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Zeitschriftenartikel zum Thema "BHLH-PAS proteins"
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Bersten, David C., Adrienne E. Sullivan, Daniel J. Peet und Murray L. Whitelaw. „bHLH–PAS proteins in cancer“. Nature Reviews Cancer 13, Nr. 12 (22.11.2013): 827–41. http://dx.doi.org/10.1038/nrc3621.
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Kolonko, Marta, und Beata Greb-Markiewicz. „bHLH–PAS Proteins: Their Structure and Intrinsic Disorder“. International Journal of Molecular Sciences 20, Nr. 15 (26.07.2019): 3653. http://dx.doi.org/10.3390/ijms20153653.
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The basic helix–loop–helix/Per-ARNT-SIM (bHLH–PAS) proteins are a class of transcriptional regulators, commonly occurring in living organisms and highly conserved among vertebrates and invertebrates. These proteins exhibit a relatively well-conserved domain structure: the bHLH domain located at the N-terminus, followed by PAS-A and PAS-B domains. In contrast, their C-terminal fragments present significant variability in their primary structure and are unique for individual proteins. C-termini were shown to be responsible for the specific modulation of protein action. In this review, we present the current state of knowledge, based on NMR and X-ray analysis, concerning the structural properties of bHLH–PAS proteins. It is worth noting that all determined structures comprise only selected domains (bHLH and/or PAS). At the same time, substantial parts of proteins, comprising their long C-termini, have not been structurally characterized to date. Interestingly, these regions appear to be intrinsically disordered (IDRs) and are still a challenge to research. We aim to emphasize the significance of IDRs for the flexibility and function of bHLH–PAS proteins. Finally, we propose modern NMR methods for the structural characterization of the IDRs of bHLH–PAS proteins.
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Crews, Stephen T., und Chen-Ming Fan. „Remembrance of things PAS: regulation of development by bHLH–PAS proteins“. Current Opinion in Genetics & Development 9, Nr. 5 (Oktober 1999): 580–87. http://dx.doi.org/10.1016/s0959-437x(99)00003-9.
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4
Reisz-Porszasz, S., M. R. Probst, B. N. Fukunaga und O. Hankinson. „Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT)“. Molecular and Cellular Biology 14, Nr. 9 (September 1994): 6075–86. http://dx.doi.org/10.1128/mcb.14.9.6075-6086.1994.
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The activated aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) bind DNA as a heterodimer. Both proteins represent a novel class of basic helix-loop-helix (bHLH)-containing transcription factors in that (i) activation of AHR requires the binding of ligand (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), (ii) the xenobiotic responsive element (XRE) recognized by the AHR/ARNT heterodimer differs from the recognition sequence for nearly all other bHLH proteins, and (iii) both proteins contain a PAS homology region, which in the Drosophila PER and SIM proteins functions as a dimerization domain. A cDNA for mouse ARNT has been cloned, and potential functional domains of ARNT were investigated by deletion analysis. A mutant lacking all regions of ARNT other than the bHLH and PAS regions is unimpaired in TCDD-dependent dimerization and subsequent XRE binding and only modestly reduced in ability to complement an ARNT-deficient mutant cell line, c4, in vivo. Both the first and second alpha helices of the bHLH region are required for dimerization. The basic region is required for XRE binding but not for dimerization. Deletion of either the A or B segments of the PAS region slightly affects TCDD-induced heterodimerization, while deletion of the complete PAS region severely affects (but does not eliminate) dimerization. Thus, ARNT possesses multiple domains required for maximal heterodimerization. Mutants deleted for PAS A, PAS B, and the complete PAS region all retain some degree of XRE binding, yet none can rescue the c4 mutant. Therefore, both the PAS A and PAS B segments, besides contributing to dimerization, apparently fulfill additional, unknown functions required for biological activity of ARNT.
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Reisz-Porszasz, S., M. R. Probst, B. N. Fukunaga und O. Hankinson. „Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT).“ Molecular and Cellular Biology 14, Nr. 9 (September 1994): 6075–86. http://dx.doi.org/10.1128/mcb.14.9.6075.
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The activated aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) bind DNA as a heterodimer. Both proteins represent a novel class of basic helix-loop-helix (bHLH)-containing transcription factors in that (i) activation of AHR requires the binding of ligand (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), (ii) the xenobiotic responsive element (XRE) recognized by the AHR/ARNT heterodimer differs from the recognition sequence for nearly all other bHLH proteins, and (iii) both proteins contain a PAS homology region, which in the Drosophila PER and SIM proteins functions as a dimerization domain. A cDNA for mouse ARNT has been cloned, and potential functional domains of ARNT were investigated by deletion analysis. A mutant lacking all regions of ARNT other than the bHLH and PAS regions is unimpaired in TCDD-dependent dimerization and subsequent XRE binding and only modestly reduced in ability to complement an ARNT-deficient mutant cell line, c4, in vivo. Both the first and second alpha helices of the bHLH region are required for dimerization. The basic region is required for XRE binding but not for dimerization. Deletion of either the A or B segments of the PAS region slightly affects TCDD-induced heterodimerization, while deletion of the complete PAS region severely affects (but does not eliminate) dimerization. Thus, ARNT possesses multiple domains required for maximal heterodimerization. Mutants deleted for PAS A, PAS B, and the complete PAS region all retain some degree of XRE binding, yet none can rescue the c4 mutant. Therefore, both the PAS A and PAS B segments, besides contributing to dimerization, apparently fulfill additional, unknown functions required for biological activity of ARNT.
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Greb-Markiewicz, Beata, und Marta Kolonko. „Subcellular Localization Signals of bHLH-PAS Proteins: Their Significance, Current State of Knowledge and Future Perspectives“. International Journal of Molecular Sciences 20, Nr. 19 (24.09.2019): 4746. http://dx.doi.org/10.3390/ijms20194746.
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The bHLH-PAS (basic helix-loop-helix/ Period-ARNT-Single minded) proteins are a family of transcriptional regulators commonly occurring in living organisms. bHLH-PAS members act as intracellular and extracellular “signals” sensors, initiating response to endo- and exogenous signals, including toxins, redox potential, and light. The activity of these proteins as transcription factors depends on nucleocytoplasmic shuttling: the signal received in the cytoplasm has to be transduced, via translocation, to the nucleus. It leads to the activation of transcription of particular genes and determines the cell response to different stimuli. In this review, we aim to present the current state of knowledge concerning signals that affect shuttling of bHLH-PAS transcription factors. We summarize experimentally verified and published nuclear localization signals/nuclear export signals (NLSs/NESs) in the context of performed in silico predictions. We have used most of the available NLS/NES predictors. Importantly, all our results confirm the existence of a complex system responsible for protein localization regulation that involves many localization signals, which activity has to be precisely controlled. We conclude that the current stage of knowledge in this area is still not complete and for most of bHLH-PAS proteins an experimental verification of the activity of further NLS/NES is needed.
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Gilles-Gonzalez, Marie-Alda, und Gonzalo Gonzalez. „Signal transduction by heme-containing PAS-domain proteins“. Journal of Applied Physiology 96, Nr. 2 (Februar 2004): 774–83. http://dx.doi.org/10.1152/japplphysiol.00941.2003.
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The most common physiological strategy for detecting the gases oxygen, carbon monoxide, and nitric oxide is signal transduction by heme-based sensors, a broad class of modular proteins in which a heme-binding domain governs the activity of a neighboring transmitter domain. Different structures are possible for the heme-binding domains in these sensors, but, so far, the Per-ARNT-Sim motif, or PAS domain, is the one most commonly encountered. Heme-binding PAS (heme-PAS) domains can accomplish ligand-dependent switching of a variety of partner domains, including histidine kinase, phosphodiesterase, and basic helix-loop-helix (bHLH) DNA-binding modules. Proteins with heme-PAS domains occur in all kingdoms of life and are quite diverse in their physiological roles. Examples include the neuronal bHLH-PAS carbon monoxide sensor NPAS2 that is implicated in the mammalian circadian clock, the acetobacterial oxygen sensor AxPDEA1 that directs cellulose production, and the rhizobial oxygen sensor FixL, which governs nitrogen fixation. What factors determine the range of detection of these sensors? How do they transduce their signal? This review examines the recent advances in answering these questions.
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Kolonko-Adamska, Marta, Vladimir N. Uversky und Beata Greb-Markiewicz. „The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development“. International Journal of Molecular Sciences 22, Nr. 6 (11.03.2021): 2868. http://dx.doi.org/10.3390/ijms22062868.
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The basic helix–loop–helix/Per-ARNT-SIM (bHLH-PAS) proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, ranging from differentiation and development control by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for regulation of their activity. Our aim was to analyze the potential connection between disordered regions of the bHLH-PAS transcription factors, post-transcriptional modifications and liquid-liquid phase separation, in the context of disease-associated missense mutations. Highly flexible disordered regions, enriched in short motives which are more ordered, are responsible for a wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account the fact that the functions of transcription factors can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the locations of missense mutations inducing disease states are clearly related to sequences directly undergoing these processes or to sequences responsible for their regulation.
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Zelzer, E., P. Wappner und B. Z. Shilo. „The PAS domain confers target gene specificity of Drosophila bHLH/PAS proteins“. Genes & Development 11, Nr. 16 (15.08.1997): 2079–89. http://dx.doi.org/10.1101/gad.11.16.2079.
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Aitola, Marjo H., und Markku T. Pelto-Huikko. „Expression of Arnt and Arnt2 mRNA in Developing Murine Tissues“. Journal of Histochemistry & Cytochemistry 51, Nr. 1 (Januar 2003): 41–54. http://dx.doi.org/10.1177/002215540305100106.
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The basic helix-loop-helix (bHLH-PAS) proteins aryl hydrocarbon receptor nuclear translocator (Arnt) and Arnt2 are transcriptional regulators that function as dimerizing partners for several bHLH-PAS proteins and also some nonrelated partners. They are involved in various biological functions, including regulation of developmental genes. In earlier studies, the developmental expression of Arnt was reported to be almost ubiquitous, whereas Arnt2 expression has been shown to be more limited, comprising neuronal tissues as the main site of expression. Here we provide a detailed description of the expression of Arnt and Arnt2 mRNA in mouse tissues during embryonic and early postnatal development. Arnt and also Arnt2 transcripts, in contrast to earlier reports, are shown to be expressed more widely during development yet show a temporally and spatially specific pattern.
Dissertationen zum Thema "BHLH-PAS proteins"
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Dougherty, Edward J. „Analysis of the role of bHLH/PAS proteins in aryl hydrocarbon receptor signaling“. [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002441.
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Manzotti, Alessandro. „Response to light stimuli in the marine diatom Phaeodactylum tricornutum : Involvement of bHLH-PAS proteins in the circadian clock and plastid physiology“. Electronic Thesis or Diss., Sorbonne université, 2022. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2022SORUS232.pdf.
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Les diatomées sont des microalgues eucaryotes qui représentent l'un des groupes de phytoplancton plus répandus. Cependant, peu d'informations sont disponibles sur la régulation de l'expression génique chez ces algues. En utilisant la diatomée modèle Phaeodactylum tricornutum, les travaux présentés ont mis en évidence le rôle des facteurs de transcription bHLH-PAS dans la régulation de deux processus lumière-dépendants. Il a été montré que la protéine bHLH1a, renommée RITMO1, est impliquée dans la modulation de la rythmicité endogène régulée par les cycles lumière-obscurité. La surexpression et la mutation KO de RITMO1 conduisent à une perturbation des oscillations journalières de la fluorescence cellulaire, de la photosynthétique et de l'expression génique en lumière continue, l'identifiant comme le premier composant de l'horloge circadienne des diatomées. Il a été montré que RITMO1 dimérise avec son paralogue bHLH1b et que la mutation de cet facteur de transcription mène à des perturbations de la rythmicité de la fluorescence cellulaire, indiquant sa co-implication dans l'horloge. Différemment, la protéine bHLH-PAS bHLH2, est impliqué dans la modulation de la photosynthèse dans un mécanisme dépendant de l'intensité lumineuse et non contrôlé par l'horloge. Souches transformées avec des ARN-interférents contre bHLH2 montrent un flux d'électrons réduit au niveau du thylakoïde et un déficit de croissance subséquent. L'expression de cette protéine dépend d'un système de signalisation rétrograde, mettant ainsi en évidence une communication croisée noyau-plaste. Cette étude représente la première caractérisation des protéines bHLH-PAS dans un organisme photosynthétiqueDiatoms are eukaryotic microalgae representing one of the most successful groups of phytoplankton. However, little information is available on the regulatory mechanisms controlling gene expression in diatoms. Through the use of the model diatom Phaeodactylum tricornutum, the work presented highlighted the role of bHLH-PAS family transcription factors in the regulation of two important light-dependent processes. On the one hand, it was shown that bHLH1a protein, renamed RITMO1, is involved in the modulation of endogenous rhythmicity regulated by light-dark cycles. Overexpression and knock-out mutation of this gene led to a disruption of daily cellular fluorescence oscillations, photosynthetic activity and gene expression under constant light condition, identifying RITMO1 as the first component of diatom circadian clock. It was shown that a paralogous transcription factor, bHLH1b, dimerizes with RITMO1 and a mutation of this protein led to disruptions of cellular fluorescence rhythmicity, indicating its co-implication in the timekeeper. Differently, bHLH-PAS protein bHLH2 has been shown to be involved in the modulation of photosynthetic activity in a light intensity-dependent mechanism not controlled by the endogenous clock. Cell lines presenting a construct for RNA-interference against bHLH2 showed reduced electron flow at the thylakoid level and a subsequent growth deficit. It has been shown that the expression of this protein is controlled by retrograde signalling, thus highlighting a crosstalk between nucleus and plastid. This study represented the first characterization of bHLH-PAS proteins in a photosynthetic organism
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Hester, Ian Wayland. „HALO, a novel bHLH-PAS protein induced by neuronal preconditioning and ischemia, mediates cytotoxicity through BAX gene upregulation“. Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/27251.
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Cortical spreading depression (CSD) induces waves of neuronal depolarization that confer neuroprotection to subsequent ischemic events in the rat brain. To gain insights into the molecular mechanisms elicited by CSD, we used representational difference analysis (RDA) to identify mRNA induced by potassium depolarization in vivo. We have isolated a cDNA encoding a novel bHLH-PAS protein distantly related to SIM2, termed HALO. Our results confirm that HALO mRNA and protein are rapidly and transiently expressed in cortical neurons following CSD but not following short duration ischemia, another form of pre-ischemic conditioning. In the untreated adult brain, HALO is expressed at low levels but is highly expressed during embryonic development in neuronal lineages. Surprisingly, delayed HALO expression is also observed following middle cerebral artery occlusion (MCAO) in rats. Reporter assays show that HALO is a transcriptional activator that associates with the bHLH-PAS sub-class co-factor ARNT2. Adenovirus-mediated expression of epitope-tagged HALO results in the direct induction of the Bax gene and sensitization of cultured cells to cytotoxic stress. Together, our data indicate that HALO is a novel bHLH-PAS transactivator transiently induced by preconditioning and that its sustained expression is detrimental. The identification of HALO may represent an important step in our understanding of the molecular mechanisms of brain preconditioning and injury.
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Morozova, Tatiana. „The Jing zinc finger protein: its transcriptional regulation by bHLH-PAS, POU, and ETS-domain transcription factors and its role in tracheal cell migration during Drosophila embryogenesis“. Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28745.
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In this research project we investigated a regulatory region upstream of the jing open reading frame containing bHLH-PAS consensus DNA binding sites in order to identify control elements conferring tracheal specificity. Three transgenic fly strains were generated that carried LacZ fusions with genomic sequences from the jing5' regulatory region. Two overlapping fragments (1.5 kb and 2.8 kb) from the jing 5'cis-regulatory region were fused to a lacZ reporter and in vivo expression patterns studied. The 1.5 kb fragment was chosen because it contains three CMEs DNA binding sites for Trh::Tgo and consensus binding sites for the Pou domain transcription factor Drifter and ETS domain transcription factor Pointed.
Transgenic embryos carrying the jing1.5-lacZ reporter show expression in the CNS midline, lateral CNS, and in the fusion cells of the trachea. During the early stages of tracheal development (stage 11), jing1.5-lacZ is expressed in the cells adjacent to the tracheal pits. However, despite the widespread distribution of Trh in trachea, jing1.5-lacZ expression was restricted to the fusion cells as confirmed by double labeling of the embryos with anti-beta-gal and the fusion cell-specific antibody, anti-Dysfusion (anti-Dys) and was dependent on trh. trh ectopically activated jing1.5-lacZ in Drosophila embryos in combination with Drifter. Furthermore, the CME sites were required for tracheal jing1.5-lacZ activation.
A larger 2.8 kb fragment, encompassing jing1.5 and with no additional CMEs, drove lacZ expression in a larger subset of tracheal cells. jing2.8-lacZ is expressed in all tracheal branches, as early as stage 11. These results suggest that activation of jing in the trachea requires regulators in addition to Trh::Tgo. jing2.8-lacZ reporter is also expressed in the CNS midline, tracheal fusion cells, segmental ectodermal stripes, and posterior spiracles consistent with endogenous jing expression.
Previous studies showed that the Jing zinc finger protein is required for both EGFR- and FGFR-dependent tyrosine kinase signaling during tracheal development. Consistent with this, Jing protein is present in the nuclei of most tracheal cells throughout development. We studied its relationship with bHLH-PAS, POD and ETS-domain transcription factors which control FGFR expression during branching in the embryonic Drosophila trachea. The influence of tyrosine kinase signaling on jing1.5-lacZ expression was determined by ectopic expression and mutant analysis. EGFR-mediated signaling activates jing1.5-lacZ expression in surviving midline glia and was required for jing1.5-lacZ tracheal fusion cell expression in rhomboid7M (rho7M) mutant embryos. In addition, genes known to regulate tracheal FGFR expression were required for jing1.5-lacZ activation in the fusion cells. Loss of pointed function and deletion of putative Pnt DNA binding sites in the jing1.5-lacZ reporter was associated with significant reductions in jing1.5-lacZ expression in fusion cells. In combination with reduced jing mRNA in pointed and drifter mutants, these results reveal that jing is regulated by Pnt and Dfr. This is consistent with a reduction in jing1.5-lacZ expression in breathless and branchless mutants which are known to regulate pointed.
Furthermore, we show that jing is required for maximal levels of btl expression. In situ hybridization on whole mount embryos revealed that btl transcript levels are significantly reduced in jing loss-of-function backgrounds. Reduction of jing mRNA by RNA interference, specifically in tracheal cells, was associated with reductions in btl mRNA. Finally, we show that expression of ling protein with truncated N-terminal transactivation domains specifically in tracheal cells was associated with reduced btl mRNA. Together, these results suggest that jing is an integral component of the positive feedback mechanism that maintains expression of itself and btl downstream of Trh/Tgo during primary branching. (Abstract shortened by UMI.)
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Holder, Jimmy Lloyd Jr. „The bHLH/PAS transcription factor SIM1 is a novel obesity gene“. 2005. http://edissertations.library.swmed.edu/pdf/HolderJ050305/HolderJimmy.pdf.
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Chu, Kuo-Jung, und 朱國榮. „The role of bHLH/PAS protein in zebrafish embryonic eye development“. Thesis, 2007. http://ndltd.ncl.edu.tw/handle/52875786288797513030.
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碩士國立臺灣海洋大學
生物科技研究所
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ARNT is one of the bHLH/PAS（Per-Arnt-Sim） proteins that forms heterodimers with HIF, SIM and AhR to regulate different gene expression, such as hypoxia inducible-related genes, xenobiotic metabolic and neuron development. Previous investigation found that knockdown of arnt2a/b/c prevented embryo retina neuron and lens cell differentiation and repressed neuroD transcription. During early stages of development, members of hif-α are constitutively expressed in the hindbrain and the placode of sensory organs, including the olfactory placode, otic placode and lateral line placode. In this study, the function of zebrafish hif-1α/2α/3α in eye development was studied. It appears that knockdown hif-1α/2α/3α has caused smaller head and eye size.Transcriptions of rho and vsx1 were repressed. Lens differentiation was delayed and the bipolar cell layer and rod cell layer development was defected. Neverthless, the expression patterns of early stage markers in hif-α motphant was different from what in ARNT2 morphants.It suggests that HIF-α and ARNT2 have distinct roles in eye development.
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Woods, Susan Lesley. „Cross-talk between SIM and other bHLH/PAS factors and the search for SIM2 target genes“. Thesis, 2004. http://hdl.handle.net/2440/65465.
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This project aimed to investigate how the murine Simgle minded (mSIM) proteins interact with other active bHLH/PAS transcription factors and provide the first study to identify direct target genes of mSIM2. We show that the murine SIM (mSIM) factors are constitutively nuclear proteins in cells and that the presence of an mSIM protein outcompetes the dioxin receptor (DR) for aryl hydrocarbon nuclear translocator 1 (ARNT1) binding, resulting in attenuation of transcription of a reporter gene induced by a constitutively active form of the DR. In contrast, the hypoxia inducible factor-1a (HIF-1a) and mSIM proteins appear equally competent to sequester ARNT1. Expression of either mSIM protein repressed, but did not totally prevent, the hypoxic activation of a reporter containing hypoxic response element (HRE) sequences from the erythropoietin (EPO) enhancer and endogenous hypoxic target genes in 293T cells. This repression occurs through competition of the HIF-1a and theSIM proteins for binding to ARNT1 but also for DNA binding sites in the HRE-reporter plasmid. In contrast to HIF-1a, which rapidly accumulates in low oxygen conditions, SIM protein levels decrease in hypoxia, most likely as a result of general translational inhibition in hypoxia stressed cells. Cross-talk between the mSIM and HIF-a or DR proteins may occur to enable the cell to adapt to multiple environmental and developmental signals and is particularly relevant in pathological states such as Down’s Syndrome (DS) or tumour types recently recognized to contain elevated levels of a short isoform of human SIM2 (hSIM2). Microarray experiments identified a large number of transcripts that are differentially regulated by mSIM2 and one of thes predominantly expressed in muscle, Myomesin2 (Myom2), was shown to potentially be the first identified direct target gene of mSIM2/ARNT1. Bacterially expressed and partially purified N-terminal portions of mSIM2/ARNT1 bound a 40bp probe derived from the Myom2 promoter sequence but not an identical probe with the 5’-AACGTG-3’ site mutated, and mutation of the putative mSIM2/ARNT1 binding site in the Myom2 promoter led to a decreased reporter induction with the mSIM2AD chimeric protein, in which the mSIM2 repression region is replaced with the activation domain from the DR. Evidence that mSIM2 regulates the transcription of endogenous Myom2 awaits the generation of a specific anti-mSIM2 antibody to allow examination of the Myom2 promoter occupation by mSIM2/ARNT1 using chromatin immunoprecipitation and the effect of mSim2 knockdown on Myom2 transcript levels. The transcriptional activity of the mSIM proteins appears to be dependent on the promoter context and cell type examined, as surprisingly we have observed the mSIM1/ARNT1 dimer activating transcription of the HRE-reporter, whilst the mSIM2/ARNT1 dimer does not activate the Myom2-reporter in 293T cells, but does activate it in 293 cells. Both SIM1 and SIM2 were previously described as harbouring repression regions in their C-termini, however, when dimerised with ARNT1, activation is sometimes observed which is dependent on the presence of the ARNT1 transactivation domain.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2004
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Farrall, Alexandra Louise. „Gene regulatory and pro-tumourigenic mechanisms of the bHLH-PAS transcription factor SIM2s“. Thesis, 2010. http://hdl.handle.net/2440/61242.
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Single-minded 2 (SIM2), a class I basic Helix-Loop-Helix/PAS (bHLH/PAS) transcription factor, is essential for early development, and the short isoform (SIM2s) is selectively up-regulated in pancreatic and prostate tumours. Mechanistic
roll(s) for SIM2 that are essential for development and in these cancers is unknown, largely due to the fact that few bona fide target genes have been described for SIM2. SIM2 must heterodimerise with the obligate class II partner factor ARNT to regulate transcription. Surprisingly, these studies reveal SIM2 plays a role in the regulation of the ARNT homologues, ARNT1 and ARNT2. Two nonexclusive mechanisms were identified; enhanced protein stabilisation, and the specific increased transcription of ARNT2. The regulation of ARNT by a class I family member was found to be unique to the SIM homologues. These findings suggest novel insights into how elevated levels of SIM2s in tumours may
confer increased transcriptional activities and/or increase the availability of the essential partner factor for other class I family members to promote their respective activities and functions in developmental and/or tumourigeneic processes. Furthermore, microarray studies in prostate DU145 cells identified the pro-cell death gene, BNIP3 (Bcl-2/adenovirus E1B 19kDa interacting protein 3), as a novel target of SIM2s
mediated repression. Further validation showed BNIP3 repression in several prostate and pancreatic carcinoma derived cell lines with ectopic expression of human SIM2s via SIM2s activities at the proximal promoter hypoxia response element (HRE), the site through which bHLH/PAS family member, Hypoxia-Inducible Factor 1α (HIF1α), induces BNIP3. SIM2s attenuates BNIP3 hypoxic induction via the HRE, and increased hypoxic induction of BNIP3 occurs with siRNA knockdown of endogenous SIM2s in prostate
PC3AR+ cells. BNIP3 is implicated in hypoxia-induced cell-death processes. PC3AR+ cells expressing ectopic SIM2s have enhanced survival upon treatment with hypoxia mimetics, DP and DMOG. LC3-II protein levels fail to induce in PC3AR+/SIM2s DMOG and hypoxia treated cells, suggesting SIM2s may attenuate autophagic cell-death processes, perhaps via BNIP3 repression. These data show, for the first time, SIM2s cross-talk on an endogenous HRE. SIM2s functional interference with HIF1α activities on BNIP3 may indicate a novel role for SIM2s in promoting tumourigenesis. Moreover, SIM2 expression has previously been implicated in the Hedgehog (Hh) signalling pathway during mouse brain development. The Hh-pathway is known to promote pancreatic and prostate tumour growth, and these studies indicate that SIM2s is indeed implicated in promoting and/or maintaining Hh-signalling in cell lines of these cancer types. Likewise, aberrant Androgen Receptor (AR)-signalling is implicated in prostate tumour development, and androgen-independent AR activity is a hallmark of aggressive prostate cancer. Unexpectedly, SIM2s expression was found to up-regulate endogenous AR protein levels in prostate carcinoma PC3AR+ cells. Furthermore, SIM2s expression is associated with androgen-dependent wtAR-transcriptional responsiveness in these cells, and SIM2s co-immunoprecipitates with endogenous AR in a hormone independent manner. Together these data suggest, for the first time, that SIM2s may function as a coactivator, and concomitant with enhancing AR levels, aid AR-signalling in prostate cancer cells. In summary, these studies sought to identify molecular mechanisms by which aberrant levels of SIM2s expression in solid tumours of the prostate and pancreas may promote tumour development. Several novel mechanisms for SIM2s activities were identified which implicate SIM2s in tumour processes. Namely SIM2s was found to be implicated in:
1) promoting pro-tumourigeneic Hh and AR signalling pathways
2) regulation of the common partner factor ARNT, and
3) attenuation of hypoxically-induced cell-death processes in tumour cells via the direct transcriptional repression of the novel SIM2s target gene, BNIP3.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2010
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De, Jong Antonia Thelma-Jean. „Interaction of bZIP and bHLH Transcription Factors with the G-box“. Thesis, 2013. http://hdl.handle.net/1807/35804.
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Transcription factors are proteins that regulate transcription of genes by binding to specific DNA sequences proximal to the gene. The specificity and affinity of protein-DNA recognition is critical for proper gene regulation. This thesis explores the mechanisms of binding to the sequence 5’CACGTG, a common recognition sequence both in plants where it is known as the G-box and in mammalian cells where it is termed the E-box. This sequence is of clinical interest because it is the target of the transcription factor Myc, an oncogene linked to many cancers. A number of alpha-helical proteins with different dimerization elements, from the basic region-leucine zipper (bZIP), basic region helix-loop-helix leucine zipper (bHLHZ) and basic region helix-loop-helix-PAS (bHLH-PAS) protein families, are capable of binding to this sequence. The basic regions of all these protein families contain residues that contact DNA and determine DNA sequence specificity while the other subdomains are responsible for dimerization specificity. First, the influence of protein-DNA contacts on sequence specificity of the plant bZIP protein EmBP-1 was probed by point mutations in the basic region. Residues that contact the DNA outside the core G-box sequence and residues that contact the phosphate backbone were found to be important for sequence specificity. Second, the impact of the dimerization subdomains of bHLHZ protein Max, the required heterodimerization partner of the Myc protein, and bHLH-PAS protein Arnt was probed by mutation, deletion and inter-family subdomain swapping studies. All studied protein families are intrinsically disordered, forming structure upon dimerization and DNA binding. The dimerization domains were found to indirectly influence DNA binding by affecting folding, dimerization ability or proper orientation of the basic regions relative to DNA. Lastly, a new strategy for selection of G-box binding proteins in the Yeast One-hybrid system is explored. Together, these studies broaden our understanding of the structure-function relationship of the DNA-binding activities of these closely related families of transcription factors. The creation and characterization of mutants with altered specificity, affinity and dimerization specificity may also be useful for biotechnology applications.
Buchteile zum Thema "BHLH-PAS proteins"
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Powell-Coffman, Jo Anne. „bHLH-PAS Proteins in C. Elegans“. In PAS Proteins: Regulators and Sensors of Development and Physiology, 51–68. Boston, MA: Springer US, 2003. http://dx.doi.org/10.1007/978-1-4615-0515-0_3.
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Crews, Stephen T. „Drosophila bHLH-PAS Developmental Regulatory Proteins“. In PAS Proteins: Regulators and Sensors of Development and Physiology, 69–108. Boston, MA: Springer US, 2003. http://dx.doi.org/10.1007/978-1-4615-0515-0_4.
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Semenza, Gregg L. „The HIF-1 Family of bHLH-PAS Proteins: Master Regulators of Oxygen Homeostasis“. In PAS Proteins: Regulators and Sensors of Development and Physiology, 183–204. Boston, MA: Springer US, 2003. http://dx.doi.org/10.1007/978-1-4615-0515-0_8.
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„BHLH-PAS Proteins“. In Encyclopedia of Cancer, 389. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_605.
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Dougherty, E. J., und R. S. Pollenz. „ARNT: A Key bHLH/PAS Regulatory Protein Across Multiple Pathways“. In Comprehensive Toxicology, 231–52. Elsevier, 2010. http://dx.doi.org/10.1016/b978-0-08-046884-6.00214-1.
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6
E.S. Mosa, Farag, Ayman O.S. El-Kadi und Khaled Barakat. „Targeting the Aryl Hydrocarbon Receptor (AhR): A Review of the In-Silico Screening Approaches to Identify AhR Modulators“. In High-Throughput Screening for Drug Discovery [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99228.
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Aryl hydrocarbon receptor (AhR) is a biological sensor that integrates environmental, metabolic, and endogenous signals to control complex cellular responses in physiological and pathophysiological functions. The full-length AhR encompasses various domains, including a bHLH, a PAS A, a PAS B, and transactivation domains. With the exception of the PAS B and transactivation domains, the available 3D structures of AhR revealed structural details of its subdomains interactions as well as its interaction with other protein partners. Towards screening for novel AhR modulators homology modeling was employed to develop AhR-PAS B domain models. These models were validated using molecular dynamics simulations and binding site identification methods. Furthermore, docking of well-known AhR ligands assisted in confirming these binding pockets and discovering critical residues to host these ligands. In this context, virtual screening utilizing both ligand-based and structure-based methods screened large databases of small molecules to identify novel AhR agonists or antagonists and suggest hits from these screens for validation in an experimental biological test. Recently, machine-learning algorithms are being explored as a tool to enhance the screening process of AhR modulators and to minimize the errors associated with structure-based methods. This chapter reviews all in silico screening that were focused on identifying AhR modulators and discusses future perspectives towards this goal.