ALBERT

All Library Books, journals and Electronic Records Telegrafenberg

X
feed icon rss

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    facet.materialart.
    Unknown
    Polyubiquitination of p53 by a ubiquitin ligase activity of p300 (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-04-12
    Description: Rapid turnover of the tumor suppressor protein p53 requires the MDM2 ubiquitin ligase, and both interact with p300-CREB-binding protein transcriptional coactivator proteins. p53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grossman, Steven R -- Deato, Maria E -- Brignone, Chrystelle -- Chan, Ho Man -- Kung, Andrew L -- Tagami, Hideaki -- Nakatani, Yoshihiro -- Livingston, David M -- CA15751/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2003 Apr 11;300(5617):342-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12690203" target="_blank"〉PubMed〈/a〉
    Keywords: Adenovirus E1A Proteins/metabolism ; Animals ; Catalysis ; Cells, Cultured ; E1A-Associated p300 Protein ; Embryo, Mammalian ; Fibroblasts/metabolism ; Humans ; Ligases/antagonists & inhibitors/metabolism ; Mice ; Nuclear Proteins/antagonists & inhibitors/*metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-mdm2 ; Recombinant Fusion Proteins/metabolism ; Recombinant Proteins/metabolism ; Trans-Activators/antagonists & inhibitors/*metabolism ; Transfection ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*metabolism ; Ubiquitin-Protein Ligases ; Ubiquitins/*metabolism
    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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 2
    facet.materialart.
    Unknown
    Role of T-bet in commitment of TH1 cells before IL-12-dependent selection (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-06-09
    Description: How cytokines control differentiation of helper T (TH) cells is controversial. We show that T-bet, without apparent assistance from interleukin 12 (IL-12)/STAT4, specifies TH1 effector fate by targeting chromatin remodeling to individual interferon-gamma (IFN-gamma) alleles and by inducing IL-12 receptor beta2 expression. Subsequently, it appears that IL-12/STAT4 serves two essential functions in the development of TH1 cells: as growth signal, inducing survival and cell division; and as trans-activator, prolonging IFN-gamma synthesis through a genetic interaction with the coactivator, CREB-binding protein. These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullen, A C -- High, F A -- Hutchins, A S -- Lee, H W -- Villarino, A V -- Livingston, D M -- Kung, A L -- Cereb, N -- Yao, T P -- Yang, S Y -- Reiner, S L -- AI-42370/AI/NIAID NIH HHS/ -- EY-07131/EY/NEI NIH HHS/ -- New York, N.Y. -- Science. 2001 Jun 8;292(5523):1907-10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11397944" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; CREB-Binding Protein ; Cell Differentiation ; Cell Division ; Cell Lineage ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Histones/metabolism ; Interferon-gamma/*biosynthesis/genetics ; Interleukin-12/*metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Nuclear Proteins/metabolism ; RNA, Messenger/genetics/metabolism ; Receptors, Interleukin/metabolism ; Receptors, Interleukin-12 ; STAT4 Transcription Factor ; Signal Transduction ; T-Box Domain Proteins ; Th1 Cells/cytology/*immunology/metabolism ; Trans-Activators/metabolism ; Transcription Factors/genetics/*metabolism
    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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 3
    facet.materialart.
    Unknown
    Selective inhibition of BET bromodomains (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-09-28
    Description: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010259/" 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/PMC3010259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Filippakopoulos, Panagis -- Qi, Jun -- Picaud, Sarah -- Shen, Yao -- Smith, William B -- Fedorov, Oleg -- Morse, Elizabeth M -- Keates, Tracey -- Hickman, Tyler T -- Felletar, Ildiko -- Philpott, Martin -- Munro, Shonagh -- McKeown, Michael R -- Wang, Yuchuan -- Christie, Amanda L -- West, Nathan -- Cameron, Michael J -- Schwartz, Brian -- Heightman, Tom D -- La Thangue, Nicholas -- French, Christopher A -- Wiest, Olaf -- Kung, Andrew L -- Knapp, Stefan -- Bradner, James E -- 13058/Cancer Research UK/United Kingdom -- G0500905/Medical Research Council/United Kingdom -- G1000807/Medical Research Council/United Kingdom -- G9400953/Medical Research Council/United Kingdom -- K08 CA128972/CA/NCI NIH HHS/ -- K08 CA128972-03/CA/NCI NIH HHS/ -- T32-075762/PHS HHS/ -- Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Dec 23;468(7327):1067-73. doi: 10.1038/nature09504. Epub 2010 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20871596" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Azirines/chemical synthesis/chemistry/*pharmacology ; Binding Sites ; Carcinoma, Squamous Cell/physiopathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatin/metabolism ; Dihydropyridines/chemical synthesis/chemistry/*pharmacology ; Female ; Humans ; Mice ; Mice, Nude ; *Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/*antagonists & inhibitors/*metabolism ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; Sequence Alignment ; Skin Neoplasms/physiopathology ; Stereoisomerism ; Transcription Factors/*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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 4
    facet.materialart.
    Unknown
    Direct inhibition of the NOTCH transcription factor complex (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-11-13
    Description: Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951323/" 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/PMC2951323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moellering, Raymond E -- Cornejo, Melanie -- Davis, Tina N -- Del Bianco, Cristina -- Aster, Jon C -- Blacklow, Stephen C -- Kung, Andrew L -- Gilliland, D Gary -- Verdine, Gregory L -- Bradner, James E -- 5T32GM007598/GM/NIGMS NIH HHS/ -- N01-CO-12400/CO/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P01 CA119070-049001/CA/NCI NIH HHS/ -- R01 CA092433/CA/NCI NIH HHS/ -- R01 CA092433-06A2/CA/NCI NIH HHS/ -- R56 CA092433/CA/NCI NIH HHS/ -- R56 CA092433-06A1/CA/NCI NIH HHS/ -- T32 GM007598/GM/NIGMS NIH HHS/ -- T32 GM007598-30/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):182-8. doi: 10.1038/nature08543.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907488" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding, Competitive ; Cell Line, Tumor ; Cell Membrane Permeability ; Cell Proliferation/drug effects ; DNA-Binding Proteins/chemistry/metabolism ; Disease Models, Animal ; Drosophila Proteins/chemistry ; Gene Expression Regulation, Neoplastic/drug effects ; Genome/drug effects/genetics ; Humans ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/chemistry ; Peptides/chemical synthesis/chemistry/metabolism/*pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/pathology ; Protein Binding/drug effects ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptor, Notch1/*antagonists & inhibitors/chemistry/metabolism ; Signal Transduction/drug effects ; Substrate Specificity ; Transcription Factors/chemistry/metabolism ; Transcriptional Activation/*drug effects
    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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 5
    facet.materialart.
    Unknown
    Mediator kinase inhibition further activates super-enhancer-associated genes in AML (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-09-30
    Description: Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641525/" 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/PMC4641525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pelish, Henry E -- Liau, Brian B -- Nitulescu, Ioana I -- Tangpeerachaikul, Anupong -- Poss, Zachary C -- Da Silva, Diogo H -- Caruso, Brittany T -- Arefolov, Alexander -- Fadeyi, Olugbeminiyi -- Christie, Amanda L -- Du, Karrie -- Banka, Deepti -- Schneider, Elisabeth V -- Jestel, Anja -- Zou, Ge -- Si, Chong -- Ebmeier, Christopher C -- Bronson, Roderick T -- Krivtsov, Andrei V -- Myers, Andrew G -- Kohl, Nancy E -- Kung, Andrew L -- Armstrong, Scott A -- Lemieux, Madeleine E -- Taatjes, Dylan J -- Shair, Matthew D -- CA66996/CA/NCI NIH HHS/ -- F31 CA180419/CA/NCI NIH HHS/ -- P01 CA066996/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- R01 CA170741/CA/NCI NIH HHS/ -- T32 GM08759/GM/NIGMS NIH HHS/ -- UL1 TR001082/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Oct 8;526(7572):273-6. doi: 10.1038/nature14904. Epub 2015 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Chemistry and Biochemistry, University of Colorado, Campus Box 596, Boulder, Colorado 80303, USA. ; Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02215, USA. ; Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Martinsried, Germany. ; Max-Planck-Institut fur Biochemie, Am Kloperspitz 18, D-82152 Martinsried, Germany. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Cancer Biology and Genetics Program and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; Bioinfo, Plantagenet, Ontario K0B 1L0, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416749" target="_blank"〉PubMed〈/a〉
    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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 6
    facet.materialart.
    Unknown
    Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2004-09-09
    Description: BCL-2 family proteins constitute a critical control point for the regulation of apoptosis. Protein interaction between BCL-2 members is a prominent mechanism of control and is mediated through the amphipathic alpha-helical BH3 segment, an essential death domain. We used a chemical strategy, termed hydrocarbon stapling, to generate BH3 peptides with improved pharmacologic properties. The stapled peptides, called "stabilized alpha-helix of BCL-2 domains" (SAHBs), proved to be helical, protease-resistant, and cell-permeable molecules that bound with increased affinity to multidomain BCL-2 member pockets. A SAHB of the BH3 domain from the BID protein specifically activated the apoptotic pathway to kill leukemia cells. In addition, SAHB effectively inhibited the growth of human leukemia xenografts in vivo. Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360987/" 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/PMC1360987/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walensky, Loren D -- Kung, Andrew L -- Escher, Iris -- Malia, Thomas J -- Barbuto, Scott -- Wright, Renee D -- Wagner, Gerhard -- Verdine, Gregory L -- Korsmeyer, Stanley J -- K08 HL074049/HL/NHLBI NIH HHS/ -- K08HL074049/HL/NHLBI NIH HHS/ -- R37CA50239/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2004 Sep 3;305(5689):1466-70.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Pediatric Hematology/Oncology and Children's Hospital Boston, Massachusetts, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15353804" target="_blank"〉PubMed〈/a〉
    Keywords: *Alkenes ; Animals ; *Apoptosis ; BH3 Interacting Domain Death Agonist Protein ; Bridged Compounds/chemical synthesis/chemistry/metabolism/*pharmacology ; Carrier Proteins/chemistry ; Cell Division/drug effects ; Cell Line, Tumor ; Cell Membrane/metabolism ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Endosomes/metabolism ; Humans ; Jurkat Cells ; Leukemia, Experimental/*drug therapy/pathology ; Leukemic Infiltration ; Mice ; Mice, SCID ; Mitochondria, Liver/drug effects/metabolism ; *Molecular Mimicry ; Neoplasm Transplantation ; Peptide Fragments/*chemistry ; Peptides/chemical synthesis/chemistry/metabolism/*pharmacology ; Protein Binding ; Protein Engineering ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/*chemistry ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Transplantation, Heterologous
    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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 7
    facet.materialart.
    Unknown
    SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-03-04
    Description: The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076007/" 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/PMC3076007/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Inuzuka, Hiroyuki -- Shaik, Shavali -- Onoyama, Ichiro -- Gao, Daming -- Tseng, Alan -- Maser, Richard S -- Zhai, Bo -- Wan, Lixin -- Gutierrez, Alejandro -- Lau, Alan W -- Xiao, Yonghong -- Christie, Amanda L -- Aster, Jon -- Settleman, Jeffrey -- Gygi, Steven P -- Kung, Andrew L -- Look, Thomas -- Nakayama, Keiichi I -- DePinho, Ronald A -- Wei, Wenyi -- GM089763/GM/NIGMS NIH HHS/ -- R01 GM089763/GM/NIGMS NIH HHS/ -- R01 GM089763-01/GM/NIGMS NIH HHS/ -- R01 GM089763-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Mar 3;471(7336):104-9. doi: 10.1038/nature09732.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21368833" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Apoptosis/drug effects ; Benzenesulfonates/pharmacology ; Biphenyl Compounds/pharmacology ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line, Tumor ; F-Box Proteins/genetics/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mice ; Molecular Sequence Data ; Myeloid Cell Leukemia Sequence 1 Protein ; Niacinamide/analogs & derivatives ; Nitrophenols/pharmacology ; Phenylurea Compounds ; Phosphorylation ; Piperazines/pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors/*chemistry/*metabolism ; Pyridines/pharmacology ; SKP Cullin F-Box Protein Ligases/*chemistry/*metabolism ; Sulfonamides/pharmacology ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; *Ubiquitination/drug effects
    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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 8
    facet.materialart.
    Unknown
    A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-20
    Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" 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/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Combined Chemotherapy Protocols ; Benzimidazoles/*pharmacology/therapeutic use ; Biomarkers, Tumor/genetics/metabolism ; *Clinical Trials, Phase II as Topic ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Fluorodeoxyglucose F18 ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*drug therapy/enzymology/*genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mutation/genetics ; Pharmacogenetics/*methods ; Positron-Emission Tomography ; Protein-Serine-Threonine Kinases/deficiency/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Randomized Controlled Trials as Topic ; Reproducibility of Results ; Taxoids/*therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome ; ras Proteins/genetics/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)
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 9
    facet.materialart.
    Unknown
    CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53 (2009)
    National Academy of Sciences
    Details
    Publication Date: 2009-09-04
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
  • 10
    facet.materialart.
    Unknown
    Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal (2002)
    National Academy of Sciences
    Details
    Publication Date: 2002-10-23
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
    Location Call Number Expected Availability
    BibTip Others were also interested in ...
    PAPER CURRENT
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...