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  • 1
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    COT drives resistance to RAF inhibition through MAP kinase pathway reactivation (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-11-26
    Description: Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed approximately 600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058384/" 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/PMC3058384/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johannessen, Cory M -- Boehm, Jesse S -- Kim, So Young -- Thomas, Sapana R -- Wardwell, Leslie -- Johnson, Laura A -- Emery, Caroline M -- Stransky, Nicolas -- Cogdill, Alexandria P -- Barretina, Jordi -- Caponigro, Giordano -- Hieronymus, Haley -- Murray, Ryan R -- Salehi-Ashtiani, Kourosh -- Hill, David E -- Vidal, Marc -- Zhao, Jean J -- Yang, Xiaoping -- Alkan, Ozan -- Kim, Sungjoon -- Harris, Jennifer L -- Wilson, Christopher J -- Myer, Vic E -- Finan, Peter M -- Root, David E -- Roberts, Thomas M -- Golub, Todd -- Flaherty, Keith T -- Dummer, Reinhard -- Weber, Barbara L -- Sellers, William R -- Schlegel, Robert -- Wargo, Jennifer A -- Hahn, William C -- Garraway, Levi A -- CA134502/CA/NCI NIH HHS/ -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- K08 CA115927/CA/NCI NIH HHS/ -- K08 CA115927-05/CA/NCI NIH HHS/ -- P50 CA093683/CA/NCI NIH HHS/ -- R01 CA134502/CA/NCI NIH HHS/ -- R33 CA128625/CA/NCI NIH HHS/ -- RC2 CA148268/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 16;468(7326):968-72. doi: 10.1038/nature09627. Epub 2010 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107320" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Cell Line, Tumor ; Clinical Trials as Topic ; *Drug Resistance, Neoplasm/drug effects/genetics ; Enzyme Activation/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Library ; Humans ; Indoles/pharmacology/therapeutic use ; MAP Kinase Kinase Kinases/genetics/*metabolism ; *MAP Kinase Signaling System ; Melanoma/drug therapy/enzymology/genetics/metabolism ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Open Reading Frames/genetics ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Proto-Oncogene Proteins/genetics/*metabolism ; Proto-Oncogene Proteins B-raf/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Proto-Oncogene Proteins c-raf/genetics/metabolism ; Sulfonamides/pharmacology/therapeutic use
    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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    A genomewide search for ribozymes reveals an HDV-like sequence in the human CPEB3 gene (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-09-23
    Description: Ribozymes are thought to have played a pivotal role in the early evolution of life, but relatively few have been identified in modern organisms. We performed an in vitro selection aimed at isolating self-cleaving RNAs from the human genome. The selection yielded several ribozymes, one of which is a conserved mammalian sequence that resides in an intron of the CPEB3 gene, which belongs to a family of genes regulating messenger RNA polyadenylation. The CPEB3 ribozyme is structurally and biochemically related to the human hepatitis delta virus (HDV) ribozymes. The occurrence of this ribozyme exclusively in mammals suggests that it may have evolved as recently as 200 million years ago. We postulate that HDV arose from the human transcriptome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Salehi-Ashtiani, Kourosh -- Luptak, Andrej -- Litovchick, Alexander -- Szostak, Jack W -- GM53936/GM/NIGMS NIH HHS/ -- HL66678/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2006 Sep 22;313(5794):1788-92.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Molecular Biology, and Center for Computational and Integrative Biology (CCIB), 7215 Simches Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16990549" target="_blank"〉PubMed〈/a〉
    Keywords: Base Pairing ; Base Sequence ; Catalysis ; Cations, Divalent/metabolism ; Conserved Sequence ; *Evolution, Molecular ; Expressed Sequence Tags ; *Genome, Human ; Genomic Library ; Hepatitis Delta Virus/genetics ; Humans ; Hydrogen-Ion Concentration ; *Introns ; Molecular Sequence Data ; Mutation ; Nucleic Acid Conformation ; Phosphorylation ; RNA, Catalytic/chemistry/genetics/*isolation & purification/*metabolism ; RNA-Binding Proteins/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    The landscape of C. elegans 3'UTRs (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-06-05
    Description: Three-prime untranslated regions (3'UTRs) of metazoan messenger RNAs (mRNAs) contain numerous regulatory elements, yet remain largely uncharacterized. Using polyA capture, 3' rapid amplification of complementary DNA (cDNA) ends, full-length cDNAs, and RNA-seq, we defined approximately 26,000 distinct 3'UTRs in Caenorhabditis elegans for approximately 85% of the 18,328 experimentally supported protein-coding genes and revised approximately 40% of gene models. Alternative 3'UTR isoforms are frequent, often differentially expressed during development. Average 3'UTR length decreases with animal age. Surprisingly, no polyadenylation signal (PAS) was detected for 13% of polyadenylation sites, predominantly among shorter alternative isoforms. Trans-spliced (versus non-trans-spliced) mRNAs possess longer 3'UTRs and frequently contain no PAS or variant PAS. We identified conserved 3'UTR motifs, isoform-specific predicted microRNA target sites, and polyadenylation of most histone genes. Our data reveal a rich complexity of 3'UTRs, both genome-wide and throughout development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142571/" 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/PMC3142571/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mangone, Marco -- Manoharan, Arun Prasad -- Thierry-Mieg, Danielle -- Thierry-Mieg, Jean -- Han, Ting -- Mackowiak, Sebastian D -- Mis, Emily -- Zegar, Charles -- Gutwein, Michelle R -- Khivansara, Vishal -- Attie, Oliver -- Chen, Kevin -- Salehi-Ashtiani, Kourosh -- Vidal, Marc -- Harkins, Timothy T -- Bouffard, Pascal -- Suzuki, Yutaka -- Sugano, Sumio -- Kohara, Yuji -- Rajewsky, Nikolaus -- Piano, Fabio -- Gunsalus, Kristin C -- Kim, John K -- R00HG004515/HG/NHGRI NIH HHS/ -- R01 GM088565/GM/NIGMS NIH HHS/ -- R01 GM088565-03/GM/NIGMS NIH HHS/ -- R01GM088565/GM/NIGMS NIH HHS/ -- U01-HG004276/HG/NHGRI NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2010 Jul 23;329(5990):432-5. doi: 10.1126/science.1191244. Epub 2010 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genomics and Systems Biology, Department of Biology, New York University, 1009 Silver Center, New York, NY 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20522740" target="_blank"〉PubMed〈/a〉
    Keywords: *3' Untranslated Regions ; Animals ; Binding Sites ; Caenorhabditis elegans/embryology/*genetics/growth & development ; Computational Biology ; Conserved Sequence ; Disorders of Sex Development ; Gene Expression Regulation, Developmental ; Gene Library ; *Genes, Helminth ; Helminth Proteins/genetics ; Histones/genetics ; Male ; MicroRNAs/metabolism ; Operon ; Poly A/metabolism ; Polyadenylation ; RNA, Helminth/*genetics ; RNA, Messenger/genetics ; Trans-Splicing
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Cerenkov radiation from moving straight strings (2007)
    American Physical Society
    Details
    Publication Date: 2007-05-18
    Print ISSN: 1550-7998
    Electronic ISSN: 1550-2368
    Topics: Physics
    Published by American Physical Society
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  • 5
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    Response surface methodology (RSM) optimization approach for degradation of Direct Blue 71 dye using CuO–ZnO nanocomposite (2017)
    Springer
    Details
    Publication Date: 2017-03-13
    Print ISSN: 1735-1472
    Electronic ISSN: 1735-2630
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by Springer
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  • 6
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    Dilaton and axion bremsstrahlung from collisions of cosmic (super)strings (2007)
    Institute of Physics
    Details
    Publication Date: 2007-06-06
    Print ISSN: 1751-8113
    Electronic ISSN: 1751-8121
    Topics: Mathematics , Physics
    Published by Institute of Physics
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  • 7
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    International hydrogen association for hydrogen energy design competition applied topic A: Portable fuel cell (2011)
    Elsevier
    Details
    Publication Date: 2011-10-01
    Print ISSN: 0360-3199
    Electronic ISSN: 1879-3487
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by Elsevier
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