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  • 1
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    Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7 (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-03-04
    Description: Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wertz, Ingrid E -- Kusam, Saritha -- Lam, Cynthia -- Okamoto, Toru -- Sandoval, Wendy -- Anderson, Daniel J -- Helgason, Elizabeth -- Ernst, James A -- Eby, Mike -- Liu, Jinfeng -- Belmont, Lisa D -- Kaminker, Josh S -- O'Rourke, Karen M -- Pujara, Kanan -- Kohli, Pawan Bir -- Johnson, Adam R -- Chiu, Mark L -- Lill, Jennie R -- Jackson, Peter K -- Fairbrother, Wayne J -- Seshagiri, Somasekar -- Ludlam, Mary J C -- Leong, Kevin G -- Dueber, Erin C -- Maecker, Heather -- Huang, David C S -- Dixit, Vishva M -- CA043540/CA/NCI NIH HHS/ -- CA80188/CA/NCI NIH HHS/ -- England -- Nature. 2011 Mar 3;471(7336):110-4. doi: 10.1038/nature09779.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA. ingrid@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21368834" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/drug effects ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic/drug effects ; Drug Resistance, Neoplasm ; F-Box Proteins/genetics/*metabolism ; Fibroblasts ; Humans ; Mice ; Mitosis/drug effects ; Myeloid Cell Leukemia Sequence 1 Protein ; Paclitaxel/pharmacology ; Pharmacogenetics ; Phosphorylation/drug effects ; Polyploidy ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-bcl-2/deficiency/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Tubulin/*metabolism ; Tubulin Modulators/*pharmacology ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; Vincristine/pharmacology
    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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    Diverse somatic mutation patterns and pathway alterations in human cancers (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-30
    Description: The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kan, Zhengyan -- Jaiswal, Bijay S -- Stinson, Jeremy -- Janakiraman, Vasantharajan -- Bhatt, Deepali -- Stern, Howard M -- Yue, Peng -- Haverty, Peter M -- Bourgon, Richard -- Zheng, Jianbiao -- Moorhead, Martin -- Chaudhuri, Subhra -- Tomsho, Lynn P -- Peters, Brock A -- Pujara, Kanan -- Cordes, Shaun -- Davis, David P -- Carlton, Victoria E H -- Yuan, Wenlin -- Li, Li -- Wang, Weiru -- Eigenbrot, Charles -- Kaminker, Joshua S -- Eberhard, David A -- Waring, Paul -- Schuster, Stephan C -- Modrusan, Zora -- Zhang, Zemin -- Stokoe, David -- de Sauvage, Frederic J -- Faham, Malek -- Seshagiri, Somasekar -- England -- Nature. 2010 Aug 12;466(7308):869-73. doi: 10.1038/nature09208. Epub 2010 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, 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/20668451" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/classification/genetics ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; Female ; GTP-Binding Protein alpha Subunits/genetics ; Genes, Neoplasm/*genetics ; Humans ; Lung Neoplasms/classification/genetics ; MAP Kinase Kinase 4/genetics ; Male ; Mutation/*genetics ; Neoplasms/enzymology/*genetics/*metabolism/pathology ; Ovarian Neoplasms/classification/genetics ; Prostatic Neoplasms/classification/genetics ; Protein Kinases/genetics ; Receptors, G-Protein-Coupled/genetics ; Signal Transduction/*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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