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Norikazu Yabuta, Chie Ota, Towa Sasakura, Yoko Naito, Daisuke Okuzaki, Kohshiro Fukushima, Hiroshi Nojima
p63, a transcriptional factor that belongs to the p53 family, regulates epidermal differentiation, stemness, cell death, tumorigenesis, metastasis, and senescence. However, its molecular mechanism remains elusive. We report here that TAp63 phosphorylated at T46/T281 specifically upregulates the late cornified envelope 1C (LCE1C) gene that is essential at a relatively late stage of epithelial development. We identified these phosphorylation sites during a search for the targets of Cyclin G-associated kinase (GAK) in vitro...
March 20, 2018: Scientific Reports
Daniel Lüdke, Charlotte Roth, Denise Hartken, Marcel Wiermer
The Arabidopsis nuclear transport receptor IMPORTIN-α3/MOS6 (MODIFIER OF SNC1, 6) is required for constitutive defense responses of the auto-immune mutant snc1 (suppressor of npr1-1, constitutive 1) and contributes to basal disease resistance, suggesting a role in nuclear import of defense-regulatory cargo proteins. We recently showed that MOS6 selectively interacts with TN13, a TIR-NBS protein involved in basal resistance to Pseudomonas syringae pv. tomato (Pst) DC3000 lacking the effectors AvrPto and AvrPtoB...
March 20, 2018: Plant Signaling & Behavior
Xiangpeng Hu, Hongwei Kan, Alex Boye, Yufeng Jiang, Chao Wu, Yan Yang
The transforming growth factor (TGF)-β/Smad signaling pathway is involved in hepatocellular carcinoma development. Smad2 and Smad3 are phosphorylated following TGF-β1 stimulation and subsequently oligomerize with Smad4 to form the Smad2/3/4 complex, which translocates into the nucleus and regulates target genes, including plasminogen activator inhibitor type 1 (PAI1). Importin (Imp)7 and Imp8 are responsible for transporting phosphorylated (p)Smad2/3 and Smad4 into the nucleus. In our previous study, it was demonstrated that mitogen-activated protein kinase (MAPK) inhibitors, including inhibitors of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 could inhibit the transcription of PAI1, but ERK inhibitor had no significant effect on the phosphorylation of Smad2/3, and the formation of Smad2/3/4 complexes, which was different from the effect of JNK or p38 inhibitor...
April 2018: Oncology Letters
Natalia Papadopoulos, Johan Lennartsson, Carl-Henrik Heldin
Translocation of full-length or fragments of receptors to the nucleus has been reported for several tyrosine kinase receptors. In this paper, we show that a fraction of full-length cell surface platelet-derived growth factor (PDGF) receptor β (PDGFRβ) accumulates in the nucleus at the chromatin and the nuclear matrix after ligand stimulation. Nuclear translocation of PDGFRβ was dependent on PDGF-BB-induced receptor dimerization, clathrin-mediated endocytosis, β-importin, and intact Golgi, occurring in both normal and cancer cells...
March 15, 2018: Journal of Cell Biology
Zhiqiang Duan, Haixu Xu, Xinqin Ji, Jiafu Zhao, Houqiang Xu, Yan Hu, Shanshan Deng, Shunlin Hu, Xiufan Liu
The matrix (M) protein of Newcastle disease virus (NDV) is demonstrated to localize in the nucleus via intrinsic nuclear localization signal (NLS), but cellular proteins involved in the nuclear import of NDV M protein and the role of M's nuclear localization in the replication and pathogenicity of NDV remain unclear. In this study, importin β1 was screened to interact with NDV M protein by yeast two-hybrid screening. This interaction was subsequently confirmed by co-immunoprecipitation and pull-down assays...
March 13, 2018: Virulence
Anindya Ganguly, Logan DeMott, Chuanmei Zhu, Daniel D McClosky, Charles T Anderson, Ram Dixit
Spatiotemporal regulation of kinesins is essential for microtubule-dependent intracellular transport. In plants, cell wall deposition depends on the FRA1 kinesin, whose abundance and motility are tightly controlled to match cellular growth rate. Here, we show that an importin-β, IMB4, regulates FRA1 activity in a developmental manner. IMB4 physically interacts with a PY motif in the FRA1 motor domain and inhibits its motility by preventing microtubule binding, while also protecting FRA1 against proteasome-mediated degradation, thus providing a mechanism to couple the motility and stability of FRA1...
February 23, 2018: Developmental Cell
A Yuda, W S Lee, P Petrovic, C A McCulloch
Cell extensions are critical structures that enable matrix remodeling in wound healing and cancer invasion but the regulation of their formation is not well-defined. We searched for new proteins that mediated cell extension formation over collagen by tandem mass tagged mass spectrometry analysis of purified extensions in 3T3 fibroblasts. Unexpectedly, importin-5, ENH isoform 1b (PDLIM5) and 26 S protease regulatory subunit 6B (PSMC4) were more abundant (> 10-fold) in membrane-penetrating cell extensions than cell bodies, which was confirmed by immunostaining and immunoblotting and also observed in human gingival fibroblasts...
February 21, 2018: Experimental Cell Research
Anna Sergeevna Sowa, Elodie Martin, Inês Morgado Martins, Jana Schmidt, Reinhard Depping, Jonasz Jeremiasz Weber, Franziska Rother, Enno Hartmann, Michael Bader, Olaf Riess, Hervé Tricoire, Thorsten Schmidt
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene leading to a polyglutamine expansion in the ataxin-3 protein. The nuclear presence and aggregation of expanded ataxin-3 are critical steps in disease pathogenesis. To identify novel therapeutic targets, we investigated the nucleocytoplasmic transport system by screening a collection of importins and exportins that potentially modulate this nuclear localization. Using cell, Drosophila , and mouse models, we focused on three transport proteins, namely, CRM1, IPO13, KPNA3, and their respective Drosophila orthologs Emb, Cdm, and Kap-α3...
February 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shirin Elizabeth Khorsandi, Siamak Salehi, Miriam Cortes, Hector Vilca-Melendez, Krishna Menon, Parthi Srinivasan, Andreas Prachalias, Wayel Jassem, Nigel Heaton
Mitochondria have their own genomic, transcriptomic and proteomic machinery but are unable to be autonomous, needing both nuclear and mitochondrial genomes. The aim of this work was to use computational biology to explore the involvement of Mitochondrial microRNAs (MitomiRs) and their interactions with the mitochondrial proteome in a clinical model of primary non function (PNF) of the donor after cardiac death (DCD) liver. Archival array data on the differential expression of miRNA in DCD PNF was re-analyzed using a number of publically available computational algorithms...
February 15, 2018: Scientific Reports
Liping Yang, Rong Wang, Shixing Yang, Zexu Ma, Shaoli Lin, Yuchen Nan, Qisheng Li, Qiyi Tang, Yan-Jin Zhang
Movement of macromolecules between the cytoplasm and the nucleus occurs through the nuclear pore complex (NPC). Karyopherins comprise a family of soluble transport factors facilitating nucleocytoplasmic translocation of proteins through the NPC. In this study, we discovered that karyopherin alpha6 (KPNA6, also known as importin alpha7) was required for the optimal replication of porcine reproductive and respiratory syndrome virus (PRRSV) and Zika virus (ZIKV), which are positive-sense, single-stranded RNA viruses replicating in the cytoplasm...
February 14, 2018: Journal of Virology
Minoru Hatayama, Jun Aruga
Proper functions of Zic proteins are essential for animals in health and disease. Here, we summarize our current understanding of the molecular properties and functions of the Zic family across animal species and paralog subtypes. Zics are basic proteins with some posttranslational modifications and can move to the cell nucleus via importin- and CRM1-based nucleocytoplasmic shuttling mechanisms. Degradation is mediated by the ubiquitin proteasome system. Many Zic proteins are capable of binding to two types of target DNA sequences (CTGCTG-core-type and GC-stretch-type)...
2018: Advances in Experimental Medicine and Biology
Cyril S Anyetei-Anum, Vincent R Roggero, Lizabeth A Allison
The thyroid hormone receptors, TRα1, TRβ1 and other subtypes, are members of the nuclear receptor superfamily that mediate the action of thyroid hormone signaling in numerous tissues to regulate important physiological and developmental processes. Their most well-characterized role is as ligand-dependent transcription factors; TRs bind thyroid hormone response elements in the presence or absence of thyroid hormone to facilitate the expression of target genes. Although primarily residing in the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm...
April 2018: Journal of Endocrinology
Arnau Hervera, Francesco De Virgiliis, Ilaria Palmisano, Luming Zhou, Elena Tantardini, Guiping Kong, Thomas Hutson, Matt C Danzi, Rotem Ben-Tov Perry, Celio X C Santos, Alexander N Kapustin, Roland A Fleck, José Antonio Del Río, Thomas Carroll, Vance Lemmon, John L Bixby, Ajay M Shah, Mike Fainzilber, Simone Di Giovanni
Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis...
February 12, 2018: Nature Cell Biology
Marie Guerard, Thomas Robin, Pascal Perron, Anne-Sophie Hatat, Laurence David-Boudet, Laetitia Vanwonterghem, Benoit Busser, Jean-Luc Coll, Sylvie Lantuejoul, Beatrice Eymin, Amandine Hurbin, Sylvie Gazzeri
Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin...
February 5, 2018: Cancer Letters
Gerard Nuovo, Hue Tran, Andres Gutierrez, Paolo Fadda, Flavia Pichiorri, Enrico Caserta, Craig C Hofmeister, Marta Chesi, P Leif Bergsagel, Don Morris, Qiao Shi, Matt Coffey, Chandini Thirukkumaran
Acute reoviral infection has been extensively studied given the virus's propensity to target malignant cells and activate caspase-3 mediated apoptosis. Reovirus infection of malignant N1E-115 mouse neuroblastoma cells led to significant increased expression of importin-β and exportin-5 mRNAs (qRTPCR) and proteins (immunohistochemistry) which was partially blocked by small interfering LNA oligomers directed against the reoviral genome. Co-expression analysis showed that the N1E-115 cells that contained reoviral capsid protein had accumulated importin-β and exportin-5, as well as activated caspase 3...
February 2018: Annals of Diagnostic Pathology
Gerard Nuovo, Vicky Amann, James Williams, Paige Vandiver, Maria Quinonez, Paolo Fadda, Bernard Paniccia, Louisa Mezache, Adel Mikhail
Understanding the metabolic profile of neurons with the hyperphosphorylated tau protein characteristic of Alzheimer's disease is essential to unraveling new potential therapies and diagnostics for the surgical pathologist. We stratified 75 brain tissues from Alzheimer's disease into hyperphosphorylated tau positive or negative and did co-expression analyses and qRTPCR for importin-β and exportin-5 plus several bcl2 family members and compared the data to controls, Down's dementia and Parkinson's disease. There was a significant increase in the expression of importin-β and exportin-5 in Alzheimer's disease relative to the three other categories (each p value<0...
February 2018: Annals of Diagnostic Pathology
Jibo Zhang, Vincent R Roggero, Lizabeth A Allison
The thyroid hormone receptors, TRα1 and TRβ1, are members of the nuclear receptor superfamily that forms one of the most abundant classes of transcription factors in multicellular organisms. Although primarily localized to the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. The fine balance between nuclear import and export of TRs has emerged as a critical control point for modulating thyroid hormone-responsive gene expression. Mutagenesis studies have defined two nuclear localization signal (NLS) motifs that direct nuclear import of TRα1: NLS-1 in the hinge domain and NLS-2 in the N-terminal A/B domain...
2018: Vitamins and Hormones
Kaixuan Zhang, Maria D Logacheva, Yu Meng, Jianping Hu, Dongpu Wan, Long Li, Janovská Dagmar, Zhiyong Wang, Milen I Georgiev, Zhuo Yu, Fuyu Yang, Mingli Yan, Meiliang Zhou
Jasmonates (JAs) are plant hormones that induce many secondary metabolites accumulation, such as rutin in buckwheat, via regulation of JAs-responsive transcription factors (TFs). Here, we report on the identification of a clade of JAs-responsive subgroup 4 MYB TFs, FtMYB13, FtMYB14, FtMYB15 and FtMYB16, directly repressing rutin biosynthesis in Fagopyrum tataricum. Immunoblot analysis showed that FtMYB13, FtMYB14 and FtMYB15 could be degraded via 26S proteasome in COI1-dependent JA signaling pathway, and this degradation is due to the SID motif in their C-terminus...
January 31, 2018: Journal of Experimental Botany
Laura Di Francesco, Annalisa Verrico, Italia Anna Asteriti, Paola Rovella, Pietro Cirigliano, Giulia Guarguaglini, Maria Eugenia Schininà, Patrizia Lavia
Karyopherin beta-1/Importin beta-1 is a conserved nuclear transport receptor, acting in protein nuclear import in interphase and as a global regulator of mitosis. These pleiotropic functions reflect its ability to interact with, and regulate, different pathways during the cell cycle, operating as a major effector of the GTPase RAN. Importin beta-1 is overexpressed in cancers characterized by high genetic instability, an observation that highlights the importance of identifying its partners in mitosis. Here we present the first comprehensive profile of importin beta-1 interactors from human mitotic cells...
January 30, 2018: Scientific Reports
Chih-Ying Lin, Lih-Yuan Lin
Zinc finger (ZF) motifs on proteins are frequently recognized as a structure for DNA binding. Accumulated reports indicate that ZF motifs contain nuclear localization signal (NLS) to facilitate the transport of ZF proteins into nucleus. We investigated the critical factors that facilitate the nuclear transport of triple C2H2 ZF proteins. Three conserved basic residues (hot spots) were identified among the ZF sequences of triple C2H2 ZF proteins that reportedly have NLS function. Additional basic residues can be found on the α-helix of the ZFs...
2018: PloS One
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