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  • 1
    ISSN: 1432-0606
    Keywords: Key words. Two-dimensional polymer measure, Closability, Dirichlet forms, Diffusion processes, Ergodicity, Quasi-invariance. AMS Classification. Primary 60J65, Secondary 60H30.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract. We prove that there exists a diffusion process whose invariant measure is the two-dimensional polymer measure ν g . The diffusion is constructed by means of the theory of Dirichlet forms on infinite-dimensional state spaces. We prove the closability of the appropriate pre-Dirichlet form which is of gradient type, using a general closability result by two of the authors. This result does not require an integration by parts formula (which does not hold for the two-dimensional polymer measure ν g ) but requires the quasi-invariance of ν g along a basis of vectors in the classical Cameron—Martin space such that the Radon—Nikodym derivatives (have versions which) form a continuous process. We also show the Dirichlet form to be irreducible or equivalently that the diffusion process is ergodic under time translations.
    Type of Medium: Electronic Resource
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  • 2
    Publication Date: 2013-10-12
    Description: Flagellin perception in Arabidopsis is through recognition of its highly conserved N-terminal epitope (flg22) by flagellin-sensitive 2 (FLS2). Flg22 binding induces FLS2 heteromerization with BRASSINOSTEROID INSENSITIVE 1-associated kinase 1 (BAK1) and their reciprocal activation followed by plant immunity. Here, we report the crystal structure of FLS2 and BAK1 ectodomains complexed with flg22 at 3.06 angstroms. A conserved and a nonconserved site from the inner surface of the FLS2 solenoid recognize the C- and N-terminal segment of flg22, respectively, without oligomerization or conformational changes in the FLS2 ectodomain. Besides directly interacting with FLS2, BAK1 acts as a co-receptor by recognizing the C terminus of the FLS2-bound flg22. Our data reveal the molecular mechanisms underlying FLS2-BAK1 complex recognition of flg22 and provide insight into the immune receptor complex activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Yadong -- Li, Lei -- Macho, Alberto P -- Han, Zhifu -- Hu, Zehan -- Zipfel, Cyril -- Zhou, Jian-Min -- Chai, Jijie -- New York, N.Y. -- Science. 2013 Nov 1;342(6158):624-8. doi: 10.1126/science.1243825. Epub 2013 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Sciences, Tsinghua University, Beijing 100084, China, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24114786" target="_blank"〉PubMed〈/a〉
    Keywords: Antigen-Antibody Complex/*chemistry ; Arabidopsis/*immunology ; Arabidopsis Proteins/*chemistry ; Crystallography, X-Ray ; Flagellin/*chemistry ; Protein Kinases/*chemistry ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-06-15
    Description: Nucleotide-binding and oligomerization domain-like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate-mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important alpha-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Zehan -- Yan, Chuangye -- Liu, Peiyuan -- Huang, Zhiwei -- Ma, Rui -- Zhang, Chenlu -- Wang, Ruiyong -- Zhang, Yueteng -- Martinon, Fabio -- Miao, Di -- Deng, Haiteng -- Wang, Jiawei -- Chang, Junbiao -- Chai, Jijie -- New York, N.Y. -- Science. 2013 Jul 12;341(6142):172-5. doi: 10.1126/science.1236381. Epub 2013 Jun 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Sciences, Tsinghua University, and Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23765277" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/chemistry ; Animals ; Apoptosis Regulatory Proteins/*antagonists & inhibitors/*chemistry ; Calcium-Binding Proteins/*antagonists & inhibitors/*chemistry ; Crystallography, X-Ray ; Mice ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-10-21
    Description: Hepatitis A virus (HAV) remains enigmatic, despite 1.4 million cases worldwide annually. It differs radically from other picornaviruses, existing in an enveloped form and being unusually stable, both genetically and physically, but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site, while structure-based predictions suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses, and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773894/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773894/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiangxi -- Ren, Jingshan -- Gao, Qiang -- Hu, Zhongyu -- Sun, Yao -- Li, Xuemei -- Rowlands, David J -- Yin, Weidong -- Wang, Junzhi -- Stuart, David I -- Rao, Zihe -- Fry, Elizabeth E -- 075491/Z/04/Wellcome Trust/United Kingdom -- G1000099/Medical Research Council/United Kingdom -- England -- Nature. 2015 Jan 1;517(7532):85-8. doi: 10.1038/nature13806. Epub 2014 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China. ; Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford OX3 7BN, UK. ; 1] National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China [2] Sinovac Biotech Co., Ltd, Beijing 100085, China. ; National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing 100050, China. ; Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. ; Sinovac Biotech Co., Ltd, Beijing 100085, China. ; 1] Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford OX3 7BN, UK [2] Diamond Light Sources, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK. ; 1] National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China [2] Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China [3] State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25327248" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capsid/chemistry ; Capsid Proteins/chemistry ; Crystallography, X-Ray ; *Evolution, Molecular ; Hepatitis A virus/*chemistry ; Hot Temperature ; Humans ; Hydrogen-Ion Concentration ; Insects/virology ; Models, Molecular ; Phylogeny ; Picornaviridae/*chemistry ; Transcytosis ; Virion/chemistry ; Virus Internalization
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-08-04
    Description: The synaptic adhesion molecules neurexin and neuroligin alter the development and function of synapses and are linked to autism in humans. Here, we found that Caenorhabditis elegans neurexin (NRX-1) and neuroligin (NLG-1) mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle microRNA (miR-1) and was blocked in mutants lacking NLG-1 or NRX-1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles (SVs) that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn, an inhibitor of SV fusion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791080/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791080/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Zhitao -- Hom, Sabrina -- Kudze, Tambudzai -- Tong, Xia-Jing -- Choi, Seungwon -- Aramuni, Gayane -- Zhang, Weiqi -- Kaplan, Joshua M -- NS32196/NS/NINDS NIH HHS/ -- R37 NS032196/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2012 Aug 24;337(6097):980-4. doi: 10.1126/science.1224896. Epub 2012 Aug 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22859820" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcholine/metabolism ; Animals ; Caenorhabditis elegans/genetics/*physiology ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Cell Adhesion Molecules, Neuronal/genetics/*metabolism ; Cholinergic Neurons/physiology ; Excitatory Postsynaptic Potentials ; Exocytosis ; Kinetics ; Mice ; MicroRNAs/genetics/metabolism ; Motor Neurons/physiology ; Mutation ; Neural Inhibition ; Neuromuscular Junction/*physiology ; Neurotransmitter Agents/metabolism ; *Synaptic Transmission ; Synaptic Vesicles/physiology ; Transcription Factors/genetics/metabolism ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2014-12-20
    Description: Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T cell help. We report that immunization with these T cell-independent type 2 (TI-2) antigens causes up-regulation of endogenous retrovirus (ERV) RNAs in antigen-specific mouse B cells. These RNAs are detected via a mitochondrial antiviral signaling protein (MAVS)-dependent RNA sensing pathway or reverse-transcribed and detected via the cGAS-cGAMP-STING pathway, triggering a second, sustained wave of signaling that promotes specific immunoglobulin M production. Deficiency of both MAVS and cGAS, or treatment of MAVS-deficient mice with reverse transcriptase inhibitors, dramatically inhibits TI-2 antibody responses. These findings suggest that ERV and two innate sensing pathways that detect them are integral components of the TI-2 B cell signaling apparatus.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391621/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4391621/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zeng, Ming -- Hu, Zeping -- Shi, Xiaolei -- Li, Xiaohong -- Zhan, Xiaoming -- Li, Xiao-Dong -- Wang, Jianhui -- Choi, Jin Huk -- Wang, Kuan-wen -- Purrington, Tiana -- Tang, Miao -- Fina, Maggy -- DeBerardinis, Ralph J -- Moresco, Eva Marie Y -- Pedersen, Gabriel -- McInerney, Gerald M -- Karlsson Hedestam, Gunilla B -- Chen, Zhijian J -- Beutler, Bruce -- P01 AI070167/AI/NIAID NIH HHS/ -- R01 AI093967/AI/NIAID NIH HHS/ -- R01 CA157996/CA/NCI NIH HHS/ -- U19 AI100627/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Dec 19;346(6216):1486-92. doi: 10.1126/science.346.6216.1486.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8502, USA. ; Department of Pediatrics and Children's Medical Center Research Institute, and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8502, USA. ; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8502, USA. Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA. ; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels vag 16, SE-171 77 Stockholm, Sweden. ; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8502, USA. Bruce.Beutler@UTSouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25525240" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/*immunology ; Animals ; Antibody Formation ; Antigens, T-Independent/*immunology ; B-Lymphocytes/*immunology ; Cytosol/immunology ; DNA/immunology ; Endogenous Retroviruses/genetics/*immunology ; Lymphocyte Activation ; Membrane Proteins/immunology ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Nucleotides, Cyclic/immunology ; Nucleotidyltransferases/genetics/*immunology ; RNA, Viral/genetics/*immunology ; Transcription, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2014-03-29
    Description: Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1alpha (HIF1alpha) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1alpha that regulates the expression of HIF1alpha targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1alpha and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105133/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Xi -- Iliopoulos, Dimitrios -- Zhang, Qing -- Tang, Qianzi -- Greenblatt, Matthew B -- Hatziapostolou, Maria -- Lim, Elgene -- Tam, Wai Leong -- Ni, Min -- Chen, Yiwen -- Mai, Junhua -- Shen, Haifa -- Hu, Dorothy Z -- Adoro, Stanley -- Hu, Bella -- Song, Minkyung -- Tan, Chen -- Landis, Melissa D -- Ferrari, Mauro -- Shin, Sandra J -- Brown, Myles -- Chang, Jenny C -- Liu, X Shirley -- Glimcher, Laurie H -- AI32412/AI/NIAID NIH HHS/ -- CA112663/CA/NCI NIH HHS/ -- K99 CA175290/CA/NCI NIH HHS/ -- K99CA175290/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R00 CA160351/CA/NCI NIH HHS/ -- R01 AI032412/AI/NIAID NIH HHS/ -- R01 CA112663/CA/NCI NIH HHS/ -- R01 HG004069/HG/NHGRI NIH HHS/ -- R01HG004069/HG/NHGRI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Apr 3;508(7494):103-7. doi: 10.1038/nature13119. Epub 2014 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA [2] Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA. ; 1] Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [3]. ; 1] Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2]. ; 1] Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China [2] Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Ya'an, Sichuan 625014, China [3]. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02215, USA. ; Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA. ; 1] Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA [2] Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA. ; Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; Houston Methodist Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA [2] Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA. ; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA. ; 1] Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA [2] Houston Methodist Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670641" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD24/metabolism ; Antigens, CD44/metabolism ; Cell Hypoxia/genetics ; Cell Line, Tumor ; Cell Proliferation ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Gene Silencing ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Mice ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local ; Prognosis ; RNA Polymerase II/metabolism ; Transcription Factors/deficiency/genetics/*metabolism ; Transcription, Genetic ; Triple Negative Breast Neoplasms/blood supply/genetics/*metabolism/*pathology ; Unfolded Protein Response
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2015-10-16
    Description: Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644103/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644103/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Piskounova, Elena -- Agathocleous, Michalis -- Murphy, Malea M -- Hu, Zeping -- Huddlestun, Sara E -- Zhao, Zhiyu -- Leitch, A Marilyn -- Johnson, Timothy M -- DeBerardinis, Ralph J -- Morrison, Sean J -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):186-91. doi: 10.1038/nature15726. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA. ; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466563" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antioxidants/metabolism ; Female ; Folic Acid/metabolism ; Gene Knockdown Techniques ; Humans ; Male ; Melanoma/blood/*metabolism/*pathology ; Methotrexate/pharmacology ; Methylenetetrahydrofolate Dehydrogenase (NADP)/deficiency/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; NADP/metabolism ; Neoplasm Metastasis/*prevention & control ; Neoplasm Transplantation ; *Oxidative Stress ; Oxidoreductases Acting on CH-NH Group Donors/deficiency/metabolism
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2018-10-31
    Description: RAS-RAF-MEK-ERK signaling has a well-defined role in cancer biology. Although aberrant pathway activation occurs mostly upstream of the kinase MEK, mutations in MEK are prevalent in some cancer subsets. Here, we found that cancer-related, activating mutations in MEK can be classified into two groups: those that relieve inhibitory interactions with the helix A region and those that are in-frame deletions of the β3-αC loop, which enhance MEK1 homodimerization. The former, helix A–associated mutants, are inhibited by traditional MEK inhibitors. However, we found that the increased homodimerization associated with the loop-deletion mutants promoted intradimer cross-phosphorylation of the activation loop and conferred differential resistance to MEK inhibitors both in vitro and in vivo. MEK1 dimerization was required both for its activation by the kinase RAF and for its catalytic activity toward the kinase ERK. Our findings not only identify a previously unknown group of MEK mutants and provide insight into some key steps in RAF-MEK-ERK activation but also have implications for the design of therapies targeting RAS-ERK signaling in cancers.
    Print ISSN: 1945-0877
    Topics: Medicine
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  • 10
    Publication Date: 2018-11-07
    Description: Animals utilize conserved mechanisms to regulate oxidative stress. The C. elegans SKN-1 protein is homologous to the vertebrate Nrf (NF-E2-related factor) family of cap ’n’ collar (CnC) transcription factors and functions as a core regulator of xenobiotic and oxidative stress responses. The WD40 repeat-containing protein WDR-23 is a key negative regulator of SKN-1 activity. We previously found that the oxidative stress induced by excess iodide can be relieved by loss of function in the BLI-3 / TSP-15 / DOXA-1 dual oxidase complex. To further understand the molecular mechanism of this process, we screened for new mutants that can survive in excess iodide and identified gain-of-function mutations in skn-1 and loss-of-function mutations in wdr-23 . The SKN-1C isoform functions in the hypodermis to affect animal’s response to excess iodide, while the SKN-1A isoform appears to play a minor role. wdr-23 (lf) can interact with bli-3 mutations in a manner different from skn-1 (gf) . Transcriptome studies suggest that excess iodide causes developmental arrest largely independent of changes in gene expression, and wdr-23 (lf) could affect the expression of a subset of genes by a mechanism different from SKN-1 activation. We propose that WDR-23 and SKN-1 coordinate with the BLI-3 / TSP-15 / DOXA-1 dual oxidase complex in response to iodide-triggered oxidative stress.
    Electronic ISSN: 2160-1836
    Topics: Biology
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