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Regulated Alternative Translocation

Philippa Melamed, Yahav Yosefzon, Cfir David, Anna Tsukerman, Lilach Pnueli
Discovery of the ten-eleven translocation 1 (TET) methylcytosine dioxygenase family of enzymes, nearly 10 years ago, heralded a major breakthrough in understanding the epigenetic modifications of DNA. Initially described as catalyzing the oxidation of methyl cytosine (5mC) to hydroxymethyl cytosine (5hmC), it is now clear that these enzymes can also catalyze additional reactions leading to active DNA demethylation. The association of TET enzymes, as well as the 5hmC, with active regulatory regions of the genome has been studied extensively in embryonic stem cells, although these enzymes are expressed widely also in differentiated tissues...
2018: Frontiers in Cell and Developmental Biology
Joubert Banjop Kharlyngdoh, Ajay Pradhan, Per-Erik Olsson
Endocrine disrupting compounds can interfere with androgen receptor (AR) signaling and disrupt steroidogenesis leading to reproductive failure. The brominated flame-retardant (BFR) 1, 2-dibromo-4-(1, 2-dibromoethyl) cyclohexane (TBECH), is an agonist to human, chicken and zebrafish AR. Recently another group of alternative BFRs, allyl 2, 4, 6-tribromophenyl ether (ATE), and 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether (DPTE) along with its metabolite 2-bromoallyl 2, 4, 6-tribromophenyl ether (BATE) were identified as potent human AR antagonists...
March 19, 2018: Scientific Reports
Xinyan Wang, Linyong Du, He Wei, Anying Zhang, Kun Yang, Hong Zhou
Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT family in response to cytokines and growth factors. In mammals, alternative splicing of STAT3 generates STAT3α and STAT3β, which have distinct and overlapping functions. In the previous study, we have identified two spliceforms of Stat3α (Stat3α1 and Stat3α2) possessing all functional domains of Stat3 in grass carp (Ctenopharyngodon idella). In the present study, two Stat3β variants (Stat3β1 and Stat3β2) without C-terminal transactivation domain were isolated from this species, and their transcripts were ubiquitously expressed in all examined tissues with the highest levels in liver...
March 16, 2018: Fish & Shellfish Immunology
Ning Xu, Yingying Zheng, Xiaochen Wang, Terry A Krulwich, Yanhe Ma, Jun Liu
Corynebacterium glutamicum is generally regarded as a moderately salt-alkali-tolerant industrial organism. However, relatively little is known about the molecular mechanisms underlying these specific adaptations. Here, we found that the Mrp1 antiporter played crucial roles in conferring both environmental Na+ -resistance and alkali-tolerance, whereas the Mrp2 antiporter was necessary in coping with high KCl stress at alkaline pH. Furthermore, the Δ mrp1mrp2 double mutant showed most severe growth retardation, and failed to grow under high salt or alkaline conditions...
March 9, 2018: Applied and Environmental Microbiology
Rui Zhang, Dan Han, Zhenyu Li, Chengwu Shen, Yahui Zhang, Jun Li, Genquan Yan, Shasha Li, Bo Hu, Jiangbing Li, Ping Liu
Increasing evidence shows that inflammation plays a vital role in the occurrence and development of ischemia/reperfusion (I/R). Suppression of excessive inflammation can ameliorate impaired cardiac function, which shows therapeutic potential for clinical treatment of myocardial ischemia/reperfusion (MI/R) diseases. In this study, we investigated whether Ginkgolide C (GC), a potent anti-inflammatory flavone, extenuated MI/R injury through inhibition of inflammation. In vivo , rats with the occlusion of the left anterior descending (LAD) coronary artery were applied to mimic MI/R injury...
2018: Frontiers in Pharmacology
Yasuhiro Matsunaga, Tsutomu Yamane, Tohru Terada, Kei Moritsugu, Hiroshi Fujisaki, Satoshi Murakami, Mitsunori Ikeguchi, Akinori Kidera
The multidrug transporter AcrB transports a broad range of drugs out of the cell by means of the proton-motive force. The asymmetric crystal structure of trimeric AcrB suggests a functionally rotating mechanism for drug transport. Despite various supportive forms of evidence from biochemical and simulation studies for this mechanism, the link between the functional rotation and proton translocation across the membrane remains elusive. Here, calculating the minimum free energy pathway of the functional rotation for the complete AcrB trimer, we describe the structural and energetic basis behind the coupling between the functional rotation and the proton translocation at atomic resolution...
March 6, 2018: ELife
Kuo-Sheng Hsu, Hung-Ying Kao
Promyelocytic leukemia protein (PML) was originally identified as a fusion partner of retinoic acid receptor alpha in acute promyelocytic leukemia patients with the (15;17) chromosomal translocation, giving rise to PML-RARα and RARα-PML fusion proteins. A body of evidence indicated that PML possesses tumor suppressing activity by regulating apoptosis, cell cycle, senescence and DNA damage responses. PML is enriched in discrete nuclear substructures in mammalian cells with 0.2-1 μm diameter in size, referred to as alternately Kremer bodies, nuclear domain 10, PML oncogenic domains or PML nuclear bodies (NBs)...
2018: Cell & Bioscience
Rosa Morra, Francesco Del Carratore, Howbeer Muhamadali, Luminita Gabriela Horga, Samantha Halliwell, Royston Goodacre, Rainer Breitling, Neil Dixon
The apparent mislocalization or excretion of cytoplasmic proteins is a commonly observed phenomenon in both bacteria and eukaryotes. However, reports on the mechanistic basis and the cellular function of this so-called "nonclassical protein secretion" are limited. Here we report that protein overexpression in recombinant cells and antibiotic-induced translation stress in wild-type Escherichia coli cells both lead to excretion of cytoplasmic protein (ECP). Condition-specific metabolomic and proteomic analyses, combined with genetic knockouts, indicate a role for both the large mechanosensitive channel (MscL) and the alternative ribosome rescue factor A (ArfA) in ECP...
January 30, 2018: MBio
Manjeera Gowravaram, Fabien Bonneau, Joanne Kanaan, Vincent D Maciej, Francesca Fiorini, Saurabh Raj, Vincent Croquette, Hervé Le Hir, Sutapa Chakrabarti
The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures of UPF1 elucidated the molecular mechanisms of its catalytic activity and regulation. In this study, we examine features of the UPF1 core and identify a structural element that adopts different conformations in the various nucleotide- and RNA-bound states of UPF1. We demonstrate, using biochemical and single molecule assays, that this structural element modulates UPF1 catalytic activity and thereby refer to it as the regulatory loop...
January 25, 2018: Nucleic Acids Research
Xiaoqiang Wang, Han Chen, Xinwei Lu, Haixia Chi, Shixin Li, Fang Huang
Proper translocation, membrane insertion and folding are crucial biophysical steps in the biogenesis of functional transmembrane peptides/proteins (TMPs). ATP-dependent chaperonins are able to regulate each of these processes, but the underlying mechanisms remain unclear. In this work, interaction between the bacterial chaperonin GroEL and a synthetic fluorescent transmembrane peptide was investigated by fluorescence anisotropy. Binding of the peptide with GroEL resulted in increased fluorescence anisotropy and intensity...
December 29, 2017: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Andrea S Rothmeier, Enbo Liu, Sagarika Chakrabarty, Jennifer Disse, Barbara M Mueller, Henrik Østergaard, Wolfram Ruf
The tissue factor (TF) pathway serves both hemostasis and cell signaling, but how cells control these divergent functions of TF remains incompletely understood. TF is the receptor and scaffold of coagulation proteases cleaving protease activated receptor (PAR) 2 that plays pivotal roles in angiogenesis and tumor development. Here we demonstrate that coagulation factor (F) VIIa elicits TF cytoplasmic domain-dependent pro-angiogenic cell signaling independent of the alternative PAR2 activator matriptase. We identify a Lys-Gly-Glu (KGE) integrin binding motif in the FVIIa protease domain that is required for association of the TF-FVIIa complex with the active conformer of integrin β1...
December 15, 2017: Blood
Richa Shrivastava, Varsha Singh, Mohammad Asif, Mahendra Pal Singh Negi, Smrati Bhadauria
AIMS: HIF is an important transcription-regulator for adaptation to cellular stress in cells of myeloid origin. Classically, expression and activity of HIF1-α is regulated by oxygen-concentration within cell. However, there exists an alternative regulatory mechanism affecting HIF1-α levels independent of oxygen concentration particularly in inflammatory cells like macrophages. Here we report the mechanism of HIF1-α upregulation in TAMs by Oncostatin-M (OSM) independent of cellular oxygen concentration...
December 12, 2017: Life Sciences
Kyle Kaniecki, Luisina De Tullio, Bryan Gibb, Youngho Kwon, Patrick Sung, Eric C Greene
Srs2 is a superfamily 1 (SF1) helicase and antirecombinase that is required for genome integrity. However, the mechanisms that regulate Srs2 remain poorly understood. Here, we visualize Srs2 as it acts upon single-stranded DNA (ssDNA) bound by the Rad51 recombinase. We demonstrate that Srs2 is a processive translocase capable of stripping thousands of Rad51 molecules from ssDNA at a rate of ∼50 monomers/s. We show that Srs2 is recruited to RPA clusters embedded between Rad51 filaments and that multimeric arrays of Srs2 assemble during translocation on ssDNA through a mechanism involving iterative Srs2 loading events at sites cleared of Rad51...
December 12, 2017: Cell Reports
Irina Shlosman, Fabrizio Marinelli, José D Faraldo-Gómez, Joseph A Mindell
Intracellular Ca2+ signals control a wide array of cellular processes. These signals require spatial and temporal regulation of the intracellular Ca2+ concentration, which is achieved in part by a class of ubiquitous membrane proteins known as sodium-calcium exchangers (NCXs). NCXs are secondary-active antiporters that power the translocation of Ca2+ across the cell membrane by coupling it to the flux of Na+ in the opposite direction, down an electrochemical gradient. Na+ and Ca2+ are translocated in separate steps of the antiport cycle, each of which is thought to entail a mechanism whereby ion-binding sites within the protein become alternately exposed to either side of the membrane...
December 13, 2017: Journal of General Physiology
Yang Wang, Jia Liu, Xin Jin, Dapeng Zhang, Dongxue Li, Fengqi Hao, Yunpeng Feng, Shan Gu, Fanlin Meng, Miaomiao Tian, Yi Zheng, Ling Xin, Xinbo Zhang, Xue Han, L Aravind, Min Wei
The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O- GlcNAcylation, which specifically targets Thr405 and Ser406 , residues of the region encoded by the alternatively spliced exon 10 in cancer cells...
December 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
Kazuhito Goda, Takeo Takahashi, Hirobumi Suzuki
The molecular interactions and translocation of signal transduction factors in individual cells can be imaged by fluorescence microscopy. Alternatively, downstream promoter activity in single cells can be imaged by bioluminescence microscopy. However, the same stimuli can lead to different gene expression responses in individual cells. For this reason, it is desirable to simultaneously image signal transduction and gene expression events in the same cells. Here, we describe a method that combines fluorescence and bioluminescence microscopy to image protein kinase C (PKC) translocation from the cytosol to the plasma membrane and the expression of nuclear factor kappa-light polypeptide B (NF-κB)-regulated genes...
December 11, 2017: Current Protocols in Cell Biology
Qin M Chen, Anthony J Maltagliati
The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character...
February 1, 2018: Physiological Genomics
Adam C Midgley, Sebastian Oltean, Vincent Hascall, Emma L Woods, Robert Steadman, Aled O Phillips, Soma Meran
The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine-rich (SR) protein-mediated exon exclusion...
November 21, 2017: Science Signaling
Shixiang Yao, Lili Deng, Kaifang Zeng
Membrane-bound transcription factors (MTFs) are located in cellular membranes due to their transmembrane domains. In plants, proteolytic processing is considered to be the main mechanism for MTF activation, which ensures the liberation of MTFs from membranes and further their translocation into the nucleus to regulate gene expression; this process skips both the transcriptional and translational stages, and thus it guarantees the prompt responses of plants to various stimuli. Currently, information concerning plant MTFs is limited to model organisms, including Arabidopsis thaliana and Oryza sativa, and little is known in other plant species at the genome level...
2017: PeerJ
Umair Ashraf, Saddam Hussain, Nadeem Akbar, Shakeel Ahmad Anjum, Waseem Hassan, Xiangru Tang
Rice cultivation in lead (Pb) polluted soils often leads to high Pb contents in rice grains. The present study investigated the dynamics of Pb uptake under different water regimes in two fragrant rice cultivars i.e., Guixiangzhan and Nongxiang-18. Results revealed that water dynamics regulated the antioxidant activities in both rice cultivars under Pb toxicity. Compared to continuous ponding (CP), taken as control, alternate wetting and drying (AWD) reduced the Pb contents in roots, stems, leaves, and grains up to 17%, 41%, 22%, and 52% in Guixiangzhan and 23%, 19%, 17%, and 37% in Nongxiang-18, respectively...
November 17, 2017: Ecotoxicology and Environmental Safety
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