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  • 1
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    Recurrent R-spondin fusions in colon cancer (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-08-17
    Description: Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690621/" 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/PMC3690621/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seshagiri, Somasekar -- Stawiski, Eric W -- Durinck, Steffen -- Modrusan, Zora -- Storm, Elaine E -- Conboy, Caitlin B -- Chaudhuri, Subhra -- Guan, Yinghui -- Janakiraman, Vasantharajan -- Jaiswal, Bijay S -- Guillory, Joseph -- Ha, Connie -- Dijkgraaf, Gerrit J P -- Stinson, Jeremy -- Gnad, Florian -- Huntley, Melanie A -- Degenhardt, Jeremiah D -- Haverty, Peter M -- Bourgon, Richard -- Wang, Weiru -- Koeppen, Hartmut -- Gentleman, Robert -- Starr, Timothy K -- Zhang, Zemin -- Largaespada, David A -- Wu, Thomas D -- de Sauvage, Frederic J -- R00 CA151672/CA/NCI NIH HHS/ -- R01 CA134759/CA/NCI NIH HHS/ -- R01-CA134759/CA/NCI NIH HHS/ -- T32 CA009138/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):660-4. doi: 10.1038/nature11282.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. sekar@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895193" target="_blank"〉PubMed〈/a〉
    Keywords: Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle Proteins/genetics ; Colonic Neoplasms/*genetics/metabolism/pathology ; DNA Copy Number Variations/genetics ; DNA-Binding Proteins/genetics ; Dioxygenases/genetics ; Exome/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Gene Fusion/*genetics ; Genes, APC ; Genes, Neoplasm/*genetics ; Humans ; Insulin-Like Growth Factor II/genetics ; Intercellular Signaling Peptides and Proteins/*genetics ; Molecular Sequence Data ; Mutation/genetics ; Polymorphism, Single Nucleotide/genetics ; Protein-Serine-Threonine Kinases/genetics ; Proto-Oncogene Proteins/genetics ; Receptor, ErbB-3/genetics ; Sequence Analysis, RNA ; Signal Transduction/genetics ; Thrombospondins/*genetics ; Transcription Factor 7-Like 2 Protein/genetics ; Tumor Suppressor Proteins/genetics ; Wnt Proteins/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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  • 2
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    Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-12-25
    Description: Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Storm, Elaine E -- Durinck, Steffen -- de Sousa e Melo, Felipe -- Tremayne, Jarrod -- Kljavin, Noelyn -- Tan, Christine -- Ye, Xiaofen -- Chiu, Cecilia -- Pham, Thinh -- Hongo, Jo-Anne -- Bainbridge, Travis -- Firestein, Ron -- Blackwood, Elizabeth -- Metcalfe, Ciara -- Stawiski, Eric W -- Yauch, Robert L -- Wu, Yan -- de Sauvage, Frederic J -- England -- Nature. 2016 Jan 7;529(7584):97-100. doi: 10.1038/nature16466. Epub 2015 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Research Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26700806" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology/pharmacology/therapeutic use ; Cell Differentiation/*drug effects ; Cell Division/drug effects ; Colorectal Neoplasms/*drug therapy/metabolism/*pathology ; Disease Progression ; Female ; Gene Expression Regulation/drug effects ; Humans ; Intestines/cytology/drug effects/metabolism/pathology ; Male ; Mice ; *Molecular Targeted Therapy ; Neoplastic Stem Cells/*drug effects/metabolism/*pathology ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/*metabolism ; Stem Cells/cytology/metabolism ; Thrombospondins/antagonists & inhibitors/immunology/*metabolism ; 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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  • 3
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    Dosage of Fgf8 determines whether cell survival is positively or negatively regulated in the developing forebrain (2003)
    National Academy of Sciences
    Details
    Publication Date: 2003-02-06
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Hfq and three Hfq-dependent small regulatory RNAs--MgrR, RyhB and McaS--coregulate the locus of enterocyte effacement in enteropathogenic Escherichia coli (2017)
    Oxford University Press
    Details
    Publication Date: 2017-01-08
    Description: Enteropathogenic Escherichia coli (EPEC) is a significant cause of infantile diarrhea and death in developing countries. The pathogenicity island l ocus of e nterocyte e ffacement (LEE) is essential for EPEC to cause diarrhea. Besides EPEC, the LEE is also present in other gastrointestinal pathogens, most notably enterohemorrhagic E. coli (EHEC). Whereas transcriptional control of the LEE has been meticulously examined, posttranscriptional regulation, including the role of Hfq-dependent small RNAs, remains undercharacterized. However, the past few years have witnessed a surge in the identification of riboregulators of the LEE in EHEC. Contrastingly, the posttranscriptional regulatory landscape of EPEC remains cryptic. Here we demonstrate that the RNA-chaperone Hfq represses the LEE of EPEC by targeting the 5' untranslated leader region of grlR in the grlRA mRNA. Three conserved small regulatory RNAs (sRNAs)—MgrR, RyhB and McaS—are involved in the Hfq-dependent regulation of grlRA . MgrR and RyhB exert their effects by directly base-pairing to the 5' region of grlR . Whereas MgrR selectively represses grlR but activates grlA , RyhB represses gene expression from the entire grlRA transcript. Meanwhile, McaS appears to target the grlRA mRNA indirectly. Thus, our results provide the first definitive evidence that implicates multiple sRNAs in regulating the LEE and the resulting virulence of EPEC.
    Print ISSN: 0928-8244
    Topics: Biology , Medicine
    Published by Oxford University Press
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