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Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male.
Navarro G, Xu W, Jacobson DA, Wicksteed B, Allard C, Zhang G, De Gendt K, Kim SH, Wu H, Zhang H, Verhoeven G, Katzenellenbogen JA, Mauvais-Jarvis F
(2016) Cell Metab 23: 837-51
MeSH Terms: Animals, Cell Line, Tumor, Cell Nucleus, Cyclic AMP, Glucose, Glucose Intolerance, Humans, Insulin, Insulin-Secreting Cells, Male, Mice, Knockout, Models, Biological, Receptors, Androgen, Signal Transduction, Testosterone
Show Abstract · Added November 13, 2017
Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β cells. We show that male mice lacking AR in β cells (βARKO) exhibit decreased glucose-stimulated insulin secretion (GSIS), leading to glucose intolerance. The AR agonist dihydrotestosterone (DHT) enhances GSIS in cultured male islets, an effect that is abolished in βARKO(-/y) islets and human islets treated with an AR antagonist. In β cells, DHT-activated AR is predominantly extranuclear and enhances GSIS by increasing islet cAMP and activating the protein kinase A. In mouse and human islets, the insulinotropic effect of DHT depends on activation of the glucagon-like peptide-1 (GLP-1) receptor, and accordingly, DHT amplifies the incretin effect of GLP-1. This study identifies AR as a novel receptor that enhances β cell function, a finding with implications for the prevention of T2D in aging men.
Copyright © 2016 Elsevier Inc. All rights reserved.
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15 MeSH Terms
TLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair.
Natarajan C, Yao SY, Sriram S
(2016) PLoS One 11: e0152163
MeSH Terms: Animals, Cell Differentiation, Cell Nucleus, Cell Polarity, Cells, Cultured, Corpus Callosum, Enzyme Activation, Intercellular Signaling Peptides and Proteins, Interleukin-33, Lysophosphatidylcholines, Macrophages, Models, Biological, Myelin Basic Protein, Myelin Sheath, Neuroglia, Oligodendroglia, Phenotype, Phosphorylation, Poly I-C, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Recombinant Proteins, Stem Cells, Toll-Like Receptor 3, Transcription, Genetic, Up-Regulation, Wound Healing, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added April 18, 2017
BACKGROUND - Impaired remyelination of demyelinated axons is a major cause of neurological disability. In inflammatory demyelinating disease of the central nervous system (CNS), although remyelination does happen, it is often incomplete, resulting in poor clinical recovery. Poly-IC a known TLR3 agonist and IL-33, a cytokine which is induced by poly-IC are known to influence recovery and promote repair in experimental models of CNS demyelination.
METHODOLOGY AND PRINCIPAL FINDINGS - We examined the effect of addition of poly-IC and IL-33 on the differentiation and maturation of oligodendrocyte precursor cells (OPC) cultured in vitro. Both Poly-IC and IL-33 induced transcription of myelin genes and the differentiation of OPC to mature myelin forming cells. Poly-IC induced IL-33 in OPC and addition of IL-33 to in vitro cultures, amplified further, IL-33 expression suggesting an autocrine regulation of IL-33. Poly-IC and IL-33 also induced phosphorylation of p38MAPK, a signaling molecule involved in myelination. Following the induction of gliotoxic injury with lysolecithin to the corpus callosum (CC), treatment of animals with poly-IC resulted in greater recruitment of OPC and increased staining for myelin in areas of demyelination. Also, poly-IC treated animals showed greater expression of IL-33 and higher expression of M2 phenotype macrophages in the CC.
CONCLUSION/SIGNIFICANCE - Our studies suggest that poly-IC and IL-33 play a role in myelin repair by enhancing expression of myelin genes and are therefore attractive therapeutic agents for use as remyelinating agents in human demyelinating disease.
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28 MeSH Terms
Inositol polyphosphate multikinase (IPMK) in transcriptional regulation and nuclear inositide metabolism.
Malabanan MM, Blind RD
(2016) Biochem Soc Trans 44: 279-85
MeSH Terms: Animals, Biocatalysis, Cell Nucleus, Gene Expression Regulation, Humans, Inositol, Phosphotransferases (Alcohol Group Acceptor), Transcription, Genetic
Show Abstract · Added January 19, 2019
Inositol polyphosphate multikinase (IPMK, ipk2, Arg(82), ArgRIII) is an inositide kinase with unusually flexible substrate specificity and the capacity to partake in many functional protein-protein interactions (PPIs). By merging these two activities, IPMK is able to execute gene regulatory functions that are very unique and only now beginning to be recognized. In this short review, we present a brief history of IPMK, describe the structural biology of the enzyme and highlight a few recent discoveries that have shed more light on the role IPMK plays in inositide metabolism, nuclear signalling and transcriptional regulation.
© 2016 Authors; published by Portland Press Limited.
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MeSH Terms
Temporal Regulation of Lipin Activity Diverged to Account for Differences in Mitotic Programs.
Makarova M, Gu Y, Chen JS, Beckley JR, Gould KL, Oliferenko S
(2016) Curr Biol 26: 237-243
MeSH Terms: Cell Nucleus, Cell Nucleus Division, Chromosome Segregation, Mitosis, Organic Chemicals, Schizosaccharomyces
Show Abstract · Added February 4, 2016
Eukaryotes remodel the nucleus during mitosis using a variety of mechanisms that differ in the timing and the extent of nuclear envelope (NE) breakdown. Here, we probe the principles enabling this functional diversity by exploiting the natural divergence in NE management strategies between the related fission yeasts Schizosaccharomyces pombe and Schizosaccharomyces japonicus [1-3]. We show that inactivation of Ned1, the phosphatidic acid phosphatase of the lipin family, by CDK phosphorylation is both necessary and sufficient to promote NE expansion required for "closed" mitosis in S. pombe. In contrast, Ned1 is not regulated during division in S. japonicus, thus limiting membrane availability and necessitating NE breakage. Interspecies gene swaps result in phenotypically normal divisions with the S. japonicus lipin acquiring an S. pombe-like mitotic phosphorylation pattern. Our results provide experimental evidence for the mitotic regulation of phosphatidic acid flux and suggest that the regulatory networks governing lipin activity diverged in evolution to give rise to strikingly dissimilar mitotic programs.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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6 MeSH Terms
Nuclear LC3 Associates with Slowly Diffusing Complexes that Survey the Nucleolus.
Kraft LJ, Manral P, Dowler J, Kenworthy AK
(2016) Traffic 17: 369-99
MeSH Terms: Active Transport, Cell Nucleus, Cell Nucleolus, HeLa Cells, Humans, Microtubule-Associated Proteins, Protein Binding, RNA, Ribosomal Proteins, Tubulin
Show Abstract · Added February 12, 2016
MAP1LC3B (microtubule-associated protein 1 light chain 3, LC3) is a key component of the autophagy pathway, contributing to both cargo selection and autophagosome formation in the cytoplasm. Emerging evidence suggests that nuclear forms of LC3 are also functionally important; however, the mechanisms that facilitate the nuclear targeting and trafficking of LC3 between the nucleus and cytoplasm under steady-state conditions are poorly understood. In this study, we examine how residues known to regulate the interactions between LC3 and other proteins or RNA (F52 L53, R68-R70 and G120) contribute to its nuclear targeting, nucleocytoplasmic transport and association with nucleoli and other nuclear components. We find that residues F52 L53 and R68-70, but not G120, regulate targeting of LC3 to the nucleus, its rates of nucleocytoplasmic transport and the apparent sizes of LC3-associated complexes in the nucleus inferred from fluorescence recovery after photobleaching (FRAP) measurements. We also show that LC3 is enriched in nucleoli and its triple arginine motif is especially important for nucleolar targeting. Finally, we identify a series of candidate nuclear LC3-interacting proteins using mass spectrometry, including MAP1B, tubulin and several 40S ribosomal proteins. These findings suggest LC3 is retained in the nucleus in association with high-molecular weight complexes that continuously scan the nucleolus.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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9 MeSH Terms
Combining Spinach-tagged RNA and gene localization to image gene expression in live yeast.
Guet D, Burns LT, Maji S, Boulanger J, Hersen P, Wente SR, Salamero J, Dargemont C
(2015) Nat Commun 6: 8882
MeSH Terms: Aptamers, Nucleotide, Cell Nucleus, Gene Expression Regulation, Fungal, Molecular Imaging, RNA, Fungal, RNA, Messenger, Saccharomyces cerevisiae, Transcription, Genetic
Show Abstract · Added February 15, 2016
Although many factors required for the formation of export-competent mRNPs have been described, an integrative view of the spatiotemporal coordinated cascade leading mRNPs from their site of transcription to their site of nuclear exit, at a single cell level, is still partially missing due to technological limitations. Here we report that the RNA Spinach aptamer is a powerful tool for mRNA imaging in live S. cerevisiae with high spatial-temporal resolution and no perturbation of the mRNA biogenesis properties. Dedicated image processing workflows are developed to allow detection of very low abundance of transcripts, accurate quantitative dynamic studies, as well as to provide a localization precision close to 100 nm at consistent time scales. Combining these approaches has provided a state-of-the-art analysis of the osmotic shock response in live yeast by localizing induced transcription factors, target gene loci and corresponding transcripts.
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8 MeSH Terms
Nuclear Oxidation of a Major Peroxidation DNA Adduct, M1dG, in the Genome.
Wauchope OR, Beavers WN, Galligan JJ, Mitchener MM, Kingsley PJ, Marnett LJ
(2015) Chem Res Toxicol 28: 2334-42
MeSH Terms: Adenine, Animals, Cell Nucleus, Cells, Cultured, Chromatography, Liquid, DNA Adducts, HEK293 Cells, Humans, Lipid Peroxidation, Macrophages, Mass Spectrometry, Oxidation-Reduction, Purine Nucleosides
Show Abstract · Added February 22, 2016
Chronic inflammation results in increased production of reactive oxygen species (ROS), which can oxidize cellular molecules including lipids and DNA. Our laboratory has shown that 3-(2-deoxy-β-d-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one (M1dG) is the most abundant DNA adduct formed from the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M1dG is mutagenic in bacterial and mammalian cells and is repaired via the nucleotide excision repair system. Here, we report that M1dG levels in intact DNA were increased from basal levels of 1 adduct per 10(8) nucleotides to 2 adducts per 10(6) nucleotides following adenine propenal treatment of RKO, HEK293, or HepG2 cells. We also found that M1dG in genomic DNA was oxidized in a time-dependent fashion to a single product, 6-oxo-M1dG (to ∼ 5 adducts per 10(7) nucleotides), and that this oxidation correlated with a decline in M1dG levels. Investigations in RAW264.7 macrophages indicate the presence of high basal levels of M1dG (1 adduct per 10(6) nucleotides) and the endogenous formation of 6-oxo-M1dG. This is the first report of the production of 6-oxo-M1dG in genomic DNA in intact cells, and it has significant implications for understanding the role of inflammation in DNA damage, mutagenesis, and repair.
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13 MeSH Terms
High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1.
Suarez S, McCollum GW, Jayagopal A, Penn JS
(2015) J Biol Chem 290: 28311-20
MeSH Terms: Apoptosis, Cell Nucleus, Cells, Cultured, Gene Knockdown Techniques, Glucose, Glyceraldehyde-3-Phosphate Dehydrogenases, Humans, Nuclear Proteins, Pericytes, Protein Transport, Retina, Ubiquitin-Protein Ligases
Show Abstract · Added April 10, 2019
Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early pathologic feature of DR. Although it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was recently identified in ocular tissues. In this article we examined the involvement of the GAPDH/Siah1 interaction in human retinal pericyte (hRP) apoptosis. HRP were cultured in 5 mm normal glucose, 25 mm l- or d-glucose for 48 h (osmotic control and high glucose treatments, respectively). Siah1 siRNA was used to down-regulate Siah1 expression. TAT-FLAG GAPDH and/or Siah1-directed peptides were used to block GAPDH and Siah1 interaction. Co-immunoprecipitation assays were conducted to analyze the effect of high glucose on the association of GAPDH and Siah1. Apoptosis was measured by Annexin V staining and caspase-3 enzymatic activity assay. High glucose increased Siah1 total protein levels, induced the association between GAPDH and Siah1, and led to GAPDH nuclear translocation. Our findings demonstrate that dissociation of the GAPDH/Siah1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of DR. Thus, the work presented in this article can provide a foundation to identify novel targets for early treatment of DR.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
Duvall-Noelle N, Karwandyar A, Richmond A, Raman D
(2016) Oncogene 35: 1122-33
MeSH Terms: Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing, Breast Neoplasms, CCAAT-Enhancer-Binding Proteins, Cell Line, Tumor, Chemokine CXCL12, Cytoskeletal Proteins, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, Epigenesis, Genetic, Gene Knockdown Techniques, Heterocyclic Compounds, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Histones, Humans, LIM Domain Proteins, Prognosis, Proteomics, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Tumor Microenvironment
Show Abstract · Added May 20, 2015
Nuclear LASP-1 (LIM and SH3 protein-1) has a direct correlation with overall survival of breast cancer patients. In this study, immunohistochemical analysis of a human breast TMA showed that LASP-1 is absent in normal human breast epithelium but the expression increases with malignancy and is highly nuclear in aggressive breast cancer. We investigated whether the chemokines and growth factors present in the tumor microenvironment could trigger nuclear translocation of LASP-1.Treatment of human breast cancer cells with CXCL12, EGF and HRG, and HMEC-CXCR2 cells with CXCL8 facilitated nuclear shuttling of LASP-1. Data from the biochemical analysis of the nuclear and cytosolic fractions further confirmed the nuclear translocation of LASP-1 upon chemokine and growth factor treatment. CXCL12-dependent nuclear import of LASP-1 could be blocked by CXCR4 antagonist, AMD-3100. Knock down of LASP-1 resulted in alterations in gene expression leading to an increased level of cell-junction and extracellular matrix proteins and an altered cytokine secretory profile. Three-dimensional cultures of human breast cancer cells on Matrigel revealed an altered colony growth, morphology and arborization pattern in LASP-1 knockdown cells. Functional analysis of the LASP-1 knockdown cells revealed increased adhesion to collagen IV and decreased invasion through the Matrigel. Proteomic analysis of immunoprecipitates of LASP-1 and subsequent validation approaches revealed that LASP-1 associated with the epigenetic machinery especially UHRF1, DNMT1, G9a and the transcription factor Snail1. Interestingly, LASP-1 associated with UHRF1, G9a, Snail1 and di- and tri-methylated histoneH3 in a CXCL12-dependent manner based on immunoprecipitation and proximity ligation assays. LASP-1 also directly bound to Snail1 which may stabilize Snail1. Thus, nuclear LASP-1 appears to functionally serve as a hub for the epigenetic machinery.
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23 MeSH Terms
Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis.
Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, Peek RM, El-Rifai W
(2015) Oncotarget 6: 17911-22
MeSH Terms: Active Transport, Cell Nucleus, Adenocarcinoma, Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Down-Regulation, Gastric Mucosa, Gene Expression Regulation, Neoplastic, HEK293 Cells, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, Mice, Knockout, Peptides, RNA, Messenger, Signal Transduction, Stomach Neoplasms, Transfection, Trefoil Factor-1, Tumor Suppressor Proteins, beta Catenin
Show Abstract · Added September 28, 2015
Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis.
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23 MeSH Terms