulbul M. Ahmed - One of the best experts on this subject based on the ideXlab platform.
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Steroid-like signalling by interferons: making sense of specific Gene Activation by cytokines
The Biochemical journal, 2012Co-Authors: Howard M. Johnson, Ezra N. Noon-song, Kaisa M. Kemppainen, Chulbul M. AhmedAbstract:Many cytokines, hormones and growth factors use the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway for cell signalling and specific Gene Activation. In the classical model, ligand is said to interact solely with the receptor extracellular domain, which triggers JAK Activation of STATs at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific Gene Activation. Given the limited number of STATs (seven) and the Activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on IFNγ (interferon γ), we have shown that ligand, receptor and activated JAKs are involved in nuclear events that are associated with specific Gene Activation, where the receptor subunit IFNGR1 (IFNγ receptor 1) functions as a transcription/co-transcription factor and the JAKs are involved in key epiGenetic events. RTKs (receptor tyrosine kinases) such as EGFR [EGF (epidermal growth factor) receptor] and FGFR [FGF (fibroblast growth factor) receptor] also undergo nuclear translocation in association with their respective ligands. EGFR and FGFR, like IFNGR1, have been shown to function as transcription/co-transcription factors. The RTKs also regulate other kinases that have epiGenetic effects. Our IFNγ model, as well as the RTKs EGFR and FGFR, have similarities to that of steroid receptor signalling. These systems consist of ligand–receptor–co-activator complexes at the Genes that they activate. The co-activators consist of transcription factors and kinases, of which the latter play an important role in the associated epiGenetics. It is our view that signalling by cytokines such as IFNγ is but a variation of specific Gene Activation by steroid hormones.
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Controlling Nuclear Jaks and Stats for Specific Gene Activation by Ifn γ and Other Cytokines: A Possible Steroid-like Connection
Journal of clinical & cellular immunology, 2011Co-Authors: Howard M. Johnson, Ezra N. Noon-song, Chulbul M. AhmedAbstract:The mechanism of specific Gene Activation by cytokines that use JAK/STAT signalling pathway is unknown. There are four different types of JAKs and seven different types of STATs. In the classical model of signaling, ligand interacts solely with the receptor extracellular domain, which triggers JAK Activation at the receptor cytoplasmic domain. Activated STATs are then said to carry out nuclear events of specific Gene Activation, including associated epiGenetic changes that cause heterochromatin destabilization. Ligand, receptor, and JAKs play no further role in the classical model. Given the limited number of STATs and the Activation of the same STATs by cytokines with different functions, the mechanism of the specificity of their signalling is not obvious. Focusing on gamma interferon (IFNγ), we have shown that ligand, receptor, and activated JAKs are involved in nuclear events that are associated with specific Gene Activation. In this model, receptor subunit IFNGR1 functions as a transcription/cotranscription factor and the JAKs are involved in key epiGenetic events that are required for specific Gene Activation. The model has implications for Gene Activation in cancer as well as stem cell differentiation.
