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1
Collas, Philippe. "Cytoplasmic control of nuclear assembly." Reproduction, Fertility and Development 10, no. 8 (1998): 581. http://dx.doi.org/10.1071/rd98049.
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The reconstitution of a replication-competent, transcriptionally active nucleus following mitosis, fertilization or nuclear transplantation involves a stepwise series of reactions, most (if not all) of which are controlled by the cytoplasmic environment. This review discusses the nature of cytoplasmic contributions to the development of the male pronucleus at fertilization, and the effect of altering the cytoplasmic environment on nuclear assembly. The system used to investigate these regulations consists of permeabilized sea urchin sperm nuclei incubated under controlled conditions in a cell-free extract of fertilized sea urchin eggs. (1) In egg cytoplasmic extract, male pronuclear formation is initiated by the disassembly of the sperm nuclear lamina as a result of lamin phosphorylation by a cytosolic protein kinase C. (2) Sperm histones are phosphorylated by an as yet unidentified soluble kinase. (3) The conical sperm nucleus decondenses into a spherical pronucleus in an ATP-and cytosolic pH-dependent manner. (4) Chromatin decondensation is associated with the replacement of sperm histones by maternal histones. (5) Nuclear membranes form by ATP-dependent binding of vesicles to chromatin and GTP-dependent fusion of these vesicles to one another. (6) Three cytoplasmic vesicle populations with distinct biochemical, chromatin-binding and fusion properties are required for nuclear envelope assembly. (7) Targeting of the bulk of nuclear membrane vesicles to chromatin is mediated by an integral membrane protein similar to human lamin B receptor. (8) The last step of male pronuclear formation, nuclear swelling, is promoted by the assembly of nuclear pores, nuclear import of soluble lamins and growth of the nuclear membranes. (9) Once inside the nucleus, lamin B associates with lamin B receptors, presumably to tether the inner nuclear membrane with the lamina. Overall, these processes are similar to those characterizing nuclear reconstitution after mitosis in somatic cells or nuclear remodeling following transplantation into oocytes or eggs. The influence of the egg cytoplasmic environment on some aspects of nuclear remodeling after nuclear transplantation is also discussed.
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Dean, Kellie A., Oliver von Ahsen, Dirk Görlich, and Howard M. Fried. "Signal recognition particle protein 19 is imported into the nucleus by importin 8 (RanBP8) and transportin." Journal of Cell Science 114, no. 19 (October 1, 2001): 3479–85. http://dx.doi.org/10.1242/jcs.114.19.3479.
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The signal recognition particle (SRP) is a cytoplasmic RNA-protein complex that targets proteins to the rough endoplasmic reticulum. Although SRP functions in the cytoplasm, RNA microinjection and cDNA transfection experiments in animal cells, as well as genetic analyses in yeast, have indicated that SRP assembles in the nucleus. Nonetheless, the mechanisms responsible for nuclear-cytoplasmic transport of SRP RNA and SRP proteins are largely unknown. Here we show that the 19 kDa protein subunit of mammalian SRP, SRP19, was efficiently imported into the nucleus in vitro by two members of the importin β superfamily of transport receptors, importin 8 and transportin; SRP19 was also imported less efficiently by several other members of the importin β family. Although transportin is known to import a variety of proteins, SRP19 import is the first function assigned to importin 8. Furthermore, we show that a significant pool of endogenous SRP19 is located in the nucleus, as well as the nucleolus. Our results show that at least one mammalian SRP protein is specifically imported into the nucleus, by members of the importin β family of transport receptors, and the findings add additional evidence for nuclear assembly of SRP.
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Kubina, Julie, Angèle Geldreich, Jón Pol Gales, Nicolas Baumberger, Clément Bouton, Lyubov A. Ryabova, Klaus D. Grasser, Mario Keller, and Maria Dimitrova. "Nuclear export of plant pararetrovirus mRNAs involves the TREX complex, two viral proteins and the highly structured 5′ leader region." Nucleic Acids Research 49, no. 15 (August 9, 2021): 8900–8922. http://dx.doi.org/10.1093/nar/gkab653.
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Abstract In eukaryotes, the major nuclear export pathway for mature mRNAs uses the dimeric receptor TAP/p15, which is recruited to mRNAs via the multisubunit TREX complex, comprising the THO core and different export adaptors. Viruses that replicate in the nucleus adopt different strategies to hijack cellular export factors and achieve cytoplasmic translation of their mRNAs. No export receptors are known in plants, but Arabidopsis TREX resembles the mammalian complex, with a conserved hexameric THO core associated with ALY and UIEF proteins, as well as UAP56 and MOS11. The latter protein is an orthologue of mammalian CIP29. The nuclear export mechanism for viral mRNAs has not been described in plants. To understand this process, we investigated the export of mRNAs of the pararetrovirus CaMV in Arabidopsis and demonstrated that it is inhibited in plants deficient in ALY, MOS11 and/or TEX1. Deficiency for these factors renders plants partially resistant to CaMV infection. Two CaMV proteins, the coat protein P4 and reverse transcriptase P5, are important for nuclear export. P4 and P5 interact and co-localise in the nucleus with the cellular export factor MOS11. The highly structured 5′ leader region of 35S RNAs was identified as an export enhancing element that interacts with ALY1, ALY3 and MOS11 in vitro.
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Jäkel, Stefan, José-Manuel Mingot, Petra Schwarzmaier, Enno Hartmann, and Dirk Görlich. "Importins fulfil a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains." EMBO Journal 21, no. 3 (February 1, 2002): 377–86. http://dx.doi.org/10.1093/emboj/21.3.377.
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Lippai, Mónika, László Tirián, Imre Boros, József Mihály, Miklós Erdélyi, István Belecz, Endre Máthé, et al. "The Ketel Gene Encodes a Drosophila Homologue of Importin-β." Genetics 156, no. 4 (December 1, 2000): 1889–900. http://dx.doi.org/10.1093/genetics/156.4.1889.
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Abstract The Drosophila melanogaster Ketel gene was identified via the KetelD dominant female sterile mutations and their ketelr revertant alleles that are recessive zygotic lethals. The maternally acting KetelD mutations inhibit cleavage nuclei formation. We cloned the Ketel gene on the basis of a common breakpoint in 38E1.2-3 in four ketelr alleles. The Ketel+ transgenes rescue ketelr-associated zygotic lethality and slightly reduce KetelD-associated dominant female sterility. Ketel is a single copy gene. It is transcribed to a single 3.6-kb mRNA, predicted to encode the 97-kD Ketel protein. The 884-amino-acid sequence of Ketel is 60% identical and 78% similar to that of human importin-β, the nuclear import receptor for proteins with a classical NLS. Indeed, Ketel supports import of appropriately designed substrates into nuclei of digitonin-permeabilized HeLa cells. As shown by a polyclonal anti-Ketel antibody, nurse cells synthesize and transfer Ketel protein into the oocyte cytoplasm from stage 11 of oogenesis. In cleavage embryos the Ketel protein is cytoplasmic. The Ketel gene appears to be ubiquitously expressed in embryonic cells. Western blot analysis revealed that the Ketel gene is not expressed in several larval cell types of late third instar larvae.
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Cvoro, Aleksandra, Aleksandra Korac, and Gordana Matic. "Alteration of glucocorticoid receptor subcellular distribution by hyperthermic stress." Archives of Biological Sciences 58, no. 3 (2006): 145–52. http://dx.doi.org/10.2298/abs0603145c.
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The aim of the present study was to examine intracellular redistribution of the glucocorticoid receptor (GR) in rat liver cells during a 24-h time period after exposure of the animals to 41?C whole body hyperthermic stress. The level of the receptor protein in the cytoplasmic and nuclear compartments was measured by immunoblotting procedures applied to both crude cytosol and immunopurified GR, as well as by immunocytochemical analyses applied to both paraffin-embedded liver sections and unfixed nuclear smears. All the experimental approaches employed in the study provided similar results, demonstrating that the transient stress-related decline of the cytoplasmic GR observed during the first five hours after exposure of the animals to whole-body hyperthermic stress is accompanied by enhanced nuclear accumulation of the receptor. The study can contribute to a better understanding of the influence of stress on the glucocorticoid signal transduction pathway. .
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Ferchichi, Imen, Samia Sassi Hannachi, Amal Baccar, Raja Marrakchi Triki, Jean Yves Cremet, Khaled Ben Romdhane, Claude Prigent, and Amel Ben Ammar El Gaaied. "Assessment of Aurora a Kinase Expression in Breast Cancer: A Tool for Early Diagnosis?" Disease Markers 34, no. 2 (2013): 63–69. http://dx.doi.org/10.1155/2013/871929.
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Aurora A kinase is overexpressed in many cancers but the status of this protein in the breast cancer often varies. We investigate the expression and localization of Aurora A protein in relation with tumor emergence and progression in breast cancer. Aurora A kinase status was evaluated in 107 patients using immunohistochemistry. The experimental findings showed that high expression of the Aurora A protein was correlated with elevated nuclear grade, low expression of progesterone receptor and positive nodal status. The experimental results showed also that the localization of this kinase shifts from cytoplasm in non malignant adjacent tissue to both cytoplasmic and nuclear compartments in tumoral tissue, suggesting an oncogenic role of the nuclear accumulation. We have, furthermore, detected the overexpression of this protein in non malignant adjacent tissue. The expression of the Aurora A kinase in non malignant tissue may represent an earlier diagnosis tool for breast cancer.
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Ghildyal, Reena, Adeline Ho, Manisha Dias, Lydia Soegiyono, Phillip G. Bardin, Kim C. Tran, Michael N. Teng, and David A. Jans. "The Respiratory Syncytial Virus Matrix Protein Possesses a Crm1-Mediated Nuclear Export Mechanism." Journal of Virology 83, no. 11 (March 18, 2009): 5353–62. http://dx.doi.org/10.1128/jvi.02374-08.
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ABSTRACT The respiratory syncytial virus (RSV) matrix (M) protein is localized in the nucleus of infected cells early in infection but is mostly cytoplasmic late in infection. We have previously shown that M localizes in the nucleus through the action of the importin β1 nuclear import receptor. Here, we establish for the first time that M's ability to shuttle to the cytoplasm is due to the action of the nuclear export receptor Crm1, as shown in infected cells, and in cells transfected to express green fluorescent protein (GFP)-M fusion proteins. Specific inhibition of Crm1-mediated nuclear export by leptomycin B increased M nuclear accumulation. Analysis of truncated and point-mutated M derivatives indicated that Crm1-dependent nuclear export of M is attributable to a nuclear export signal (NES) within residues 194 to 206. Importantly, inhibition of M nuclear export resulted in reduced virus production, and a recombinant RSV carrying a mutated NES could not be rescued by reverse genetics. That this is likely to be due to the inability of a nuclear export deficient M to localize to regions of virus assembly is indicated by the fact that a nuclear-export-deficient GFP-M fails to localize to regions of virus assembly when expressed in cells infected with wild-type RSV. Together, our data suggest that Crm1-dependent nuclear export of M is central to RSV infection, representing the first report of such a mechanism for a paramyxovirus M protein and with important implications for related paramyxoviruses.
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Thiel, Gerald, Tobias Schmidt, and Oliver G. Rössler. "Ca2+ Microdomains, Calcineurin and the Regulation of Gene Transcription." Cells 10, no. 4 (April 12, 2021): 875. http://dx.doi.org/10.3390/cells10040875.
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Ca2+ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca2+ concentration upon stimulation. The elevated Ca2+ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca2+ at different locations in the cell. Ca2+ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca2+ ions. A major function of the rise in intracellular Ca2+ is the change of the genetic expression pattern of the cell via the activation of Ca2+-responsive transcription factors. It has been proposed that Ca2+-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca2+. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca2+ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca2+ induces an intracellular signaling cascade, involving the activation of the Ca2+/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca2+/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca2+ concentration in the cytoplasm and the nucleus, the role of Ca2+ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca2+ signaling and gene expression.
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Brockman, J. A., D. C. Scherer, T. A. McKinsey, S. M. Hall, X. Qi, W. Y. Lee, and D. W. Ballard. "Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation." Molecular and Cellular Biology 15, no. 5 (May 1995): 2809–18. http://dx.doi.org/10.1128/mcb.15.5.2809.
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The eukaryotic transcription factor NF-kappa B plays a central role in the induced expression of human immunodeficiency virus type 1 and in many aspects of the genetic program mediating normal T-cell activation and growth. The nuclear activity of NF-kappa B is tightly regulated from the cytoplasmic compartment by an inhibitory subunit called I kappa B alpha. This cytoplasmic inhibitor is rapidly phosphorylated and degraded in response to a diverse set of NF-kappa B-inducing agents, including T-cell mitogens, proinflammatory cytokines, and viral transactivators such as the Tax protein of human T-cell leukemia virus type 1. To explore these I kappa B alpha-dependent mechanisms for NF-kappa B induction, we identified novel mutants of I kappa B alpha that uncouple its inhibitory and signal-transducing functions in human T lymphocytes. Specifically, removal of the N-terminal 36 amino acids of I kappa B alpha failed to disrupt its ability to form latent complexes with NF-kappa B in the cytoplasm. However, this deletion mutation prevented the induced phosphorylation, degradative loss, and functional release of I kappa B alpha from NF-kappa B in Tax-expressing cells. Alanine substitutions introduced at two serine residues positioned within this N-terminal regulatory region of I kappa B alpha also yielded constitutive repressors that escaped from Tax-induced turnover and that potently inhibited immune activation pathways for NF-kappa B induction, including those initiated from antigen and cytokine receptors. In contrast, introduction of a phosphoserine mimetic at these sites rectified this functional defect, a finding consistent with a causal linkage between the phosphorylation status and proteolytic stability of this cytoplasmic inhibitor. Together, these in vivo studies define a critical signal response domain in I kappa B alpha that coordinately controls the biologic activities of I kappa B alpha and NF-kappa B in response to viral and immune stimuli.
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Kamran, Mohammad Zahid, Prachi Patil, and Rajiv P. Gude. "Role of STAT3 in Cancer Metastasis and Translational Advances." BioMed Research International 2013 (2013): 1–15. http://dx.doi.org/10.1155/2013/421821.
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Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor, originally discovered as a transducer of signal from cell surface receptors to the nucleus. It is activated by tyrosine phosphorylation at position 705 leading to its dimerization, nuclear translocation, DNA binding, and activation of gene transcription. Under normal physiological conditions, STAT3 activation is tightly regulated. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a pivotal role in tumor growth and metastasis. It regulates cellular proliferation, invasion, migration, and angiogenesis that are critical for cancer metastasis. In this paper, we first describe the mechanism of STAT3 regulation followed by how STAT3 is involved in cancer metastasis, then we summarize the various small molecule inhibitors that inhibit STAT3 signaling.
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Hegedűsová, Eva, Sneha Kulkarni, Brandon Burgman, Juan D. Alfonzo, and Zdeněk Paris. "The general mRNA exporters Mex67 and Mtr2 play distinct roles in nuclear export of tRNAs in Trypanosoma brucei." Nucleic Acids Research 47, no. 16 (August 8, 2019): 8620–31. http://dx.doi.org/10.1093/nar/gkz671.
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Abstract Transfer RNAs (tRNAs) are central players in protein synthesis, which in Eukarya need to be delivered from the nucleus to the cytoplasm by specific transport receptors, most of which belong to the evolutionarily conserved beta-importin family. Based on the available literature, we identified two candidates, Xpo-t and Xpo-5 for tRNA export in Trypanosoma brucei. However, down-regulation of expression of these genes did not disrupt the export of tRNAs to the cytoplasm. In search of alternative pathways, we tested the mRNA export complex Mex67-Mtr2, for a role in tRNA nuclear export, as described previously in yeast. Down-regulation of either exporter affected the subcellular distribution of tRNAs. However, contrary to yeast, TbMex67 and TbMtr2 accumulated different subsets of tRNAs in the nucleus. While TbMtr2 perturbed the export of all the tRNAs tested, silencing of TbMex67, led to the nuclear accumulation of tRNAs that are typically modified with queuosine. In turn, inhibition of tRNA nuclear export also affected the levels of queuosine modification in tRNAs. Taken together, the results presented demonstrate the dynamic nature of tRNA trafficking in T. brucei and its potential impact not only on the availability of tRNAs for protein synthesis but also on their modification status.
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Cheng, Fan, Patricia J. McLaughlin, Michael F. Verderame, and Ian S. Zagon. "Dependence on Nuclear Localization Signals of the Opioid Growth Factor Receptor in the Regulation of Cell Proliferation." Experimental Biology and Medicine 234, no. 5 (May 2009): 532–41. http://dx.doi.org/10.3181/0901-rm-16.
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The opioid growth factor receptor (OGFr) mediates the inhibitory action of OGF on cell replication of normal and neoplastic cells. The spatiotemporal course of OGFr nucleocytoplasmic trafficking was determined with a probe of full-length OGFr fused to enhanced green fluorescent protein (eGFP). Translation of OGFr required 8.5 hours, and transit into the nucleus required 8 hours; OGFr remained in the nucleus for 8 days. OGFr was initially expressed on the outer nuclear envelope, transited to the paranuclear cytoplasm, and into the nucleus. Transport through the nuclear pore was elucidated by mutation of the nuclear localization signal (NLS) sequences in full-length OGFr. Mutation of each NLS reduced nuclear localization by 5%–50%, whereas simultaneous mutation of NLS383–386 and NLS456–460 abolished OGFr-eGFP nuclear localization in 80% of the cells. To determine whether intact NLSs are important for the inhibition of cell proliferation, DNA synthesis was monitored with BrdU. Wild-type OGFr-eGFP–transfected cells had 20% BrdU-positive cells, whereas cells with simultaneous mutation of all three NLS sites had a 70% labeling index. These results indicate that the regulation of cell proliferation by the OGF-OGFr axis is dependent on nucleocytoplasmic translocation and reliant on the integrity of two NLSs in OGFr to interact with transport receptors.
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Soden, J., A. Stevens, and DW Ray. "Genetic engineering of the glucocorticoid receptor by fusion with the herpes viral protein VP22 causes selective loss of transactivation." Journal of Endocrinology 172, no. 3 (March 1, 2002): 615–25. http://dx.doi.org/10.1677/joe.0.1720615.
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The development of methods for engineering proteins with novel properties opens the way to manipulating intracellular processes in a therapeutically useful way. Glucocorticoids, acting via glucocorticoid receptors (GR), are potent anti-inflammatory agents, acting to oppose nuclear factor kappa B (NF kappa B) function. The herpes viral protein, VP22, has been reported to confer intercellular trafficking activity on 'cargo' proteins, potentially facilitating gene therapy with intracellular proteins. VP22GR, resulting from the addition of VP22 to the N terminal of GR, was equipotent with the wild-type GR in opposing NF kappa B p65-driven expression of an NF kappa B reporter gene. Surprisingly, VP22GR was incapable of inducing transactivation of positive glucocorticoid reporter genes (MMTV-luc and TAT3-luc). Furthermore, the VP22GR had powerful dominant negative activity on both endogenous and exogenous GR transactivation. VP22GR was cytoplasmic in quiescent cells, and after hormone addition underwent nuclear translocation to share the same distribution as the GR. The ability of the VP22GR to selectively confer and enhance glucocorticoid-dependent transrepression of NF kappa B may be of use therapeutically in e.g. transplant rejection, inflammatory arthritis or asthma.
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Szołtys, M., M. Słomczyńska, J. Galas, M. Duda, and A. Sakiewicz. "Expression of androgen receptor and 3β-hydroxysteroid dehydrogenase in corpora lutea during pregnancy in the rat." Reproduction, Fertility and Development 19, no. 2 (2007): 356. http://dx.doi.org/10.1071/rd06095.
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Immunoexpression of androgen receptor (AR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) was investigated in three generations of corpora lutea (CLs), found in the ovaries of rats on Days 1, 2, 5, 9, 14 and 20 of pregnancy. The youngest generation of CLs functioned during the whole pregnancy, whereas the older and the oldest generations underwent earlier regression. The newly formed CLs exhibited weak cytoplasmic 3β-HSD expression. During subsequent days, a gradual increase in 3β-HSD immunolabelling was observed, followed by a decrease on Day 20. In the older and the oldest CLs, surviving luteal cells demonstrated strong, although in the oldest CLs mostly perinuclear, 3β-HSD immunoreaction. The newly formed CLs showed weak nuclear AR immunolabelling, which became stronger during the following days. On Day 20, luteal cells demonstrated a weaker nuclear immunoreaction. The older and oldest generations of CLs exhibited weaker and almost negative AR immunolabelling, respectively. Of special interest was the richly vascularised apical region of young CLs. Here luteal cells with more intensive 3β-HSD staining predominated, whereas cytoplasmic AR immunoreaction was accompanied by positive or negative nuclear AR immunoexpression. The present studies showed differences in AR and 3β-HSD distribution within various generations of CLs and within particular regions of the same young CL.
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Barros, Claudio D. T., Maira A. Cardoso, Paulo M. Bisch, Helena M. Araujo, and Francisco J. P. Lopes. "A reaction-diffusion network model predicts a dual role of Cactus/IκB to regulate Dorsal/NFκB nuclear translocation in Drosophila." PLOS Computational Biology 17, no. 5 (May 27, 2021): e1009040. http://dx.doi.org/10.1371/journal.pcbi.1009040.
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Dorsal-ventral patterning of the Drosophila embryo depends on the NFκB superfamily transcription factor Dorsal (Dl). Toll receptor activation signals for degradation of the IκB inhibitor Cactus (Cact), leading to a ventral-to-dorsal nuclear Dl gradient. Cact is critical for Dl nuclear import, as it binds to and prevents Dl from entering the nuclei. Quantitative analysis of cact mutants revealed an additional Cact function to promote Dl nuclear translocation in ventral regions of the embryo. To investigate this dual Cact role, we developed a predictive model based on a reaction-diffusion regulatory network. This network distinguishes non-uniform Toll-dependent Dl nuclear import and Cact degradation, from the Toll-independent processes of Cact degradation and reversible nuclear-cytoplasmic Dl flow. In addition, it incorporates translational control of Cact levels by Dl. Our model successfully reproduces wild-type data and emulates the Dl nuclear gradient in mutant dl and cact allelic combinations. Our results indicate that the dual role of Cact depends on the dynamics of Dl-Cact trimers along the dorsal-ventral axis: In the absence of Toll activation, free Dl-Cact trimers retain Dl in the cytoplasm, limiting the flow of Dl into the nucleus; in ventral-lateral regions, Dl-Cact trimers are recruited by Toll activation into predominant signaling complexes and promote Dl nuclear translocation. Simulations suggest that the balance between Toll-dependent and Toll-independent processes are key to this dynamics and reproduce the full assortment of Cact effects. Considering the high evolutionary conservation of these pathways, our analysis should contribute to understanding NFκB/c-Rel activation in other contexts such as in the vertebrate immune system and disease.
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Nakagawa, Masahiro, Munetake Shimabe, Nahoko Nishimoto, Naoko Watanabe-Okochi, Motoshi Ichikawa, Yasuhito Nannya, Yoichi Imai, and Mineo Kurokawa. "AML1/Runx1 Is a Cytoplasmic Attenuator of NF-Kb Signaling: Implication in Pathogenesis and Targeted Therapy of AML1-Related Leukemia." Blood 114, no. 22 (November 20, 2009): 1962. http://dx.doi.org/10.1182/blood.v114.22.1962.1962.
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Abstract Abstract 1962 Poster Board I-985 Introduction: AML1/Runx1 is one of the most frequent targets of chromosomal abnormalities in human leukemia. Functional impairment of AML1 caused by point mutation is also reported in patients with leukemia or myelodysplastic syndrome (MDS). However, molecular basis for leukemogenesis caused by functional impairment of AML1 is still elusive. In this study, we clarified the deregulated signaling pathway induced by loss of AML1. Results: To find the direct target of AML1, we compared gene expression profile between AML1-conditionally deleted and normal KSL cells using Cre-ER system. Gene set enrichment analysis (GSEA) using molecular signature database (MSigDB) clarified enhanced expression of NF-kB target genes in AML1 deficient cells. In addition, NF-kB inhibitor attenuated the enhanced colony forming activity of bone marrow cells from AML1 conditional knockout (cKO) mice. These data indicate the aberrant activation of NF-kB signaling pathway in stem/progenitor cells of AML1 deficient mice. NF-kB is a transcription factor which is involved in many physiological phenomena including proliferation, survival, and inflammation. Because deregulated activation of NF-kB signaling has been reported to be responsible for many types of tumors including hematological malignancies, we assumed that lack of AML1-mediated suppression of NF-kB signaling lead to malignant transformation of hematopoietic cells. p65, one of the major components of NF-kB stays in cytoplasm with IkB in a steady state. Once receiving stimulating signals from cell surface receptors such as TNF-a receptor, IkB is phosphorylated by IKK complex and subsequently degraded through the ubiquitin-proteasome pathway, resulting in nuclear translocation of p65 and transactivation of NF-kB target genes. First, we found that AML1 inhibits nuclear translocation of p65 and that nuclear localization of p65 is enhanced in AML1 deficient cells, which is cancelled by NF-kB inhibitors. In addition, AML1 inhibited p65 phosphorylation at serine 536, which is important for its activation. We found that AML1 physically interacts with IKK complex and thus suppresses its kinase activity, which accounts for a mechanistic basis for inhibition of NF-kB signaling by AML1. Suppression of IKK kinase activity by AML1 results in inhibition of both nuclear translocation of p65 and activation of NF-kB target genes. Next, we examined how leukemia-related AML1 mutants affect NF-kB signaling. Remarkably, AML1 D171N mutant found in MDS neither inhibited nuclear translocation of p65 nor attenuated the kinase activity of IKK complex. Similar results were obtained with AML1/ETO generated in leukemia with t(8;21). Mouse bone marrow cells immortalized by AML1/ETO showed enhanced nuclear localization of p65 compared with those immortalized by MLL/ENL, another leukemia-related fusion protein. Indeed, AML1/ETO immortalized cells are more sensitive to NF-kB inhibitor-mediated growth suppression, indicating a critical role of NF-kB signaling in transformation by AML1/ETO. To verify the activation of NF-kB signaling by AML1/ETO in human hematopoietic cells, we analyzed the gene expression data reported by Valk et al. in silico. We found that NF-kB signaling is distinctly activated in AML1-related leukemia patients. These results suggest that aberrant activation of NF-kB signaling induced by functional impairment of AML1 may contribute to the development of leukemia via proliferation signals. Conclusions: We found that AML1 is a cytoplasmic attenuator of NF-kB signaling pathway. Functional impairment of AML1 caused by genetic disruption results in distinct activation of NF-kB signaling by altering IKK kinetic activity. This aberrant activation may play a central role in pathogenesis of AML1-related leukemia and MDS. Therefore, NF-kB signaling is one of the attractive candidates for molecular targeted therapy against AML1-related hematological disorders. Disclosures: No relevant conflicts of interest to declare.
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Farabegoli, Fulvia, Marzia Govoni, Carmen Ciavarella, Marina Orlandi, and Alessio Papi. "A RXR Ligand 6-OH-11-O-Hydroxyphenanthrene with Antitumour Properties Enhances (−)-Epigallocatechin-3-gallate Activity in Three Human Breast Carcinoma Cell Lines." BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/853086.
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(−)-Epigallocatechin-3-gallate (EGCG) and chemotherapeutic agents cotreatment can improve cytotoxicity against cancer cells. We showed that EGCG and the rexinoid 6-OH-11-O-hydroxyphenanthrene (IIF), given together, were cytotoxic toward MCF-7, MCF-7TAM, and MDA-MB-231, three breast carcinoma cell lines showing different molecular characteristics. Cell growth arrest and apoptosis were greater after EGCG and IIF cotreatment than after individual administration. Cytotoxicity was related to upregulation of 67-kDa laminin receptor (LR67), one of the principal molecular targets of EGCG, and activation of the nuclear retinoic X receptors (RXRs) pathway. Furthermore, the transcription factor Forkhead box O3 (Foxo3a), a protein able to trigger apoptosis through upregulation of genes necessary for cell death, was activated. EGCG and IIF cotreatment produced a significant nuclear import of Foxo3a from the cytoplasm in MCF-7, MCF-7TAM, and MDA-MB-231 cells. In MCF-7TAM cells only, Foxo3a nuclear localization was associated with p473AKT downregulation. For the first time we showed that when EGCG and IIF, two harmless molecules, were given together, they might increase cytotoxicity in three breast carcinoma cell lines, two of them being representative of poorly responsive breast carcinoma types.
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Chiba, Tomoki, Hidetoshi Inoko, Minoru Kimura, and Takehito Sato. "Role of nuclear IκBs in inflammation regulation." BioMolecular Concepts 4, no. 2 (April 1, 2013): 187–96. http://dx.doi.org/10.1515/bmc-2012-0039.
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AbstractA wide variety of environmental cues, including inflammatory cytokines, ligands for pattern recognition receptors and endogenous danger signals, activate the inducible transcription factor nuclear factor-κB (NF-κB), which is a central regulator of inflammatory and immune responses. Excessive activation of NF-κB results in the development of severe diseases, such as chronic inflammatory disorders, autoimmune diseases and cancer. Therefore, the transcriptional activity of NF-κB is tightly regulated at multiple steps. One mechanism is mediated by the inhibitor of κB (IκB), a well-defined regulator of NF-κB that resides in the cytoplasm and prevents NF-κB from nuclear entry by sequestration. Recently, several atypical IκBs that reside in the nucleus were identified: Bcl-3, IκBζ, IκBNS and IκBη. In contrast to conventional IκBs, these atypical IκBs positively and negatively modulate NF-κB-mediated transcription. The function of atypical IκBs is independent of the prevention of NF-κB nuclear entry. Therefore, atypical IκBs are considered distinct from conventional IκBs and have been termed ‘nuclear IκBs.’ In addition to these members, our recent study indicated that IκBL, originally reported as a susceptibility gene for rheumatoid arthritis, also serves as a nuclear IκB. Biological and genetic studies strongly suggest that nuclear IκBs play important roles in the pathogenesis of inflammatory and autoimmune diseases via the regulation of both innate and adaptive immunity. In this review, we discuss the recent advances in our understanding of nuclear IκBs in the context of NF-κB-mediated transcriptional regulation and inflammatory responses.
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Jaini, Ritika, Matthew G. Loya, Alexander T. King, Stetson Thacker, Nicholas B. Sarn, Qi Yu, George R. Stark, and Charis Eng. "Germline PTEN mutations are associated with a skewed peripheral immune repertoire in humans and mice." Human Molecular Genetics 29, no. 14 (June 26, 2020): 2353–64. http://dx.doi.org/10.1093/hmg/ddaa118.
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Abstract Individuals with germline mutations in the gene encoding phosphatase and tensin homolog on chromosome ten (PTEN) are diagnosed with PTEN hamartoma tumor syndrome (PHTS) and are at high risk for developing breast, thyroid and other cancers and/or autoimmunity or neurodevelopmental issues including autism spectrum disorders. Although well recognized as a tumor suppressor, involvement of PTEN mutations in mediating such a diverse range of phenotypes indicates a more central involvement for PTEN in immunity than previously recognized. To address this, sequencing of the T-cell receptor variable-region β-chain was performed on peripheral blood from PHTS patients. Based on patient findings, we performed mechanistic studies in two Pten knock-in murine models, distinct from each other in cell compartment-specific predominance of Pten. We found that PTEN mutations in humans and mice are associated with a skewed T- and B-cell gene repertoire, characterized by increased prevalence of high-frequency clones. Immunological characterization showed that Pten mutants have increased B-cell proliferation and a proclivity towards increased T-cell reactivity upon Toll-like-receptor stimulation. Furthermore, decreases in nuclear but not cytoplasmic Pten levels associated with a reduction in expression of the autoimmune regulator (Aire), a critical mediator of central immune tolerance. Mechanistically, we show that nuclear PTEN most likely regulates Aire expression via its emerging role in splicing regulation. We conclude that germline disruption of PTEN, both in human and mouse, results in compromised central immune tolerance processes that may significantly impact individual stress responses and therefore predisposition to autoimmunity and cancer.
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Li, Mingxun, Qisong Gao, Zhichen Tian, Xubin Lu, Yujia Sun, Zhi Chen, Huimin Zhang, Yongjiang Mao, and Zhangping Yang. "MIR221HG Is a Novel Long Noncoding RNA that Inhibits Bovine Adipocyte Differentiation." Genes 11, no. 1 (December 26, 2019): 29. http://dx.doi.org/10.3390/genes11010029.
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Adipogenesis is a complicated but precisely orchestrated process mediated by a series of transcription factors. Our previous study has identified a novel long noncoding RNA (lncRNA) that was differentially expressed during bovine adipocyte differentiation. Because this lncRNA overlaps with miR-221 in the genome, it was named miR-221 host gene (MIR221HG). The purpose of this study was to clone the full length of MIR221HG, detect its subcellular localization, and determine the effects of MIR221HG on bovine adipocyte differentiation. The 5′ rapid amplification of cDNA ends (RACE) and 3′ RACE analyses demonstrated that MIR221HG is a transcript of 1064 nucleotides, is located on the bovine X chromosome, and contains a single exon. Bioinformatics analyses suggested that MIR221HG is an lncRNA and the promoter of MIR221HG includes the binding consensus sequences of the forkhead box C1 (FOXC1) and krüppel-like factor5 (KLF5). The semi-quantitative PCR and quantitative real-time PCR (qRT-PCR) of nuclear and cytoplasmic fractions revealed that MIR221HG mainly resides in the nucleus. Inhibition of MIR221HG significantly increased adipocyte differentiation, as indicated by a dramatic increment in the number of mature adipocytes and in the expression of the respective adipogenic markers, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), and fatty acid binding protein 4 (FABP4). Our results provide a basis for elucidating the mechanism by which MIR221HG regulates adipocyte differentiation.
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Ferlosio, Amedeo, Elena Doldo, Sara Agostinelli, Gaetana Costanza, Federica Centofanti, Angelo Sidoni, and Augusto Orlandi. "Cellular retinol binding protein 1 transfection reduces proliferation and AKT-related gene expression in H460 non-small lung cancer cells." Molecular Biology Reports 47, no. 9 (September 2020): 6879–86. http://dx.doi.org/10.1007/s11033-020-05744-5.
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Abstract In recent years, new treatments with novel action mechanisms have been explored for advanced non-small cell lung cancer (NSCLC). Retinoids promote cancer cell differentiation and death and their trafficking and action is mediated from specific cytoplasmic and nuclear receptors, respectively. The purpose of this study was to investigate the effect of Cellular retinol binding protein-1 (CRBP-1) transfection in H460 human NSCLC cell line, normally not expressing CRBP-1. H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBP-1 gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans Retinoic Acid (atRA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array and results analysed by one-way analysis of variance (ANOVA) or by t-student test. CRBP-1+ showed reduced proliferation and viability in basal condition and after atRA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBP-1+ H460 cells associated to the down-regulation of pAKT/pERK/pEGFR-related genes. In particular, gene array documented the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, p27, Jun. Restoration of CRBP-1 expression in H460 cells reduced proliferation and viability in both basal condition and after atRA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBP-1-related intracellular pathways contribute to counteract NSCLC progression in order to suggest a potential tool to improve efficacy of retinoid anti lung cancer adjuvant therapy.
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Suárez, Mariana, Lucía Canclini, and Adriana Esteves. "Identification of a non-classical three-dimensional nuclear localization signal in the intestinal fatty acid binding protein." PLOS ONE 15, no. 11 (November 12, 2020): e0242312. http://dx.doi.org/10.1371/journal.pone.0242312.
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The intestinal fatty acid binding protein (FABP) is a small protein expressed along the small intestine that bind long-chain fatty acids and other hydrophobic ligands. Several lines of evidence suggest that, once in the nucleus, it interacts with nuclear receptors, activating them and thus transferring the bound ligand into the nucleus. Previous work by our group suggests that FABP2 would participate in the cytoplasm-nucleus translocation of fatty acids. Because the consensus NLS is absent in the sequence of FABP2, we propose that a 3D signal could be responsible for its nuclear translocation. The results obtained by transfection assays of recombinant wild type and mutated forms of Danio rerio Fabp2 in Caco-2 cell cultures, showed that lysine 17, arginine 29 and lysine 30 residues, which are located in the helix-turn-helix region, would constitute a functional non-classical three-dimensional NLS.
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Lampiasi, Nadia, Roberta Russo, Igor Kireev, Olga Strelkova, Oxana Zhironkina, and Francesca Zito. "Osteoclasts Differentiation from Murine RAW 264.7 Cells Stimulated by RANKL: Timing and Behavior." Biology 10, no. 2 (February 4, 2021): 117. http://dx.doi.org/10.3390/biology10020117.
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The development of multi-nucleated cells is critical for osteoclasts (OCs) maturation and function. Our objective was to extend knowledge on osteoclastogenesis, focusing on pre-OC fusion timing and behavior. RAW 264.7 cells, which is a murine monocyte-macrophage cell line, provide a valuable and widely used tool for in vitro studies on osteoclastogenesis mechanisms. Cells were treated with the receptor activator of nuclear factor κ-B ligand (RANKL) for 1–4 days and effects on cell morphology, cytoskeletal organization, protein distribution, and OC-specific gene expression examined by TEM, immunofluorescence, and qPCR. Multinucleated cells began to appear at two days of Receptor Activator of Nuclear factor κ-B Ligand (RANKL) stimulation, increasing in number and size in the following days, associated with morphological and cytoskeletal organization changes. Interesting cellular extensions were observed in three days within cells labeled with wheat germ agglutinin (WGA)-Fluorescein isothiocyanate (FITC). The membrane, cytoplasmic, or nuclear distribution of RANK, TRAF6, p-p38, pERK1/2, and NFATc1, respectively, was related to OCs maturation timing. The gene expression for transcription factors regulating osteoclastogenesis (NFATc1, c-fos, RelA, MITF), molecules involved in RANKL-signaling transduction (TRAF6), cytoskeleton regulation (RhoA), fusion (DC-STAMP), migration (MMP9), and OC-specific enzymes (TRAP, CtsK), showed different trends related to OC differentiation timing. Our findings provide an integrated view on the morphological and molecular changes occurring during RANKL stimulation of RAW 264.7 cells, which are important to better understand the OCs’ maturation processes.
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Pelech, Steven L., Jasbinder S. Sanghera, and Maleki Daya-Makin. "Protein kinase cascades in meiotic and mitotic cell cycle control." Biochemistry and Cell Biology 68, no. 12 (December 1, 1990): 1297–330. http://dx.doi.org/10.1139/o90-194.
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Eukaryotic cell cycle progression during meiosis and mitosis is extensively regulated by reversible protein phosphorylation. Many cell surface receptors for mitogens are ligand-stimulated protein-tyrosine kinases that control the activation of a network of cytoplasmic and nuclear protein-serine(threonine) kinases. Over 30 plasma membrane associated protein-tyrosine kinases are encoded by proto-oncogenes, i.e., genes that have the potential to facilitate cancer when disregulated. Proteins such as ribosomal protein S6, microtubule-associated protein-2, myelin basic protein, and casein have been used to detect intracellular protein-serine(threonine) kinases that are activated further downstream in growth factor signalling transduction cascades. Genetic analysis of yeast cell division control (cdc) mutants has revealed another 20 or so protein-serine(threonine) kinases. One of these, specified by the cdc-2 gene in Schizosaccharomyces pombe, has homologs that are stimulated during M phase in maturing sea star and frog oocytes and mammalian somatic cells. Furthermore, during meiotic maturation in these echinoderm and amphibian oocytes, this is followed by activation of many of the same protein-serine(threonine) kinases that are stimulated when quiescent mammalian somatic cells are prompted with mitogens to traverse from G0 to G1 phase. These findings imply that a similar protein kinase cascade may oversee progression at multiple points in the cell cycle.Key words: protein kinases, mitosis, meiosis, oncogenes, cell division control.
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Ito, Kazuhiro, Steve Getting, and Catherine Charron. "Mode of Glucocorticoid Actions in Airway Disease." Scientific World JOURNAL 6 (2006): 1750–69. http://dx.doi.org/10.1100/tsw.2006.274.
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Synthetic glucocorticoids are the most potent anti-inflammatory agents used to treat chronic inflammatory disease, such as asthma. However, a small number (<5%) of asthmatic patients and almost all patients with chronic obstructive pulmonary disease (COPD) do not respond well, or at all, to glucocorticoid therapy. If the molecular mechanism of glucocorticoid insensitivity is uncovered, it may in turn provide insight into the key mechanism of glucocorticoid action and allow a rational way to implement treatment regimens that restore glucocorticoid sensitivity. Glucocorticoids exert their effects by binding to a cytoplasmic glucocorticoid receptor (GR), which is subjected to post-translational modifications. Receptor phosphorylation, acetylation, nitrosylation, ubiquitinylation, and other modifications influence hormone binding, nuclear translocation, and protein half-life. Analysis of GR interactions to other molecules, such as coactivators or corepressors, may explain the genetic specificity of GR action. Priming with inflammatory cytokine or oxidative/nitrative stress is a mechanism for the glucocorticoid resistance observed in chronic inflammatory airway disease via reduction of corepressors or GR modification. Therapies targeting these aspects of the GR activation pathway may reverse glucocorticoid resistance in patients with glucocorticoid-insensitive airway disease and some patients with other inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.
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Jones, A. Lesley. "The localization and interactions of huntingtin." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 354, no. 1386 (June 29, 1999): 1021–27. http://dx.doi.org/10.1098/rstb.1999.0454.
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Huntingtin was localized by using a series of antibodies that detected different areas of the protein from the immediate N–terminus to the C–terminal region of the protein. The more C–terminal antibodies gave a cytoplasmic localization in neurons of the brain in controls and cases of Huntington'sdisease (HD). The N–terminal antibody, however, gave a distinctive pattern of immunoreactivity in the HD brain, with marked staining of axon tracts and white matter and the detection of densely staining intranuclear inclusions. This implies some processing differences between mutated and normal huntingtin. We have also localized two interacting proteins, cystathionine β–synthase and the nuclear receptor co–repressor (N–CoR), in brain. Cystathionine beta–synthase was not relocalized in HD brain, but the N–CoR was excluded from neuronal nuclei in HD brain, and a further protein that exists in the same repression complex, mSin3, was similarly excluded. We conclude that the co–repressor might have a part in HD pathology.
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Kazlauskas, Arunas, Sara Sundström, Lorenz Poellinger, and Ingemar Pongratz. "The hsp90 Chaperone Complex Regulates Intracellular Localization of the Dioxin Receptor." Molecular and Cellular Biology 21, no. 7 (April 1, 2001): 2594–607. http://dx.doi.org/10.1128/mcb.21.7.2594-2607.2001.
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ABSTRACT The molecular chaperone complex hsp90-p23 interacts with the dioxin receptor, a ligand-dependent basic helix-loop-helix (bHLH)/Per-Arnt-Sim domain transcription factor. Whereas biochemical and genetic evidence indicates that hsp90 is important for maintenance of a high-affinity ligand binding conformation of the dioxin receptor, the role of hsp90-associated proteins in regulation of the dioxin receptor function remains unclear. Here we demonstrate that the integrity of the hsp90 complex characterized by the presence of the hsp90-associated cochaperone p23 and additional cochaperone proteins is important for regulation of the intracellular localization of the dioxin receptor by two mechanisms. First, in the absence of ligand, the dioxin receptor-hsp90 complex was associated with the immunophilin-like protein XAP2 to mediate cytoplasmic retention of the dioxin receptor. Second, upon exposure to ligand, the p23-associated hsp90 complex mediated interaction of the dioxin receptor with the nuclear import receptor protein pendulin and subsequent nuclear translocation of the receptor. Interestingly, these two modes of regulation target two distinct functional domains of the dioxin receptor. Whereas the nuclear localization signal-containing and hsp90-interacting bHLH domain of the receptor regulates ligand-dependent nuclear import, the interaction of the p23-hsp90-XAP2 complex with the ligand binding domain of the dioxin receptor was essential to mediate cytoplasmic retention of the ligand-free receptor form. In conclusion, these data suggest a novel role of the hsp90 molecular chaperone complex in regulation of the intracellular localization of the dioxin receptor.
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Shulga, N., P. Roberts, Z. Gu, L. Spitz, M. M. Tabb, M. Nomura, and D. S. Goldfarb. "In vivo nuclear transport kinetics in Saccharomyces cerevisiae: a role for heat shock protein 70 during targeting and translocation." Journal of Cell Biology 135, no. 2 (October 15, 1996): 329–39. http://dx.doi.org/10.1083/jcb.135.2.329.
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The transport of proteins into the nucleus is a receptor-mediated process that is likely to involve between 50-100 gene products, including many that comprise the nuclear pore complex. We have developed an assay in Saccharomyces cerevisiae for the nuclear transport of green fluorescent protein fused to the SV-40 large T antigen nuclear localization signal (NLS-GFP). This assay allows the measurement of relative NLS-GFP nuclear import rates in wild-type and mutant cells under various physiological conditions. Probably the best understood component of the nuclear transport apparatus is Srp1p, the NLS receptor, which binds NLS-cargo in the cytoplasm and accompanies it into the nucleus. When compared to SRP1+ cells, NLS-GFP import rates in temperature-sensitive srp1-31 cells were slower and showed a lower temperature optimum. The in vivo transport defect of the srp1-31 cells was correlated with the purified protein's thermal sensitivity, as assayed by in vitro NLS peptide binding. We show that the kinetics of NLS-directed nuclear transport in wild-type cells is stimulated by the elevated expression of SSA1, which encodes a cytoplasmic heat shock protein 70 (Hsp70). Elevated Hsp70 levels are sufficient to suppress the NLS-GFP import defects in srp1-31 and nup82-3 cells. NUP82 encodes a protein that functions within the nuclear pore complex subsequent to docking. These results provide genetic evidence that Hsp70 acts during both targeting and translocation phases of nuclear transport, possibly as a molecular chaperone to promote the formation and stability of the Srp1p-NLS-cargo complex.
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Baumann, Christopher T., Padma Maruvada, Gordon L. Hager, and Paul M. Yen. "Nuclear Cytoplasmic Shuttling by Thyroid Hormone Receptors." Journal of Biological Chemistry 276, no. 14 (January 4, 2001): 11237–45. http://dx.doi.org/10.1074/jbc.m011112200.
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Guiochon-Mantel, Anne, and Edwin Milgrom. "Cytoplasmic-nuclear trafficking of steroid hormone receptors." Trends in Endocrinology & Metabolism 4, no. 10 (December 1993): 322–28. http://dx.doi.org/10.1016/1043-2760(93)90074-o.
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Matsuoka, T., M. Tokoro, S. Shin, T. Amano, Y. Hosoi, K. Saeki, A. Iritani, and K. Matsumoto. "179 MODULATION OF RHOPHILIN-2 MAY REGULATE THE PROGRESSION OF CELL DIVISION IN FERTILIZED MOUSE EGGS." Reproduction, Fertility and Development 20, no. 1 (2008): 169. http://dx.doi.org/10.1071/rdv20n1ab179.
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It has been reported that activity of Rho, one of the GTPases, is essential for division of nuclei and cytoplasm of fertilized mouse eggs. Since it has been reported that alteration of activities of GTPases modifies their ability to attach to each of their effector proteins in somatic cells, effector proteins seem to be able to control not only progression but also repression of cell division by changing their cellular localizations through activities of GTPases. For this reason, Rhophilin-2, one of the effector proteins of Rho, seems to be involved in the decision of progression of division of fertilized mouse eggs. To examine whether this involvement works in fertilized mouse eggs, cellular localization of Rho and Rhophilin-2 in fertilized mouse eggs that were treated with Rho inhibitor were analyzed. Moreover, cellular localization of GABA A receptor association protein (GABARAP), which was identified in our previous study (Matsuoka et al. 2006 Reprod. Fertil. Dev. 18, 176–177) as a protein that interacts with Rhophilin-2, was also analyzed. Fertilized mouse eggs were obtained from in vitro fertilization technique. One group of fertilized eggs was obtained at 24 h after insemination as experimental control. To obtain the mouse eggs in which Rho activities were inhibited, Clostridium botulinum C3 exoenzyme (C3-CB), an inhibitor of Rho activity, was injected into the other group of fertilized mouse eggs at 12 h after insemination, and were collected after 12 h of subsequent culture. Cellular localization of Rho (n = 100), Rhophilin-2 (n = 10). and GABARAP (n = 10) in the collected oocytes was analyzed by using immunofluorescence. Our results showed that Rho and Rhophilin-2 were co-localized at the midbody microtubule, which is an important device for cytoplasmic division in control eggs. However, the inhibition of Rho activity did not modify the co-localization of Rho and Rhophilin-2. On the other hand, localization of GABARAP was modified by the inhibition of Rho activity, and GABARAP was detected around the nuclei of fertilized eggs in which Rho activity was inhibited. In the next experiment, we examined whether interaction of Rhophilin-2 and GABARAP was modified by the inhibition of Rho activity by using a co-immunoprecipitation assay (co-IP) (n = 100). The interaction of Rhophilin-2 and GABARAP was found to disappear after inhibition of Rho activity. These results suggest that activity of Rho seems to regulate cytoplasmic division through Rhophilin-2 modification. Moreover, Rho seem to modulate the nuclear division of fertilized mouse eggs by regulating the interaction between Rhophilin-2 and GABARAP. This study was supported by a Grant-in-Aid for the 21st Century COE Program of the Japan Mext and by a grant for the Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technology Excellence of the JST.
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Nakamachi, Yuji, Kenichiro Ohnuma, Kenichi Uto, Yoriko Noguchi, Jun Saegusa, and Seiji Kawano. "MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats." Annals of the Rheumatic Diseases 75, no. 3 (January 16, 2015): 601–8. http://dx.doi.org/10.1136/annrheumdis-2014-206417.
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ObjectiveMicroRNAs (miRNAs) are small endogenous, non-coding RNAs that act as post-transcriptional regulators. We analysed the in vivo effect of miRNA-124 (miR-124, the rat analogue of human miR-124a) on adjuvant-induced arthritis (AIA) in rats.MethodsAIA was induced in Lewis rats by injecting incomplete Freund's adjuvant with heat-killed Mycobacterium tuberculosis. Precursor (pre)-miR-124 was injected into the right hind ankle on day 9. Morphological changes in the ankle joint were assessed by micro-CT and histopathology. Cytokine expression was examined by western blotting and real-time RT-PCR. The effect of miR-124 on predicted target messenger RNAs (mRNAs) was examined by luciferase reporter assays. The effect of pre-miR-124 or pre-miR-124a on the differentiation of human osteoclasts was examined by tartrate-resistant acid phosphatase staining.ResultsWe found that miR-124 suppressed AIA in rats, as demonstrated by decreased synoviocyte proliferation, leucocyte infiltration and cartilage or bone destruction. Osteoclast counts and expression level of receptor activator of the nuclear factor κB ligand (RANKL), integrin β1 (ITGB1) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) were reduced in AIA rats treated with pre-miR-124. Luciferase analysis showed that miR-124 directly targeted the 3′UTR of the rat NFATc1, ITGB1, specificity protein 1 and CCAAT/enhancer-binding protein α mRNAs. Pre-miR-124 also suppressed NFATc1 expression in RAW264.7 cells. Both miR-124 and miR-124a directly targeted the 3′-UTR of human NFATc1 mRNA, and both pre-miR-124 and pre-miR-124a suppressed the differentiation of human osteoclasts.ConclusionsWe found that miR-124 ameliorated AIA by suppressing critical prerequisites for arthritis development, such as RANKL and NFATc1. Thus, miR-124a is a candidate for therapeutic use for human rheumatoid arthritis.
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Blüml, Stephan, Martin Friedrich, Tobias Lohmeyer, Emine Sahin, Victoria Saferding, Julia Brunner, Antonia Puchner, et al. "Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells." Annals of the Rheumatic Diseases 74, no. 1 (September 27, 2013): 227–33. http://dx.doi.org/10.1136/annrheumdis-2013-203486.
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ObjectiveLocal bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions.MethodsWe analysed osteoclastogenesis of wildtype (wt) and PTEN−/− cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model.ResultsWe show that myeloid-specific PTEN−/− mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN−/− mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN−/− mice.ConclusionsThese data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.
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D’Cruz, Akshay A., Mary Speir, Meghan Bliss-Moreau, Sylvia Dietrich, Shu Wang, Alyce A. Chen, Mathilde Gavillet, et al. "The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils." Science Signaling 11, no. 546 (September 4, 2018): eaao1716. http://dx.doi.org/10.1126/scisignal.aao1716.
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Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain–like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase–independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8–dependent apoptotic or RIPK3/MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8–dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.
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Franzelius, Cornelia, and Karl Eisele. "Interaction of Testosterone and Testosterone Receptor Complexes with Nuclei of Skeletal Muscle from Intact Male Mice and from Mice Bearing the Testicular Feminization (Tfm) Mutant Gene." Zeitschrift für Naturforschung C 43, no. 3-4 (April 1, 1988): 243–48. http://dx.doi.org/10.1515/znc-1988-3-415.
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With the nuclear exchange assay and the nuclear retention assay it is shown that the androgen insensitivity of Tfm mice is probably due to a defect of the nuclear acceptor sites for the testosterone receptor complex. Furtheron the results obtained point strongly to the possibility that hormone free androgen receptor is localized in the nuclei and in the cytoplasma according to the “equilibrium model”. A practicable method for separation of unbound steroids from nuclei is described.
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Ward, M. P., J. T. Mosher, and S. T. Crews. "Regulation of bHLH-PAS protein subcellular localization during Drosophila embryogenesis." Development 125, no. 9 (May 1, 1998): 1599–608. http://dx.doi.org/10.1242/dev.125.9.1599.
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The Drosophila Single-minded and Tango basic-helix-loop-helix-PAS protein heterodimer controls transcription and embryonic development of the CNS midline cells, while the Trachealess and Tango heterodimer controls tracheal cell and salivary duct transcription and development. Expression of both single-minded and trachealess is highly restricted to their respective cell lineages, however tango is broadly expressed. The developmental control of subcellular localization of these proteins is investigated because of their similarity to the mammalian basic-helix-loop-helix-PAS Aromatic hydrocarbon receptor whose nuclear localization is dependent on ligand binding. Confocal imaging of Single-minded and Trachealess protein localization indicate that they accumulate in cell nuclei when initially synthesized in their respective cell lineages and remain nuclear throughout embryogenesis. Ectopic expression experiments show that Single-minded and Trachealess are localized to nuclei in cells throughout the ectoderm and mesoderm, indicating that nuclear accumulation is not regulated in a cell-specific fashion and unlikely to be ligand dependent. In contrast, nuclear localization of Tango is developmentally regulated; it is localized to the cytoplasm in most cells except the CNS midline, salivary duct, and tracheal cells where it accumulates in nuclei. Genetic and ectopic expression experiments indicate that Tango nuclear localization is dependent on the presence of a basic-helix-loop-helix-PAS protein such as Single-minded or Trachealess. Conversely, Drosophila cell culture experiments show that Single-minded and Trachealess nuclear localization is dependent on Tango since they are cytoplasmic in the absence of Tango. These results suggest a model in which Single-minded and Trachealess dimerize with Tango in the cytoplasm of the CNS midline cells and trachea, respectively, and the dimeric complex accumulates in nuclei in a ligand-independent mode and regulates lineage-specific transcription. The lineage-specific action of Single-minded and Trachealess derives from transcriptional activation of their genes in their respective lineages, not from extracellular signaling.
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Catera, Rosa, Katerina Hatzi, Till Seiler, Steven L. Allen, Kanti R. Rai, Charles C. Chu, and Nicholas Chiorazzi. "Binding of CLL B-Cell Receptors to Viable and Apoptotic Human Cells Offers Insight into the Role of Autoantigens in Leukemic Transformation." Blood 110, no. 11 (November 16, 2007): 741. http://dx.doi.org/10.1182/blood.v110.11.741.741.
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Abstract IgVH gene mutation status correlates with clinical course in chronic lymphocytic leukemia (CLL), with the unmutated group usually having a worse outcome. Because the binding domains of B-cell receptors (BCRs) among patients exhibit considerable genetic and structural similarity, it has been suggested that a limited set of antigens drive clonal expansion in CLL. We reasoned that characterizing antigenic reactivities of CLL BCRs would provide insight into the development of the disease. Hence we cloned and expressed BCRs from 28 CLL patients (18 unmutated and 10 mutated) as monoclonal antibodies (mAbs). We tested these by immunofluorescence for reactivity with the human epithelial cell line HEp-2, often used to identify nuclear autoantigens in autoimmune disorders such as systemic lupus erythematosus (SLE). Furthermore since apoptotic cells are a source of autoantigens in autoimmune conditions, we also tested the mAbs for reactivity with apoptotic and viable B and T cells, from RAMOS (B) and Jurkat (T) cell lines and from normal subjects and CLL patients. All 28 mAbs showed binding to intracellular structures of HEp-2 cells, reminiscent of SLE. Unlike SLE, the binding was predominantly cytoplasmic. Only one mAb, expressing VH4-59, bound HEp-2 cell nuclei. When tested for reactivity with B and T cell surfaces by indirect immunofluorescence and flow cytometry, only 13 (10 unmutated and 3 mutated) of the 28 mAbs bound at least one lymphoid cell type. Among the cell-reactive mAbs, 8 bound apoptotic cells without discriminating between B and T cells. All these expressed unmutated IgVH genes; 5 were VH1 family members (3 exhibited VH1-69-D3-3-JH6 with different HCDR3s and L chain rearrangements, 1 expressed VH1-03, and 1 expressed VH1-02) and the last 3 belonged to a stereotypic set comprising VH4-39-D6-13-JH5 + Vk1D-39-Jk1. Notably, 5 mAbs, expressing VH4-34, reacted only with viable cells. Two of these used unmutated 4-34 genes and bound both B and T cells; altering their companion VLJL rearrangements eliminated virtually all cell binding. The other 3 mAbs, members of the stereotypic set with a mutated VH4-34-D5-18-JH6 rearrangement, bound only viable B cells, predominantly of the naïve subset. Substitution of their L chains led to a decrease in B cell binding, although to a lesser degree than for the unmutated VH4-34 mAbs. The one mAb reacting with HEp-2 nuclei failed to react with apoptotic or viable B and T cells. Of note, no VH3-expressing mAbs reacted with cell surface targets. In sum, even though all 28 CLL mAbs reacted with intracellular targets, only ~45% (n=13) reacted with lymphoid cell surfaces. Of those, 8 bound only apoptotic cells and 5 bound viable cells. All mAbs binding viable cells expressed VH4-34, with mutated mAbs binding solely B cells, and unmutated binding both. Interestingly, although the 8 mAbs binding apoptotic B or T cells were all unmutated, another 8 unmutated, but HEp-2-reactive, mAbs failed to bind any surface targets. Thus unmutated polyreactive BCRs exhibit a degree of specificity in antigen binding conferred by VH family and gene use and their companion VHDJH and VLJL. Finally, these data highlight a role for apoptosis as a source of already existing or newly created autoantigens in the promotion and evolution of CLL.
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Okuyama Kishima, Marina, Karen Brajão de Oliveira, Carolina Batista Ariza, Carlos Eduardo Coral de Oliveira, Roberta Losi Guembarovski, Bruna Karina Banin Hirata, Felipe Campos de Almeida, et al. "Genetic Polymorphism and Expression of CXCR4 in Breast Cancer." Analytical Cellular Pathology 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/289510.
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CXCR4genetic polymorphisms, as well as their expression level, have been associated with cancer development and prognosis. The present study aimed to investigate the influence ofCXCR4rs2228014 polymorphism on its mRNA and protein expression in breast cancer samples. It was observed that patients presented higherCXCR4mRNA relative expression (5.7-fold) than normal mammary gland, but this expression was not correlated with patients clinicopathological features (nuclear grade, nodal status, ER status, PR status, p53 staining, Ki67 index, and HER-2 status). Moreover,CXCR4mRNA relative expression also did not differ regarding the presence or absence of T allele (p=0.301). In the immunohistochemical assay, no difference was observed for CXCR4 cytoplasmic protein staining in relation to different genotypes (p=0.757); however, high cytoplasmic CXCR4 staining was verified in invasive breast carcinoma (p<0.01). All in all, the results from present study indicated that rs2228014 genetic variant does not alterCXCR4mRNA or protein expression. However, this receptor was more expressed in tumor compared to normal tissue, in both RNA and protein levels, suggesting its promising applicability in the general context of mammary carcinogenesis.
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Blackwell, Ernest, Izabel M. Halatek, Hye-Jin N. Kim, Alexis T. Ellicott, Andrey A. Obukhov, and David E. Stone. "Effect of the Pheromone-Responsive Gα and Phosphatase Proteins of Saccharomyces cerevisiae on the Subcellular Localization of the Fus3 Mitogen-Activated Protein Kinase." Molecular and Cellular Biology 23, no. 4 (February 15, 2003): 1135–50. http://dx.doi.org/10.1128/mcb.23.4.1135-1150.2003.
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ABSTRACT The mating-specific Gα protein of Saccharomyces cerevisiae, Gpa1, stimulates adaptation to pheromone by a mechanism independent of Gβγ sequestration. Genetic evidence suggests that Gpa1 targets the Fus3 mitogen-activated protein kinase, and it has recently been shown that the two proteins interact in cells responding to pheromone. To test the possibility that Gpa1 downregulates the mating signal by affecting the localization of Fus3, we created a Fus3-green fluorescent protein (GFP) fusion protein. In vegetative cells, Fus3-GFP was found in both the cytoplasm and the nucleus. Pheromone stimulated a measurable increase in the ratio of nuclear to cytoplasmic Fus3-GFP. In contrast, the relative level of nuclear Fus3-GFP decreased as cells recovered from pheromone arrest and did not increase when cells adapted to chronic stimulus were challenged again. Accumulation of Fus3-GFP in the nuclei of stimulated cells was also inhibited by overexpression of either wild-type Gpa1, the E364K hyperadaptive mutant form of Gpa1, or the Msg5 dually specific phosphatase. The effects of Gpa1 and Msg5 on Fus3 are partially interdependent. In a genetic screen for adaptive defective mutants, a nonsense allele of the nucleocytoplasmic transport receptor, Kap104, was identified. Truncation of the Kap104 cargo-binding domain blocked the effect of both Gpa1E364K and Msg5 on Fus3-GFP localization. Based on these results, we propose that Gpa1 and Msg5 work in concert to downregulate the mating signal and that they do so by inhibiting the pheromone-induced increase of Fus3 in the nucleus. Kap104 is required for the Gα/phosphatase-mediated effect on Fus3 localization.
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Thibonnier, Marc, Andrea L. Bayer, and Zhihong Leng. "Cytoplasmic and nuclear signaling pathways of V1-vascular vasopressin receptors." Regulatory Peptides 45, no. 1-2 (April 1993): 79–84. http://dx.doi.org/10.1016/0167-0115(93)90186-c.
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Fahrenkrog, Birthe, Wolfgang Hübner, Anna Mandinova, Nelly Panté, Walter Keller, and Ueli Aebi. "The Yeast Nucleoporin Nup53p Specifically Interacts with Nic96p and Is Directly Involved in Nuclear Protein Import." Molecular Biology of the Cell 11, no. 11 (November 2000): 3885–96. http://dx.doi.org/10.1091/mbc.11.11.3885.
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The bidirectional nucleocytoplasmic transport of macromolecules is mediated by the nuclear pore complex (NPC) which, in yeast, is composed of ∼30 different proteins (nucleoporins). Pre-embedding immunogold-electron microscopy revealed that Nic96p, an essential yeast nucleoporin, is located about the cytoplasmic and the nuclear periphery of the central channel, and near or at the distal ring of the yeast NPC. Genetic approaches further implicated Nic96p in nuclear protein import. To more specifically explore the potential role of Nic96p in nuclear protein import, we performed a two-hybrid screen withNIC96 as the bait against a yeast genomic library to identify transport factors and/or nucleoporins involved in nuclear protein import interacting with Nic96p. By doing so, we identified the yeast nucleoporin Nup53p, which also exhibits multiple locations within the yeast NPC and colocalizes with Nic96p in all its locations. Whereas Nup53p is directly involved in NLS-mediated protein import by its interaction with the yeast nuclear import receptor Kap95p, it appears not to participate in NES-dependent nuclear export.
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Pierce, Jacqueline B., George van der Merwe, and Dev Mangroo. "Protein Kinase A Is Part of a Mechanism That Regulates Nuclear Reimport of the Nuclear tRNA Export Receptors Los1p and Msn5p." Eukaryotic Cell 13, no. 2 (December 2, 2013): 209–30. http://dx.doi.org/10.1128/ec.00214-13.
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ABSTRACTThe two main signal transduction mechanisms that allow eukaryotes to sense and respond to changes in glucose availability in the environment are the cyclic AMP (cAMP)/protein kinase A (PKA) and AMP-activated protein kinase (AMPK)/Snf1 kinase-dependent pathways. Previous studies have shown that the nuclear tRNA export process is inhibited inSaccharomyces cerevisiaedeprived of glucose. However, the signal transduction pathway involved and the mechanism by which glucose availability regulates nuclear-cytoplasmic tRNA trafficking are not understood. Here, we show that inhibition of nuclear tRNA export is caused by a block in nuclear reimport of the tRNA export receptors during glucose deprivation. Cytoplasmic accumulation of the tRNA export receptors during glucose deprivation is not caused by activation of Snf1p. Evidence obtained suggests that PKA is part of the mechanism that regulates nuclear reimport of the tRNA export receptors in response to glucose availability. This mechanism does not appear to involve phosphorylation of the nuclear tRNA export receptors by PKA. The block in nuclear reimport of the tRNA export receptors appears to be caused by activation of an unidentified mechanism when PKA is turned off during glucose deprivation. Taken together, the data suggest that PKA facilitates return of the tRNA export receptors to the nucleus by inhibiting an unidentified activity that facilitates cytoplasmic accumulation of the tRNA export receptors when glucose in the environment is limiting. A PKA-independent mechanism was also found to regulate nuclear tRNA export in response to glucose availability. This mechanism, however, does not regulate nuclear reimport of the tRNA export receptors.
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Chen, Juan, Yan Li, Jianlei Wu, Yakun Liu, and Shan Kang. "Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors." Biology of Reproduction 105, no. 1 (March 19, 2021): 164–78. http://dx.doi.org/10.1093/biolre/ioab052.
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Abstract Malignant ovarian germ cell tumors (MOGCTs) are rare and heterogeneous ovary tumors. We aimed to identify potential germline mutations and somatic mutations in MOGCTs by whole-exome sequencing. The peripheral blood and tumor samples from these patients were used to identify germline mutations and somatic mutations, respectively. For those genes with copy number alterations (deletion and duplication region), functional annotation was performed. Immunohistochemistry was performed to evaluate the expression of mutated genes corresponding to CNA deletion region and duplication region. In peripheral blood, copy number loss and gain were mostly found in yolk sac tumors (YSTs). Moreover, POU5F1 was the most significant mutated gene with mutation frequency >10% in both CNA deletion and duplication region. In addition, strong cytoplasm staining of POU5F1 (corresponding to CNA deletion region and duplication region) was found in two YST and nuclear staining in two dysgerminomas tumor samples. Genes corresponding to CNA deletion region were significantly enriched in the signaling pathway of regulating pluripotency of stem cells. In addition, genes corresponding to CNA duplication region were significantly enriched in the signaling pathways of RIG-I (DExD/H-box helicase 58)-like receptor, Toll-like receptor and nuclear factor (NF)-kappa. Keratin 4 (KRT4), ribosomal protein L14 (RPL14), proprotein convertase subtilisin/kexin type 6 (PCSK6), poly(A)-binding protein cytoplasmic 3 (PABPC3), and sterile alpha and TIR motif containing 1 (SARM1) mutations were detected in both peripheral blood and tumor samples. Identification of potential germline mutations and somatic mutations in MOGCTs may provide a new field in understanding the genetic feature of the rare biological tumor type in the ovary.
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Schnabel, A., and M. A. Asmussen. "Definition and properties of disequilibria within nuclear-mitochondrial-chloroplast and other nuclear-dicytoplasmic systems." Genetics 123, no. 1 (September 1, 1989): 199–215. http://dx.doi.org/10.1093/genetics/123.1.199.
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Abstract We define and determine the interrelationships among five sets of disequilibrium parameters that measure two- and three-locus nonrandom associations in nuclear-dicytoplasmic systems. These assume a diploid nuclear locus and two haploid cytoplasmic loci, with special reference to nuclear-mitochondrial-chloroplast systems. Three sets of two-locus disequilibria measure the association between haplotypes at the two cytoplasmic loci (DMC) and associations between each cytoplasmic locus and nuclear alleles or genotypes (DM, D1M, D2M, D3M; DC, D1C, D2C, D3C). In addition, we present two classes of higher-order disequilibria that measure nonrandom allelic or genotypic associations involving all three loci. The first class quantifies associations between the nuclear locus and the two cytoplasmic loci taken jointly (DA/MC, DAA/MC, DAa/MC, Daa/MC, etc.), whereas the second measures only those associations remaining after all two-locus associations have been taken into account (DA/M/C, DAA/M/C, DAa/M/C, Daa/M/C). Based on combinations of these five sets of measures, we suggest a variety of parameterizations of three-locus, nuclear-dicytoplasmic systems. The dynamics of these disequilibria are then investigated under models of random and mixed mating, either with both cytoplasmic genomes inherited through the same parent or through opposite parents. Except for associations between the cytoplasmic haplotypes, which are constant when the two cytoplasmic genomes are inherited through the same parent, all disequilibria ultimately decay to zero. These randomizations do not necessarily occur monotonically, however, and in some cases are preceded by an initial increase in magnitude or sign change. For both inheritance patterns, the asymptotic decay rates are steadily retarded by increasing levels of self-fertilization. This behavior contrasts with that in the extreme case of complete selfing, for which only the heterozygote disequilibria always decay to zero. For all models considered, the dynamics of the two-locus cytonuclear subsystems are solely a function of the mating system, whereas the dynamical behavior and sign patterns of the cytoplasmic and three-locus disequilibria also depend strongly on the mode of cytoplasmic inheritance.
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Lin, A. L., and S. A. Shain. "Estrogen-mediated cytoplasmic and nuclear distribution of rat cardiovascular estrogen receptors." Arteriosclerosis: An Official Journal of the American Heart Association, Inc. 5, no. 6 (November 1985): 668–77. http://dx.doi.org/10.1161/01.atv.5.6.668.
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Parikh, I., K. G. Rajendran, J. L. Su, T. Lopez, and M. Sar. "Are estrogen receptors cytoplasmic or nuclear? Some immunocytochemical and biochemical studies." Journal of Steroid Biochemistry 27, no. 1-3 (January 1987): 185–92. http://dx.doi.org/10.1016/0022-4731(87)90309-8.
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van der Hulst, R. G. M., P. Meirmans, P. H. van Tienderen, and J. M. M. van Damme. "Nuclear–Cytoplasmic male-sterility in diploid dandelions." Heredity 93, no. 1 (May 12, 2004): 43–50. http://dx.doi.org/10.1038/sj.hdy.6800478.
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Belandia, Borja, and Malcolm G. Parker. "Nuclear Receptors." Cell 114, no. 3 (August 2003): 277–80. http://dx.doi.org/10.1016/s0092-8674(03)00599-3.
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Lin, A. L., R. Gonzalez, and S. A. Shain. "Androgen directs apparent cytoplasmic and nuclear distribution of rat cardiovascular androgen receptors." Arteriosclerosis: An Official Journal of the American Heart Association, Inc. 5, no. 6 (November 1985): 659–67. http://dx.doi.org/10.1161/01.atv.5.6.659.
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