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  • History, Ancient  (15)
  • Protein Conformation  (14)
  • Cells, Cultured  (13)
  • Nature Publishing Group (NPG)  (41)
  • American Association for the Advancement of Science
  • 2005-2009  (41)
  • 1940-1944
  • 2009  (41)
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  • 2005-2009  (41)
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  • 2009  (41)
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  • 2008  (37)
  • 1
    Publication Date: 2009-02-27
    Description: Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841516/" 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/PMC2841516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gu, YuanYuan -- Harley, Isaac T W -- Henderson, Lindsay B -- Aronow, Bruce J -- Vietor, Ilja -- Huber, Lukas A -- Harley, John B -- Kilpatrick, Jeffrey R -- Langefeld, Carl D -- Williams, Adrienne H -- Jegga, Anil G -- Chen, Jing -- Wills-Karp, Marsha -- Arshad, S Hasan -- Ewart, Susan L -- Thio, Chloe L -- Flick, Leah M -- Filippi, Marie-Dominique -- Grimes, H Leighton -- Drumm, Mitchell L -- Cutting, Garry R -- Knowles, Michael R -- Karp, Christopher L -- R01 AI024717/AI/NIAID NIH HHS/ -- R01 HL068890/HL/NHLBI NIH HHS/ -- R01 HL068890-01/HL/NHLBI NIH HHS/ -- R01 HL068927/HL/NHLBI NIH HHS/ -- R01 HL068927-01/HL/NHLBI NIH HHS/ -- R01 HL079312/HL/NHLBI NIH HHS/ -- R01 HL079312-01A1/HL/NHLBI NIH HHS/ -- R37 AI024717/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Apr 23;458(7241):1039-42. doi: 10.1038/nature07811. Epub 2009 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242412" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cohort Studies ; Cystic Fibrosis/*genetics/*pathology ; Disease Models, Animal ; Genotype ; Humans ; Immediate-Early Proteins/deficiency/*genetics ; Inflammation/genetics/pathology ; Mice ; Mice, Inbred C57BL ; Neutrophils/immunology/metabolism ; Polymorphism, Single Nucleotide/genetics ; Pseudomonas aeruginosa/immunology/pathogenicity ; Transcription Factor RelA/metabolism
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  • 2
    Publication Date: 2009-12-25
    Description: Multiple somatic rearrangements are often found in cancer genomes; however, the underlying processes of rearrangement and their contribution to cancer development are poorly characterized. Here we use a paired-end sequencing strategy to identify somatic rearrangements in breast cancer genomes. There are more rearrangements in some breast cancers than previously appreciated. Rearrangements are more frequent over gene footprints and most are intrachromosomal. Multiple rearrangement architectures are present, but tandem duplications are particularly common in some cancers, perhaps reflecting a specific defect in DNA maintenance. Short overlapping sequences at most rearrangement junctions indicate that these have been mediated by non-homologous end-joining DNA repair, although varying sequence patterns indicate that multiple processes of this type are operative. Several expressed in-frame fusion genes were identified but none was recurrent. The study provides a new perspective on cancer genomes, highlighting the diversity of somatic rearrangements and their potential contribution to cancer development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398135/" 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/PMC3398135/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stephens, Philip J -- McBride, David J -- Lin, Meng-Lay -- Varela, Ignacio -- Pleasance, Erin D -- Simpson, Jared T -- Stebbings, Lucy A -- Leroy, Catherine -- Edkins, Sarah -- Mudie, Laura J -- Greenman, Chris D -- Jia, Mingming -- Latimer, Calli -- Teague, Jon W -- Lau, King Wai -- Burton, John -- Quail, Michael A -- Swerdlow, Harold -- Churcher, Carol -- Natrajan, Rachael -- Sieuwerts, Anieta M -- Martens, John W M -- Silver, Daniel P -- Langerod, Anita -- Russnes, Hege E G -- Foekens, John A -- Reis-Filho, Jorge S -- van 't Veer, Laura -- Richardson, Andrea L -- Borresen-Dale, Anne-Lise -- Campbell, Peter J -- Futreal, P Andrew -- Stratton, Michael R -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- CA089393/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1005-10. doi: 10.1038/nature08645.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033038" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/*genetics ; Cell Line, Tumor ; Cells, Cultured ; *Chromosome Aberrations ; DNA Breaks ; Female ; Gene Rearrangement/*genetics ; Genome, Human/*genetics ; Genomic Library ; Humans ; Sequence Analysis, DNA
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  • 3
    Publication Date: 2009-03-20
    Description: Thirty years after oxygen isotope records from microfossils deposited in ocean sediments confirmed the hypothesis that variations in the Earth's orbital geometry control the ice ages, fundamental questions remain over the response of the Antarctic ice sheets to orbital cycles. Furthermore, an understanding of the behaviour of the marine-based West Antarctic ice sheet (WAIS) during the 'warmer-than-present' early-Pliocene epoch ( approximately 5-3 Myr ago) is needed to better constrain the possible range of ice-sheet behaviour in the context of future global warming. Here we present a marine glacial record from the upper 600 m of the AND-1B sediment core recovered from beneath the northwest part of the Ross ice shelf by the ANDRILL programme and demonstrate well-dated, approximately 40-kyr cyclic variations in ice-sheet extent linked to cycles in insolation influenced by changes in the Earth's axial tilt (obliquity) during the Pliocene. Our data provide direct evidence for orbitally induced oscillations in the WAIS, which periodically collapsed, resulting in a switch from grounded ice, or ice shelves, to open waters in the Ross embayment when planetary temperatures were up to approximately 3 degrees C warmer than today and atmospheric CO(2) concentration was as high as approximately 400 p.p.m.v. (refs 5, 6). The evidence is consistent with a new ice-sheet/ice-shelf model that simulates fluctuations in Antarctic ice volume of up to +7 m in equivalent sea level associated with the loss of the WAIS and up to +3 m in equivalent sea level from the East Antarctic ice sheet, in response to ocean-induced melting paced by obliquity. During interglacial times, diatomaceous sediments indicate high surface-water productivity, minimal summer sea ice and air temperatures above freezing, suggesting an additional influence of surface melt under conditions of elevated CO(2).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naish, T -- Powell, R -- Levy, R -- Wilson, G -- Scherer, R -- Talarico, F -- Krissek, L -- Niessen, F -- Pompilio, M -- Wilson, T -- Carter, L -- DeConto, R -- Huybers, P -- McKay, R -- Pollard, D -- Ross, J -- Winter, D -- Barrett, P -- Browne, G -- Cody, R -- Cowan, E -- Crampton, J -- Dunbar, G -- Dunbar, N -- Florindo, F -- Gebhardt, C -- Graham, I -- Hannah, M -- Hansaraj, D -- Harwood, D -- Helling, D -- Henrys, S -- Hinnov, L -- Kuhn, G -- Kyle, P -- Laufer, A -- Maffioli, P -- Magens, D -- Mandernack, K -- McIntosh, W -- Millan, C -- Morin, R -- Ohneiser, C -- Paulsen, T -- Persico, D -- Raine, I -- Reed, J -- Riesselman, C -- Sagnotti, L -- Schmitt, D -- Sjunneskog, C -- Strong, P -- Taviani, M -- Vogel, S -- Wilch, T -- Williams, T -- England -- Nature. 2009 Mar 19;458(7236):322-8. doi: 10.1038/nature07867.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Antarctic Research Centre, Victoria University of Wellington, Kelburn Parade, PO Box 600, Wellington 6012, New Zealand. tim.naish@vuw.ac.nz〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19295607" target="_blank"〉PubMed〈/a〉
    Keywords: Antarctic Regions ; Atmosphere/analysis/chemistry ; Calibration ; Carbon Dioxide/analysis ; Diatoms/chemistry/isolation & purification ; Fossils ; History, Ancient ; *Ice Cover ; Oxygen Isotopes ; Temperature
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  • 4
    Publication Date: 2009-11-26
    Description: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818760/" 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/PMC2818760/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dang, Lenny -- White, David W -- Gross, Stefan -- Bennett, Bryson D -- Bittinger, Mark A -- Driggers, Edward M -- Fantin, Valeria R -- Jang, Hyun Gyung -- Jin, Shengfang -- Keenan, Marie C -- Marks, Kevin M -- Prins, Robert M -- Ward, Patrick S -- Yen, Katharine E -- Liau, Linda M -- Rabinowitz, Joshua D -- Cantley, Lewis C -- Thompson, Craig B -- Vander Heiden, Matthew G -- Su, Shinsan M -- P01 CA104838/CA/NCI NIH HHS/ -- P01 CA104838-05/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- R01 CA105463-06/CA/NCI NIH HHS/ -- R21 CA128620/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):739-44. doi: 10.1038/nature08617. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19935646" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/genetics ; Brain Neoplasms/*genetics/*metabolism/pathology ; Catalytic Domain ; Cell Line ; Crystallography, X-Ray ; Disease Progression ; Enzyme Assays ; Glioma/genetics/metabolism/pathology ; Glutarates/*metabolism ; Histidine/genetics/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Ketoglutaric Acids/metabolism ; Models, Molecular ; Mutant Proteins/*genetics/*metabolism ; Mutation/genetics ; Protein Conformation
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  • 5
    Publication Date: 2009-10-23
    Description: NF-kappaB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-kappaB signalling during the past twenty years, the requirement for NF-kappaB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-kappaB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-kappaB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappaB inhibition. Furthermore, the inhibition of NF-kappaB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-kappaB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780341/" 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/PMC2780341/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meylan, Etienne -- Dooley, Alison L -- Feldser, David M -- Shen, Lynn -- Turk, Erin -- Ouyang, Chensi -- Jacks, Tyler -- P30 CA014051/CA/NCI NIH HHS/ -- P30 CA014051-37/CA/NCI NIH HHS/ -- P30 CA014051-38/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Nov 5;462(7269):104-7. doi: 10.1038/nature08462. Epub 2009 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Koch Institute for Integrative Cancer Research, and Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847165" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/*metabolism/*pathology ; Animals ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Cells, Cultured ; DNA/metabolism ; *Disease Models, Animal ; Fibroblasts ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*metabolism/*pathology ; Mice ; NF-kappa B/antagonists & inhibitors/*metabolism ; Oncogene Protein p21(ras)/genetics/metabolism ; *Signal Transduction ; Transcription Factor RelA/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
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  • 6
    Publication Date: 2009-02-06
    Description: The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778612/" 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/PMC2778612/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diehn, Maximilian -- Cho, Robert W -- Lobo, Neethan A -- Kalisky, Tomer -- Dorie, Mary Jo -- Kulp, Angela N -- Qian, Dalong -- Lam, Jessica S -- Ailles, Laurie E -- Wong, Manzhi -- Joshua, Benzion -- Kaplan, Michael J -- Wapnir, Irene -- Dirbas, Frederick M -- Somlo, George -- Garberoglio, Carlos -- Paz, Benjamin -- Shen, Jeannie -- Lau, Sean K -- Quake, Stephen R -- Brown, J Martin -- Weissman, Irving L -- Clarke, Michael F -- R01 CA100225/CA/NCI NIH HHS/ -- R01 CA100225-05/CA/NCI NIH HHS/ -- U54 CA126524/CA/NCI NIH HHS/ -- U54 CA126524-04/CA/NCI NIH HHS/ -- England -- Nature. 2009 Apr 9;458(7239):780-3. doi: 10.1038/nature07733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194462" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/physiopathology ; Cells, Cultured ; DNA Damage/genetics/radiation effects ; Female ; Gene Expression ; Humans ; Mammary Glands, Human/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplastic Stem Cells/*metabolism/*radiation effects ; Radiation Tolerance/*physiology ; Reactive Oxygen Species/*metabolism
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  • 7
    Publication Date: 2009-05-15
    Description: Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3-5), a master regulator of haematopoiesis, and give rise to haematopoietic cells. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential. Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41(+)c-Kit(+) haematopoietic progenitor cells, concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling, compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782763/" 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/PMC2782763/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adamo, Luigi -- Naveiras, Olaia -- Wenzel, Pamela L -- McKinney-Freeman, Shannon -- Mack, Peter J -- Gracia-Sancho, Jorge -- Suchy-Dicey, Astrid -- Yoshimoto, Momoko -- Lensch, M William -- Yoder, Mervin C -- Garcia-Cardena, Guillermo -- Daley, George Q -- R01 AI080759/AI/NIAID NIH HHS/ -- R01 AI080759-01/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 25;459(7250):1131-5. doi: 10.1038/nature08073. Epub 2009 May 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19440194" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aorta/cytology/embryology ; *Cell Differentiation ; Cell Line ; Cells, Cultured ; Core Binding Factor Alpha 2 Subunit/genetics ; Embryonic Stem Cells ; Endothelium-Dependent Relaxing Factors/pharmacology ; Female ; Gene Expression Regulation, Developmental ; Hematopoiesis/*physiology ; Hematopoietic Stem Cells/*cytology/drug effects ; Mice ; Nitric Oxide/pharmacology ; Pregnancy ; *Stress, Mechanical
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  • 8
    Publication Date: 2009-06-12
    Description: Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729916/" 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/PMC2729916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tubbs, Julie L -- Latypov, Vitaly -- Kanugula, Sreenivas -- Butt, Amna -- Melikishvili, Manana -- Kraehenbuehl, Rolf -- Fleck, Oliver -- Marriott, Andrew -- Watson, Amanda J -- Verbeek, Barbara -- McGown, Gail -- Thorncroft, Mary -- Santibanez-Koref, Mauro F -- Millington, Christopher -- Arvai, Andrew S -- Kroeger, Matthew D -- Peterson, Lisa A -- Williams, David M -- Fried, Michael G -- Margison, Geoffrey P -- Pegg, Anthony E -- Tainer, John A -- CA018137/CA/NCI NIH HHS/ -- CA097209/CA/NCI NIH HHS/ -- CA59887/CA/NCI NIH HHS/ -- GM070662/GM/NIGMS NIH HHS/ -- R01 CA059887/CA/NCI NIH HHS/ -- R01 CA059887-12/CA/NCI NIH HHS/ -- R01 CA059887-13/CA/NCI NIH HHS/ -- R01 GM070662/GM/NIGMS NIH HHS/ -- R01 GM070662-01/GM/NIGMS NIH HHS/ -- R01 GM070662-02/GM/NIGMS NIH HHS/ -- R01 GM070662-03/GM/NIGMS NIH HHS/ -- R01 GM070662-04/GM/NIGMS NIH HHS/ -- R01 GM070662-05/GM/NIGMS NIH HHS/ -- R01 GM070662-06/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Jun 11;459(7248):808-13. doi: 10.1038/nature08076.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516334" target="_blank"〉PubMed〈/a〉
    Keywords: Alkyl and Aryl Transferases/*chemistry/*metabolism ; Alkylation ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; *DNA Damage ; *DNA Repair ; Guanine/analogs & derivatives/chemistry/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2009-05-12
    Description: Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities1. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states. The dysregulation of PHD fingers has been implicated in several human diseases, including cancers and immune or neurological disorders. Here we report that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the carboxy-terminal PHD finger of PHF23 or JARID1A (also known as KDM5A or RBBP2), to a common fusion partner nucleoporin-98 (NUP98) as identified in human leukaemias, generated potent oncoproteins that arrested haematopoietic differentiation and induced acute myeloid leukaemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukaemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukaemic transformation. NUP98-PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1 and Pbx1), and enforced their active gene transcription in murine haematopoietic stem/progenitor cells. Mechanistically, NUP98-PHD fusions act as 'chromatin boundary factors', dominating over polycomb-mediated gene silencing to 'lock' developmentally critical loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukaemia stem cells. Collectively, our studies represent, to our knowledge, the first report that deregulation of the PHD finger, an 'effector' of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, catastrophizes cellular fate decision-making, and even causes oncogenesis during mammalian development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697266/" 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/PMC2697266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Gang G -- Song, Jikui -- Wang, Zhanxin -- Dormann, Holger L -- Casadio, Fabio -- Li, Haitao -- Luo, Jun-Li -- Patel, Dinshaw J -- Allis, C David -- K99 CA151683/CA/NCI NIH HHS/ -- R37 GM053512/GM/NIGMS NIH HHS/ -- R37 GM053512-30/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):847-51. doi: 10.1038/nature08036.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19430464" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics/physiology ; Animals ; Cell Transformation, Neoplastic ; Cells, Cultured ; Chromatin/*metabolism ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Genes, Homeobox/genetics ; Hematologic Neoplasms/genetics/*metabolism/*pathology ; Hematopoiesis/genetics ; Hematopoietic Stem Cells/metabolism/pathology ; Histones/chemistry/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics/*metabolism ; Lysine/metabolism ; Magnetic Resonance Spectroscopy ; Methylation ; Mice ; Models, Molecular ; Nuclear Pore Complex Proteins/chemistry/genetics/metabolism ; Oncogene Proteins, Fusion/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Retinoblastoma-Binding Protein 2 ; Transcription, Genetic ; Tumor Suppressor Proteins/*chemistry/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2009-01-02
    Description: The transcription factor NF-kappaB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types. Antigen receptor stimulation assembles an NF-kappaB activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-kappaB kinase complex, but signal transduction is not fully understood. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Here we report that both screens identified casein kinase 1alpha (CK1alpha) as a bifunctional regulator of NF-kappaB. CK1alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappaB. ABC DLBCL cells required CK1alpha for constitutive NF-kappaB activity, indicating that CK1alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688735/" 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/PMC2688735/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bidere, Nicolas -- Ngo, Vu N -- Lee, Jeansun -- Collins, Cailin -- Zheng, Lixin -- Wan, Fengyi -- Davis, R Eric -- Lenz, Georg -- Anderson, D Eric -- Arnoult, Damien -- Vazquez, Aime -- Sakai, Keiko -- Zhang, Jun -- Meng, Zhaojing -- Veenstra, Timothy D -- Staudt, Louis M -- Lenardo, Michael J -- NIH0011349228/PHS HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2009 Mar 5;458(7234):92-6. doi: 10.1038/nature07613. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118383" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; CARD Signaling Adaptor Proteins/metabolism ; Casein Kinases/*metabolism ; Caspases/metabolism ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Feedback, Physiological ; Guanylate Cyclase/metabolism ; Humans ; I-kappa B Kinase/metabolism ; Jurkat Cells ; Lymphoma, Large B-Cell, Diffuse/enzymology/*metabolism/*pathology ; NF-kappa B/*metabolism ; Neoplasm Proteins/metabolism ; Protein Binding ; Receptors, Antigen/*metabolism ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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