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  • 1
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    Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-09
    Description: B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948082/" 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/PMC2948082/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bollag, Gideon -- Hirth, Peter -- Tsai, James -- Zhang, Jiazhong -- Ibrahim, Prabha N -- Cho, Hanna -- Spevak, Wayne -- Zhang, Chao -- Zhang, Ying -- Habets, Gaston -- Burton, Elizabeth A -- Wong, Bernice -- Tsang, Garson -- West, Brian L -- Powell, Ben -- Shellooe, Rafe -- Marimuthu, Adhirai -- Nguyen, Hoa -- Zhang, Kam Y J -- Artis, Dean R -- Schlessinger, Joseph -- Su, Fei -- Higgins, Brian -- Iyer, Raman -- D'Andrea, Kurt -- Koehler, Astrid -- Stumm, Michael -- Lin, Paul S -- Lee, Richard J -- Grippo, Joseph -- Puzanov, Igor -- Kim, Kevin B -- Ribas, Antoni -- McArthur, Grant A -- Sosman, Jeffrey A -- Chapman, Paul B -- Flaherty, Keith T -- Xu, Xiaowei -- Nathanson, Katherine L -- Nolop, Keith -- K24 CA097588/CA/NCI NIH HHS/ -- P50 CA093372/CA/NCI NIH HHS/ -- P50 CA093372-01/CA/NCI NIH HHS/ -- R01 CA118871/CA/NCI NIH HHS/ -- R01 CA118871-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 30;467(7315):596-9. doi: 10.1038/nature09454.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA. gbollag@plexxikon.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20823850" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Dogs ; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism ; Humans ; Indoles/administration & dosage/adverse effects/chemistry/*therapeutic use ; MAP Kinase Signaling System/drug effects ; Macaca fascicularis ; Melanoma/*drug therapy/*enzymology/genetics/pathology ; Models, Molecular ; Mutant Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Mutation/*genetics ; Neoplasm Metastasis ; Phosphorylation/drug effects ; Positron-Emission Tomography ; Proto-Oncogene Proteins B-raf/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Rats ; Substrate Specificity ; Sulfonamides/administration & dosage/adverse effects/chemistry/*therapeutic use ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-04-10
    Description: Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xiao-Wei -- Yan, Xiao-Jing -- Zhou, Zi-Ren -- Yang, Fei-Fei -- Wu, Zi-Yu -- Sun, Hong-Bin -- Liang, Wen-Xue -- Song, Ai-Xin -- Lallemand-Breitenbach, Valerie -- Jeanne, Marion -- Zhang, Qun-Ye -- Yang, Huai-Yu -- Huang, Qiu-Hua -- Zhou, Guang-Biao -- Tong, Jian-Hua -- Zhang, Yan -- Wu, Ji-Hui -- Hu, Hong-Yu -- de The, Hugues -- Chen, Sai-Juan -- Chen, Zhu -- New York, N.Y. -- Science. 2010 Apr 9;328(5975):240-3. doi: 10.1126/science.1183424.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20378816" target="_blank"〉PubMed〈/a〉
    Keywords: Arsenic/*metabolism ; Arsenicals/*metabolism/*pharmacology ; Cell Line ; Humans ; Leukemia, Promyelocytic, Acute/drug therapy/genetics ; Mutant Proteins/chemistry/metabolism ; Mutation ; Nuclear Proteins/chemistry/genetics/*metabolism ; Oncogene Proteins, Fusion/chemistry/genetics/*metabolism ; Oxazines/metabolism ; Oxides/*metabolism/*pharmacology ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Retinoic Acid/metabolism ; Recombinant Fusion Proteins/chemistry/metabolism ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Transcription Factors/chemistry/genetics/*metabolism ; Tumor Suppressor Proteins/chemistry/genetics/*metabolism ; Ubiquitination ; Zinc Fingers
    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
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    Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-07-27
    Description: Glycoprotein adhesion receptors such as selectins contribute to tissue injury in stroke. Ischemic neurons strongly expressed C1q, which may target them for complement-mediated attack or C1qRp-mediated clearance. A hybrid molecule was used to simultaneously inhibit both complement activation and selectin-mediated adhesion. The extracellular domain of soluble complement receptor-1 (sCR1) was sialyl Lewis x glycosylated (sCR1sLex) to inhibit complement activation and endothelial-platelet-leukocyte interactions. sCR1 and sCR1sLex colocalized to ischemic cerebral microvessels and C1q-expressing neurons, inhibited neutrophil and platelet accumulation, and reduced cerebral infarct volumes. Additional benefit was conferred by sialyl Lewis x glycosylation of the unmodified parent sCR1 molecule.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, J -- Kim, L J -- Mealey, R -- Marsh, H C Jr -- Zhang, Y -- Tenner, A J -- Connolly, E S Jr -- Pinsky, D J -- R01 HL55397/HL/NHLBI NIH HHS/ -- R01 HL59488/HL/NHLBI NIH HHS/ -- R01 NS35144/NS/NINDS NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Jul 23;285(5427):595-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10417391" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Platelets/physiology ; Cell Adhesion ; Cerebral Cortex/blood supply/immunology/metabolism ; Cerebral Infarction/drug therapy ; Cerebrovascular Circulation ; Cerebrovascular Disorders/*drug therapy/immunology/physiopathology ; Complement Activation ; Complement C1q/metabolism ; Glycosylation ; Humans ; Ischemic Attack, Transient/*drug therapy/immunology/physiopathology ; Leukocytes/physiology ; Mice ; Neurons/immunology/metabolism ; Neuroprotective Agents/administration & dosage/adverse ; effects/metabolism/*therapeutic use ; Neutrophils/physiology ; Oligosaccharides/administration & dosage/adverse effects/metabolism/*therapeutic ; use ; Platelet Adhesiveness ; Receptors, Complement/administration & dosage/metabolism/*therapeutic use ; Reperfusion Injury/drug therapy/immunology/metabolism ; Selectins/metabolism ; Time Factors
    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
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    Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-06-02
    Description: Acetylation of core histone tails plays a fundamental role in transcription regulation. In addition to acetylation, other posttranslational modifications, such as phosphorylation and methylation, occur in core histone tails. Here, we report the purification, molecular identification, and functional characterization of a histone H4-specific methyltransferase PRMT1, a protein arginine methyltransferase. PRMT1 specifically methylates arginine 3 (Arg 3) of H4 in vitro and in vivo. Methylation of Arg 3 by PRMT1 facilitates subsequent acetylation of H4 tails by p300. However, acetylation of H4 inhibits its methylation by PRMT1. Most important, a mutation in the S-adenosyl-l-methionine-binding site of PRMT1 substantially crippled its nuclear receptor coactivator activity. Our finding reveals Arg 3 of H4 as a novel methylation site by PRMT1 and indicates that Arg 3 methylation plays an important role in transcriptional regulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, H -- Huang, Z Q -- Xia, L -- Feng, Q -- Erdjument-Bromage, H -- Strahl, B D -- Briggs, S D -- Allis, C D -- Wong, J -- Tempst, P -- Zhang, Y -- GM63067-01/GM/NIGMS NIH HHS/ -- P30 CA08748/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2001 Aug 3;293(5531):853-7. Epub 2001 May 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11387442" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Amino Acid Sequence ; Animals ; Arginine/*metabolism ; Binding Sites ; Cell Nucleus/metabolism ; HeLa Cells ; Histones/chemistry/*metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Intracellular Signaling Peptides and Proteins ; Lysine/metabolism ; Methylation ; Methyltransferases/chemistry/genetics/isolation & purification/*metabolism ; Molecular Sequence Data ; Mutation ; Oocytes ; Protein-Arginine N-Methyltransferases ; Receptors, Androgen/*metabolism ; Recombinant Proteins/metabolism ; S-Adenosylmethionine/metabolism ; *Transcriptional Activation ; Xenopus
    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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  • 5
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    Role of histone H3 lysine 27 methylation in Polycomb-group silencing (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-09-28
    Description: Polycomb group (PcG) proteins play important roles in maintaining the silent state of HOX genes. Recent studies have implicated histone methylation in long-term gene silencing. However, a connection between PcG-mediated gene silencing and histone methylation has not been established. Here we report the purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex. We demonstrate that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27). Using chromatin immunoprecipitation assays, we show that H3-K27 methylation colocalizes with, and is dependent on, E(Z) binding at an Ultrabithorax (Ubx) Polycomb response element (PRE), and that this methylation correlates with Ubx repression. Methylation on H3-K27 facilitates binding of Polycomb (PC), a component of the PRC1 complex, to histone H3 amino-terminal tail. Thus, these studies establish a link between histone methylation and PcG-mediated gene silencing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Ru -- Wang, Liangjun -- Wang, Hengbin -- Xia, Li -- Erdjument-Bromage, Hediye -- Tempst, Paul -- Jones, Richard S -- Zhang, Yi -- New York, N.Y. -- Science. 2002 Nov 1;298(5595):1039-43. Epub 2002 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12351676" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carrier Proteins/isolation & purification/metabolism ; Cell Cycle Proteins/metabolism ; Chromatin/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Drosophila ; Drosophila Proteins/genetics/*metabolism ; *Gene Silencing ; Genes, Homeobox ; HeLa Cells ; *Histone-Lysine N-Methyltransferase ; Histones/*metabolism ; *Homeodomain Proteins ; Humans ; Lysine/*metabolism ; Methylation ; Methyltransferases/isolation & purification/metabolism ; Nuclear Proteins/metabolism ; Nucleosomes/metabolism ; Peptide Mapping ; Polycomb Repressive Complex 1 ; Polycomb Repressive Complex 2 ; Precipitin Tests ; Protein Methyltransferases ; Proteins/isolation & purification/metabolism ; RNA Interference ; Repressor Proteins/isolation & purification/metabolism ; Response Elements ; Temperature ; *Transcription Factors
    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
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    Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1 (2000)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2000-01-29
    Description: Malfolded proteins in the endoplasmic reticulum (ER) induce cellular stress and activate c-Jun amino-terminal kinases (JNKs or SAPKs). Mammalian homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress. The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation. Dominant-negative TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the ER proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Urano, F -- Wang, X -- Bertolotti, A -- Zhang, Y -- Chung, P -- Harding, H P -- Ron, D -- DK47119/DK/NIDDK NIH HHS/ -- ES08681/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 2000 Jan 28;287(5453):664-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skirball Institute of Biomolecular Medicine, Departments of Medicine, Cell Biology and the Kaplan Cancer Center, New York University Medical School, New York, NY 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10650002" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cells, Cultured ; Endoplasmic Reticulum/*metabolism ; Endoribonucleases/genetics/*metabolism ; Enzyme Activation ; Gene Targeting ; Humans ; JNK Mitogen-Activated Protein Kinases ; *Membrane Proteins ; Mitogen-Activated Protein Kinases/*metabolism ; Multienzyme Complexes/genetics/*metabolism ; Protein Kinases/genetics/*metabolism ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Proteins/chemistry/genetics/*metabolism ; Rats ; Recombinant Fusion Proteins/metabolism ; TNF Receptor-Associated Factor 2 ; Thapsigargin/pharmacology ; Two-Hybrid System Techniques ; eIF-2 Kinase/metabolism
    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
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    Origins and functional impact of copy number variation in the human genome (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-09
    Description: Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330748/" 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/PMC3330748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Conrad, Donald F -- Pinto, Dalila -- Redon, Richard -- Feuk, Lars -- Gokcumen, Omer -- Zhang, Yujun -- Aerts, Jan -- Andrews, T Daniel -- Barnes, Chris -- Campbell, Peter -- Fitzgerald, Tomas -- Hu, Min -- Ihm, Chun Hwa -- Kristiansson, Kati -- Macarthur, Daniel G -- Macdonald, Jeffrey R -- Onyiah, Ifejinelo -- Pang, Andy Wing Chun -- Robson, Sam -- Stirrups, Kathy -- Valsesia, Armand -- Walter, Klaudia -- Wei, John -- Wellcome Trust Case Control Consortium -- Tyler-Smith, Chris -- Carter, Nigel P -- Lee, Charles -- Scherer, Stephen W -- Hurles, Matthew E -- 077006/Z/05/Z/Wellcome Trust/United Kingdom -- 077008/Wellcome Trust/United Kingdom -- 077009/Wellcome Trust/United Kingdom -- 077014/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- GM081533/GM/NIGMS NIH HHS/ -- HG004221/HG/NHGRI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Apr 1;464(7289):704-12. doi: 10.1038/nature08516. Epub 2009 Oct 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812545" target="_blank"〉PubMed〈/a〉
    Keywords: Continental Population Groups/genetics ; DNA Copy Number Variations/*genetics ; Gene Duplication ; Genetic Predisposition to Disease/*genetics ; Genome, Human/*genetics ; Genome-Wide Association Study ; Genotype ; Haplotypes/genetics ; Humans ; Mutagenesis/*genetics ; Oligonucleotide Array Sequence Analysis ; Polymorphism, Single Nucleotide/genetics ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    The sequence and de novo assembly of the giant panda genome (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-17
    Description: Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951497/" 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/PMC3951497/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ruiqiang -- Fan, Wei -- Tian, Geng -- Zhu, Hongmei -- He, Lin -- Cai, Jing -- Huang, Quanfei -- Cai, Qingle -- Li, Bo -- Bai, Yinqi -- Zhang, Zhihe -- Zhang, Yaping -- Wang, Wen -- Li, Jun -- Wei, Fuwen -- Li, Heng -- Jian, Min -- Li, Jianwen -- Zhang, Zhaolei -- Nielsen, Rasmus -- Li, Dawei -- Gu, Wanjun -- Yang, Zhentao -- Xuan, Zhaoling -- Ryder, Oliver A -- Leung, Frederick Chi-Ching -- Zhou, Yan -- Cao, Jianjun -- Sun, Xiao -- Fu, Yonggui -- Fang, Xiaodong -- Guo, Xiaosen -- Wang, Bo -- Hou, Rong -- Shen, Fujun -- Mu, Bo -- Ni, Peixiang -- Lin, Runmao -- Qian, Wubin -- Wang, Guodong -- Yu, Chang -- Nie, Wenhui -- Wang, Jinhuan -- Wu, Zhigang -- Liang, Huiqing -- Min, Jiumeng -- Wu, Qi -- Cheng, Shifeng -- Ruan, Jue -- Wang, Mingwei -- Shi, Zhongbin -- Wen, Ming -- Liu, Binghang -- Ren, Xiaoli -- Zheng, Huisong -- Dong, Dong -- Cook, Kathleen -- Shan, Gao -- Zhang, Hao -- Kosiol, Carolin -- Xie, Xueying -- Lu, Zuhong -- Zheng, Hancheng -- Li, Yingrui -- Steiner, Cynthia C -- Lam, Tommy Tsan-Yuk -- Lin, Siyuan -- Zhang, Qinghui -- Li, Guoqing -- Tian, Jing -- Gong, Timing -- Liu, Hongde -- Zhang, Dejin -- Fang, Lin -- Ye, Chen -- Zhang, Juanbin -- Hu, Wenbo -- Xu, Anlong -- Ren, Yuanyuan -- Zhang, Guojie -- Bruford, Michael W -- Li, Qibin -- Ma, Lijia -- Guo, Yiran -- An, Na -- Hu, Yujie -- Zheng, Yang -- Shi, Yongyong -- Li, Zhiqiang -- Liu, Qing -- Chen, Yanling -- Zhao, Jing -- Qu, Ning -- Zhao, Shancen -- Tian, Feng -- Wang, Xiaoling -- Wang, Haiyin -- Xu, Lizhi -- Liu, Xiao -- Vinar, Tomas -- Wang, Yajun -- Lam, Tak-Wah -- Yiu, Siu-Ming -- Liu, Shiping -- Zhang, Hemin -- Li, Desheng -- Huang, Yan -- Wang, Xia -- Yang, Guohua -- Jiang, Zhi -- Wang, Junyi -- Qin, Nan -- Li, Li -- Li, Jingxiang -- Bolund, Lars -- Kristiansen, Karsten -- Wong, Gane Ka-Shu -- Olson, Maynard -- Zhang, Xiuqing -- Li, Songgang -- Yang, Huanming -- Wang, Jian -- Wang, Jun -- R01 HG003229/HG/NHGRI NIH HHS/ -- R01 HG003229-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2010 Jan 21;463(7279):311-7. doi: 10.1038/nature08696. Epub 2009 Dec 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉BGI-Shenzhen, Shenzhen 518083, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010809" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Animals ; China ; Conserved Sequence/genetics ; Contig Mapping ; Diet/veterinary ; Dogs ; Evolution, Molecular ; Female ; Fertility/genetics/physiology ; Genome/*genetics ; *Genomics ; Heterozygote ; Humans ; Multigene Family/genetics ; Polymorphism, Single Nucleotide/genetics ; Receptors, G-Protein-Coupled/genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Synteny/genetics ; Ursidae/classification/*genetics/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-09-18
    Description: The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Shih-Min A -- Mishina, Yuji M -- Liu, Shanming -- Cheung, Atwood -- Stegmeier, Frank -- Michaud, Gregory A -- Charlat, Olga -- Wiellette, Elizabeth -- Zhang, Yue -- Wiessner, Stephanie -- Hild, Marc -- Shi, Xiaoying -- Wilson, Christopher J -- Mickanin, Craig -- Myer, Vic -- Fazal, Aleem -- Tomlinson, Ronald -- Serluca, Fabrizio -- Shao, Wenlin -- Cheng, Hong -- Shultz, Michael -- Rau, Christina -- Schirle, Markus -- Schlegl, Judith -- Ghidelli, Sonja -- Fawell, Stephen -- Lu, Chris -- Curtis, Daniel -- Kirschner, Marc W -- Lengauer, Christoph -- Finan, Peter M -- Tallarico, John A -- Bouwmeester, Tewis -- Porter, Jeffery A -- Bauer, Andreas -- Cong, Feng -- England -- Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356. Epub 2009 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759537" target="_blank"〉PubMed〈/a〉
    Keywords: Axin Protein ; Cell Division/drug effects ; Cell Line ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy/metabolism ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Proteomics ; Repressor Proteins/chemistry/*metabolism ; Signal Transduction/*drug effects ; Tankyrases/*antagonists & inhibitors/metabolism ; Transcription, Genetic/drug effects ; Ubiquitin/metabolism ; Ubiquitination ; Wnt Proteins/*antagonists & inhibitors/metabolism ; beta Catenin/antagonists & inhibitors/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    The mutation spectrum revealed by paired genome sequences from a lung cancer patient (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-05-28
    Description: Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung carcinomas in smokers being the predominant form of the disease. Although previous studies have identified important common somatic mutations in lung cancers, they have primarily focused on a limited set of genes and have thus provided a constrained view of the mutational spectrum. Recent cancer sequencing efforts have used next-generation sequencing technologies to provide a genome-wide view of mutations in leukaemia, breast cancer and cancer cell lines. Here we present the complete sequences of a primary lung tumour (60x coverage) and adjacent normal tissue (46x). Comparing the two genomes, we identify a wide variety of somatic variations, including 〉50,000 high-confidence single nucleotide variants. We validated 530 somatic single nucleotide variants in this tumour, including one in the KRAS proto-oncogene and 391 others in coding regions, as well as 43 large-scale structural variations. These constitute a large set of new somatic mutations and yield an estimated 17.7 per megabase genome-wide somatic mutation rate. Notably, we observe a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes and in promoter regions up to 5 kilobases upstream of all protein-coding genes. Furthermore, we observe a higher rate of amino acid-changing mutations in kinase genes. We present a comprehensive view of somatic alterations in a single lung tumour, and provide the first evidence, to our knowledge, of distinct selective pressures present within the tumour environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, William -- Jiang, Zhaoshi -- Liu, Jinfeng -- Haverty, Peter M -- Guan, Yinghui -- Stinson, Jeremy -- Yue, Peng -- Zhang, Yan -- Pant, Krishna P -- Bhatt, Deepali -- Ha, Connie -- Johnson, Stephanie -- Kennemer, Michael I -- Mohan, Sankar -- Nazarenko, Igor -- Watanabe, Colin -- Sparks, Andrew B -- Shames, David S -- Gentleman, Robert -- de Sauvage, Frederic J -- Stern, Howard -- Pandita, Ajay -- Ballinger, Dennis G -- Drmanac, Radoje -- Modrusan, Zora -- Seshagiri, Somasekar -- Zhang, Zemin -- England -- Nature. 2010 May 27;465(7297):473-7. doi: 10.1038/nature09004.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20505728" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinoma, Non-Small-Cell Lung/*genetics ; DNA Mutational Analysis ; Genome, Human/*genetics ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; Models, Biological ; Point Mutation/*genetics ; Selection, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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