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  • 1
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    Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-10-12
    Description: We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jun -- Huang, Wendong -- Chua, Steven S -- Wei, Ping -- Moore, David D -- R01 DK46546/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2002 Oct 11;298(5592):422-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12376703" target="_blank"〉PubMed〈/a〉
    Keywords: Acetaminophen/metabolism/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/metabolism/toxicity ; Androstanols/pharmacology ; Animals ; Aryl Hydrocarbon Hydroxylases/genetics/metabolism ; Benzoquinones/metabolism ; Cytochrome P-450 CYP1A2/genetics/metabolism ; Cytochrome P-450 CYP2E1/genetics/metabolism ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Glutathione/metabolism ; Glutathione S-Transferase pi ; Glutathione Transferase/genetics/metabolism ; Humans ; Imines/metabolism ; Isoenzymes/genetics/metabolism ; Liver/*drug effects/*metabolism/pathology ; Mice ; Mice, Knockout ; Mice, Transgenic ; Oxidoreductases, N-Demethylating/genetics/metabolism ; Phenobarbital/pharmacology ; Pyridines/pharmacology ; RNA, Messenger/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/agonists/antagonists & ; inhibitors/genetics/*metabolism ; Time Factors ; Transcription Factors/agonists/antagonists & inhibitors/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)
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  • 2
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    Migrastatin analogues target fascin to block tumour metastasis (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-04-16
    Description: Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857318/" 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/PMC2857318/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lin -- Yang, Shengyu -- Jakoncic, Jean -- Zhang, J Jillian -- Huang, Xin-Yun -- CA136837/CA/NCI NIH HHS/ -- R01 CA136837/CA/NCI NIH HHS/ -- R01 CA136837-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2010 Apr 15;464(7291):1062-6. doi: 10.1038/nature08978.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, Cornell University Weill Medical College, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20393565" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Animals ; Antineoplastic Agents/chemistry/metabolism/pharmacology/therapeutic use ; Binding Sites/drug effects ; Breast Neoplasms/drug therapy/pathology ; Carrier Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Crystallography, X-Ray ; Drug Resistance, Neoplasm/genetics ; Female ; Humans ; Lung Neoplasms/prevention & control/secondary ; Macrolides/*chemistry/metabolism/*pharmacology/therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Microfilament Proteins/*antagonists & inhibitors/chemistry/genetics/metabolism ; Models, Molecular ; Mutation/genetics ; Neoplasm Invasiveness/pathology/prevention & control ; Neoplasm Metastasis/drug therapy/pathology/*prevention & control ; Piperidones/*chemistry/metabolism/*pharmacology/therapeutic use ; Protein Conformation
    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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    Activating mutations in ALK provide a therapeutic target in neuroblastoma (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-17
    Description: Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587486/" 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/PMC2587486/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉George, Rani E -- Sanda, Takaomi -- Hanna, Megan -- Frohling, Stefan -- Luther, William 2nd -- Zhang, Jianming -- Ahn, Yebin -- Zhou, Wenjun -- London, Wendy B -- McGrady, Patrick -- Xue, Liquan -- Zozulya, Sergey -- Gregor, Vlad E -- Webb, Thomas R -- Gray, Nathanael S -- Gilliland, D Gary -- Diller, Lisa -- Greulich, Heidi -- Morris, Stephan W -- Meyerson, Matthew -- Look, A Thomas -- CA21765/CA/NCI NIH HHS/ -- CA69129/CA/NCI NIH HHS/ -- K08 NS047983/NS/NINDS NIH HHS/ -- K08 NS047983-03/NS/NINDS NIH HHS/ -- K08 NS047983-04/NS/NINDS NIH HHS/ -- K08 NS047983-05/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):975-8. doi: 10.1038/nature07397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923525" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Enzyme Activation/genetics ; Genome, Human/genetics ; Humans ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; Mice ; Mutation/*genetics ; Neuroblastoma/enzymology/*genetics/pathology/*therapy ; Polymorphism, Single Nucleotide/genetics ; Protein Structure, Tertiary/genetics ; Protein-Tyrosine Kinases/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Receptor Protein-Tyrosine Kinases ; Sequence Analysis, DNA
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-03
    Description: On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades. Recent studies have demonstrated specific functions for p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110beta (also known as Pik3cb), but not that of p110alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750091/" 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/PMC2750091/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jia, Shidong -- Liu, Zhenning -- Zhang, Sen -- Liu, Pixu -- Zhang, Lei -- Lee, Sang Hyun -- Zhang, Jing -- Signoretti, Sabina -- Loda, Massimo -- Roberts, Thomas M -- Zhao, Jean J -- P01 CA050661/CA/NCI NIH HHS/ -- P01 CA050661-200001/CA/NCI NIH HHS/ -- P01 CA089021/CA/NCI NIH HHS/ -- P01 CA089021-06A1/CA/NCI NIH HHS/ -- P50 CA089393/CA/NCI NIH HHS/ -- P50 CA089393-08S1/CA/NCI NIH HHS/ -- P50 CA090381/CA/NCI NIH HHS/ -- P50 CA090381-05/CA/NCI NIH HHS/ -- R01 CA030002/CA/NCI NIH HHS/ -- R01 CA030002-27/CA/NCI NIH HHS/ -- R01 CA134502/CA/NCI NIH HHS/ -- R01 CA134502-01/CA/NCI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):776-9. doi: 10.1038/nature07091. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594509" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Proliferation/drug effects ; *Cell Transformation, Neoplastic ; Epidermal Growth Factor/pharmacology ; Fibroblasts/cytology ; Glucose/*metabolism ; Glucose Intolerance/enzymology/genetics ; Homeostasis ; Humans ; Insulin/*metabolism/pharmacology ; Insulin Resistance/genetics ; Liver/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; PTEN Phosphohydrolase/deficiency/genetics ; Phosphatidylinositol 3-Kinases/deficiency/genetics/*metabolism ; Phosphorylation/drug effects ; Prostatic Neoplasms/enzymology/genetics/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-09-23
    Description: MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3' untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3' untranslated region.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tay, Yvonne -- Zhang, Jinqiu -- Thomson, Andrew M -- Lim, Bing -- Rigoutsos, Isidore -- AI54973/AI/NIAID NIH HHS/ -- DK47636/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1124-8. doi: 10.1038/nature07299. Epub 2008 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell and Developmental Biology, Genome Institute of Singapore, Agency for Science Technology and Research, #08-01, Genome, 60 Biopolis Street, Singapore 138672, Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18806776" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blotting, Western ; Cell Differentiation/*genetics ; Cell Line ; DNA-Binding Proteins/*genetics/metabolism ; Embryonic Stem Cells/*cytology/metabolism ; *Gene Expression Regulation, Developmental ; HMGB Proteins/*genetics/metabolism ; Homeodomain Proteins/*genetics/metabolism ; Mice ; MicroRNAs/*genetics/metabolism ; Mutation ; Octamer Transcription Factor-3/*genetics/metabolism ; Open Reading Frames/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; SOXB1 Transcription Factors ; Transcription Factors/*genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-04-11
    Description: The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucy, Teresa A -- Smith, Peter G -- Milhollen, Michael A -- Berger, Allison J -- Gavin, James M -- Adhikari, Sharmila -- Brownell, James E -- Burke, Kristine E -- Cardin, David P -- Critchley, Stephen -- Cullis, Courtney A -- Doucette, Amanda -- Garnsey, James J -- Gaulin, Jeffrey L -- Gershman, Rachel E -- Lublinsky, Anna R -- McDonald, Alice -- Mizutani, Hirotake -- Narayanan, Usha -- Olhava, Edward J -- Peluso, Stephane -- Rezaei, Mansoureh -- Sintchak, Michael D -- Talreja, Tina -- Thomas, Michael P -- Traore, Tary -- Vyskocil, Stepan -- Weatherhead, Gabriel S -- Yu, Jie -- Zhang, Julie -- Dick, Lawrence R -- Claiborne, Christopher F -- Rolfe, Mark -- Bolen, Joseph B -- Langston, Steven P -- England -- Nature. 2009 Apr 9;458(7239):732-6. doi: 10.1038/nature07884.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. teresa.soucy@mpi.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19360080" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cells, Cultured ; Cullin Proteins/metabolism ; Cyclopentanes/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Female ; Humans ; Mice ; Neoplasms/*drug therapy ; Proteasome Inhibitors ; Pyrimidines/*pharmacology ; Transplantation, Heterologous ; Ubiquitin-Activating Enzymes/*metabolism ; Ubiquitins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-09-17
    Description: Apoptosis and the subsequent clearance of dying cells occurs throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with DOCK1 and the GTPase RAC1, promotes internalization of the dying cells. Here we report the generation of ELMO1-deficient mice, which we found to be unexpectedly viable and grossly normal. However, they had a striking testicular pathology, with disrupted seminiferous epithelium, multinucleated giant cells, uncleared apoptotic germ cells and decreased sperm output. Subsequent in vitro and in vivo analyses revealed a crucial role for ELMO1 in the phagocytic clearance of apoptotic germ cells by Sertoli cells lining the seminiferous epithelium. The engulfment receptor BAI1 and RAC1 (upstream and downstream of ELMO1, respectively) were also important for Sertoli-cell-mediated engulfment. Collectively, these findings uncover a selective requirement for ELMO1 in Sertoli-cell-mediated removal of apoptotic germ cells and make a compelling case for a relationship between engulfment and tissue homeostasis in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773546/" 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/PMC3773546/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elliott, Michael R -- Zheng, Shuqiu -- Park, Daeho -- Woodson, Robin I -- Reardon, Michael A -- Juncadella, Ignacio J -- Kinchen, Jason M -- Zhang, Jun -- Lysiak, Jeffrey J -- Ravichandran, Kodi S -- R01 GM064709/GM/NIGMS NIH HHS/ -- R01 HD057242/HD/NICHD NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):333-7. doi: 10.1038/nature09356.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20844538" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Angiogenic Proteins/metabolism ; Animals ; *Apoptosis ; Cell Line ; Homeostasis ; Male ; Mice ; Mice, Inbred C57BL ; Neuropeptides/metabolism ; Phagocytosis/*physiology ; Phosphatidylserines/metabolism ; Seminiferous Epithelium/cytology/pathology ; Sertoli Cells/*cytology/*metabolism/pathology ; Signal Transduction ; Spermatozoa/*cytology/pathology ; rac GTP-Binding Proteins/metabolism ; rac1 GTP-Binding Protein
    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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    Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-15
    Description: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901986/" 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/PMC2901986/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jianming -- Adrian, Francisco J -- Jahnke, Wolfgang -- Cowan-Jacob, Sandra W -- Li, Allen G -- Iacob, Roxana E -- Sim, Taebo -- Powers, John -- Dierks, Christine -- Sun, Fangxian -- Guo, Gui-Rong -- Ding, Qiang -- Okram, Barun -- Choi, Yongmun -- Wojciechowski, Amy -- Deng, Xianming -- Liu, Guoxun -- Fendrich, Gabriele -- Strauss, Andre -- Vajpai, Navratna -- Grzesiek, Stephan -- Tuntland, Tove -- Liu, Yi -- Bursulaya, Badry -- Azam, Mohammad -- Manley, Paul W -- Engen, John R -- Daley, George Q -- Warmuth, Markus -- Gray, Nathanael S -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-03/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jan 28;463(7280):501-6. doi: 10.1038/nature08675. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072125" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*chemistry/metabolism/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Benzamides ; Binding Sites ; Bone Marrow Transplantation ; Cell Line, Tumor ; Crystallization ; Disease Models, Animal ; Drug Resistance, Neoplasm/*drug effects ; Female ; Fusion Proteins, bcr-abl/*chemistry/genetics/metabolism ; Humans ; Imatinib Mesylate ; Inhibitory Concentration 50 ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug ; therapy/enzymology/*metabolism ; Male ; Mass Spectrometry ; Mice ; Models, Molecular ; Mutation/genetics ; Piperazines/chemistry/pharmacology ; Protein Structure, Tertiary ; Pyrimidines/chemistry/metabolism/pharmacology ; Transplantation, Heterologous
    Print ISSN: 0028-0836
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  • 9
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    RAF inhibitors that evade paradoxical MAPK pathway activation (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-10-16
    Description: Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chao -- Spevak, Wayne -- Zhang, Ying -- Burton, Elizabeth A -- Ma, Yan -- Habets, Gaston -- Zhang, Jiazhong -- Lin, Jack -- Ewing, Todd -- Matusow, Bernice -- Tsang, Garson -- Marimuthu, Adhirai -- Cho, Hanna -- Wu, Guoxian -- Wang, Weiru -- Fong, Daniel -- Nguyen, Hoa -- Shi, Songyuan -- Womack, Patrick -- Nespi, Marika -- Shellooe, Rafe -- Carias, Heidi -- Powell, Ben -- Light, Emily -- Sanftner, Laura -- Walters, Jason -- Tsai, James -- West, Brian L -- Visor, Gary -- Rezaei, Hamid -- Lin, Paul S -- Nolop, Keith -- Ibrahim, Prabha N -- Hirth, Peter -- Bollag, Gideon -- England -- Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466569" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Female ; Genes, ras/genetics ; Heterocyclic Compounds, 2-Ring/adverse effects/pharmacology ; Humans ; Indoles/adverse effects/pharmacology ; MAP Kinase Signaling System/*drug effects/genetics ; Mice ; Mitogen-Activated Protein Kinases/*metabolism ; Models, Biological ; Mutation/genetics ; Protein Kinase Inhibitors/adverse effects/*pharmacology ; Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics ; Sulfonamides/adverse effects/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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  • 10
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    Rab35 controls actin bundling by recruiting fascin as an effector protein (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-09-05
    Description: Actin filaments are key components of the eukaryotic cytoskeleton that provide mechanical structure and generate forces during cell shape changes, growth, and migration. Actin filaments are dynamically assembled into higher-order structures at specified locations to regulate diverse functions. The Rab family of small guanosine triphosphatases is evolutionarily conserved and mediates intracellular vesicle trafficking. We found that Rab35 regulates the assembly of actin filaments during bristle development in Drosophila and filopodia formation in cultured cells. These effects were mediated by the actin-bundling protein fascin, which directly associated with active Rab35. Targeting Rab35 to the outer mitochondrial membrane triggered actin recruitment, demonstrating a role for an intracellular trafficking protein in localized actin assembly.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jun -- Fonovic, Marko -- Suyama, Kaye -- Bogyo, Matthew -- Scott, Matthew P -- U54 RR020843/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2009 Sep 4;325(5945):1250-4. doi: 10.1126/science.1174921.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19729655" target="_blank"〉PubMed〈/a〉
    Keywords: Actin Cytoskeleton/*metabolism/ultrastructure ; Actins/*metabolism ; Animals ; Carrier Proteins/*metabolism ; Cell Line ; Cell Membrane/metabolism ; Drosophila/anatomy & histology/growth & development/metabolism ; Drosophila Proteins/genetics/*metabolism ; HeLa Cells ; Humans ; Mice ; Microfilament Proteins/*metabolism ; Mitochondrial Membranes/metabolism ; NIH 3T3 Cells ; Pseudopodia/metabolism/ultrastructure ; RNA Interference ; Recombinant Fusion Proteins/metabolism ; rab GTP-Binding Proteins/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)
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