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Pesquisa : D08.811.913.696.620.682.725.500 [Categoria DeCS]
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[PMID]:27777238
[Au] Autor:Tasian SK; Teachey DT; Li Y; Shen F; Harvey RC; Chen IM; Ryan T; Vincent TL; Willman CL; Perl AE; Hunger SP; Loh ML; Carroll M; Grupp SA
[Ad] Endereço:Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.
[Ti] Título:Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia.
[So] Source:Blood;129(2):177-187, 2017 01 12.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Philadelphia chromosome (Ph)-like B-cell acute lymphoblastic leukemia (Ph-like ALL) is associated with activated JAK/STAT, Abelson kinase (ABL), and/or phosphatidylinositol 3-kinase (PI3K) signaling and poor clinical outcomes. PI3K pathway signaling inhibitors have been minimally investigated in Ph-like ALL. We hypothesized that targeted inhibition of PI3Kα, PI3Kδ, PI3K/mTOR, or target of rapamycin complex 1/2 (TORC1/TORC2) would decrease leukemia proliferation and abrogate aberrant kinase signaling and that combined PI3K pathway and JAK inhibition or PI3K pathway and SRC/ABL inhibition would have superior efficacy compared to inhibitor monotherapy. We treated 10 childhood ALL patient-derived xenograft models harboring various Ph-like genomic alterations with 4 discrete PI3K pathway protein inhibitors and observed marked leukemia reduction and in vivo signaling inhibition in all models. Treatment with dual PI3K/mTOR inhibitor gedatolisib resulted in near eradication of ALL in cytokine receptor-like factor 2 (CRLF2)/JAK-mutant models with mean 92.2% (range, 86.0%-99.4%) reduction vs vehicle controls (P < .0001) and in prolonged animal survival. Gedatolisib also inhibited ALL proliferation in ABL/platelet-derived growth factor receptor (PDGFR)-mutant models with mean 66.9% (range, 42.0%-87.6%) reduction vs vehicle (P < .0001). Combined gedatolisib and ruxolitinib treatment of CRLF2/JAK-mutant models more effectively inhibited ALL proliferation than either inhibitor alone (P < .001) and further enhanced survival. Similarly, superior efficacy of combined gedatolisib and dasatinib was observed in ABL/PDGFR-mutant models (P < .001). Overall, PI3K/mTOR inhibition potently decreased ALL burden in vivo; antileukemia activity was further enhanced with combination inhibitor therapy. Clinical trials testing combinations of kinase inhibitors in Ph-like ALL patients are indicated.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
Inibidores de Proteínas Quinases/farmacologia
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Janus Quinases/antagonistas & inibidores
Camundongos
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores
Distribuição Aleatória
Serina-Treonina Quinases TOR/antagonistas & inibidores
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.10.2 (Janus Kinases); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-05-707653


  2 / 1413 MEDLINE  
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[PMID]:29232713
[Au] Autor:Cheong HSJ; VanBerkum MFA
[Ad] Endereço:Department of Biological Sciences, Wayne State University, Detroit, United States of America.
[Ti] Título:Long disordered regions of the C-terminal domain of Abelson tyrosine kinase have specific and additive functions in regulation and axon localization.
[So] Source:PLoS One;12(12):e0189338, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Abelson tyrosine kinase (Abl) is a key regulator of actin-related morphogenetic processes including axon guidance, where it functions downstream of several guidance receptors. While the long C-terminal domain (CTD) of Abl is required for function, its role is poorly understood. Here, a battery of mutants of Drosophila Abl was created that systematically deleted large segments of the CTD from Abl or added them back to the N-terminus alone. The functionality of these Abl transgenes was assessed through rescue of axon guidance defects and adult lethality in Abl loss-of-function, as well as through gain-of-function effects in sensitized slit or frazzled backgrounds that perturb midline guidance in the Drosophila embryonic nerve cord. Two regions of the CTD play important and distinct roles, but additive effects for other regions were also detected. The first quarter of the CTD, including a conserved PxxP motif and its surrounding sequence, regulates Abl function while the third quarter localizes Abl to axons. These regions feature long stretches of intrinsically disordered sequence typically found in hub proteins and are associated with diverse protein-protein interactions. Thus, the CTD of Abl appears to use these disordered regions to establish a variety of different signaling complexes required during formation of axon tracts.
[Mh] Termos MeSH primário: Axônios
Proteínas Proto-Oncogênicas c-abl/metabolismo
[Mh] Termos MeSH secundário: Animais
Drosophila/embriologia
Proteínas Proto-Oncogênicas c-abl/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189338


  3 / 1413 MEDLINE  
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[PMID]:29053950
[Au] Autor:Michnick SW
[Ad] Endereço:Département de Biochimie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada; Centre Robert-Cedergren, Bio-Informatique et Génomique, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC H3C 3J7, Canada. Electronic address: stephen.michnick@umontreal.ca.
[Ti] Título:More than One Way to Skin a Catalyst.
[So] Source:Cell Chem Biol;24(10):1196-1197, 2017 Oct 19.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this issue of Cell Chemical Biology, Diaz et al. (2017) report a strategy to achieve temporal, spatial, and stoichiometric control over the protein kinase cAbl in living cells. They achieve this by splitting cAbl into two inactive fragments that form an active kinase upon small molecule addition, potentially providing a general way to probe the wiring of signal transduction networks.
[Mh] Termos MeSH primário: Biocatálise
Engenharia de Proteínas
Proteínas Proto-Oncogênicas c-abl/metabolismo
[Mh] Termos MeSH secundário: Ativação Enzimática/efeitos dos fármacos
Células HeLa
Seres Humanos
Proteínas Proto-Oncogênicas c-abl/genética
Transdução de Sinais/efeitos dos fármacos
Quinases da Família src/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.10.2 (Proto-Oncogene Proteins c-abl); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE


  4 / 1413 MEDLINE  
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[PMID]:28945248
[Au] Autor:Saleh T; Rossi P; Kalodimos CG
[Ad] Endereço:Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
[Ti] Título:Atomic view of the energy landscape in the allosteric regulation of Abl kinase.
[So] Source:Nat Struct Mol Biol;24(11):893-901, 2017 Nov.
[Is] ISSN:1545-9985
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) synergistically generate a multilayered allosteric mechanism that enables Abl kinase to function as a finely tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effects of various activating or inhibiting stimuli on Abl kinase activity. The data provide a mechanistic basis explaining genetic observations and reveal a previously unknown activator region within Abl. Our findings show that drug-resistance mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.
[Mh] Termos MeSH primário: Proteínas Proto-Oncogênicas c-abl/química
Proteínas Proto-Oncogênicas c-abl/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Seres Humanos
Espectroscopia de Ressonância Magnética
Modelos Moleculares
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1038/nsmb.3470


  5 / 1413 MEDLINE  
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[PMID]:28919041
[Au] Autor:Diaz JE; Morgan CW; Minogue CE; Hebert AS; Coon JJ; Wells JA
[Ad] Endereço:Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
[Ti] Título:A Split-Abl Kinase for Direct Activation in Cells.
[So] Source:Cell Chem Biol;24(10):1250-1258.e4, 2017 Oct 19.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To dissect the cellular roles of individual kinases, it is useful to design tools for their selective activation. We describe the engineering of a split-cAbl kinase (sKin-Abl) that is rapidly activated in cells with rapamycin and allows temporal, dose, and compartmentalization control. Our design strategy involves an empirical screen in mammalian cells and identification of split site in the N lobe. This split site leads to complete loss of activity, which can be restored upon small-molecule-induced dimerization in cells. Remarkably, the split site is transportable to the related Src Tyr kinase and the distantly related Ser/Thr kinase, AKT, suggesting broader applications to kinases. To quantify the fold induction of phosphotyrosine (pTyr) modification, we employed quantitative proteomics, NeuCode SILAC. We identified a number of known Abl substrates, including autophosphorylation sites and novel pTyr targets, 432 pTyr sites in total. We believe that this split-kinase technology will be useful for direct activation of protein kinases in cells.
[Mh] Termos MeSH primário: Engenharia de Proteínas
Proteínas Proto-Oncogênicas c-abl/metabolismo
[Mh] Termos MeSH secundário: Ativação Enzimática/efeitos dos fármacos
Células HEK293
Seres Humanos
Fosforilação
Fosfotirosina/metabolismo
Proteínas Proto-Oncogênicas c-abl/genética
Sirolimo/farmacologia
Quinases da Família src/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
21820-51-9 (Phosphotyrosine); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl); EC 2.7.10.2 (src-Family Kinases); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE


  6 / 1413 MEDLINE  
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[PMID]:28891817
[Au] Autor:Nishi H; Furuhashi K; Cullere X; Saggu G; Miller MJ; Chen Y; Rosetti F; Hamilton SL; Yang L; Pittman SP; Liao J; Herter JM; Berry JC; DeAngelo DJ; Zhu C; Tsokos GC; Mayadas TN
[Ad] Endereço:Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
[Ti] Título:Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases.
[So] Source:J Clin Invest;127(10):3810-3826, 2017 Oct 02.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The kidney glomerular capillaries are frequent sites of immune complex deposition and subsequent neutrophil accumulation in post-infectious and rapidly progressive glomerulonephritis. However, the mechanisms of neutrophil recruitment remain enigmatic, and there is no targeted therapeutic to avert this proximal event in glomerular inflammation. The uniquely human activating Fc receptor FcγRIIA promotes glomerular neutrophil accumulation and damage in anti-glomerular basement membrane-induced (anti-GBM-induced) glomerulonephritis when expressed on murine neutrophils. Here, we found that neutrophils are directly captured by immobilized IgG antibodies under physiological flow conditions in vitro through FcγRIIA-dependent, Abl/Src tyrosine kinase-mediated F-actin polymerization. Biophysical measurements showed that the lifetime of FcγRIIA-IgG bonds increased under mechanical force in an F-actin-dependent manner, which could enable the capture of neutrophils under physiological flow. Kidney intravital microscopy revealed that circulating neutrophils, which were similar in diameter to glomerular capillaries, abruptly arrested following anti-GBM antibody deposition via neutrophil FcγRIIA and Abl/Src kinases. Accordingly, inhibition of Abl/Src with bosutinib reduced FcγRIIA-mediated glomerular neutrophil accumulation and renal injury in experimental, crescentic anti-GBM nephritis. These data identify a pathway of neutrophil recruitment within glomerular capillaries following IgG deposition that may be targeted by bosutinib to avert glomerular injury.
[Mh] Termos MeSH primário: Compostos de Anilina/farmacologia
Glomerulonefrite/imunologia
Imunoglobulina G/imunologia
Glomérulos Renais/imunologia
Neutrófilos/imunologia
Nitrilos/farmacologia
Quinolinas/farmacologia
Receptores de IgG/imunologia
[Mh] Termos MeSH secundário: Animais
Capilares/imunologia
Capilares/patologia
Glomerulonefrite/genética
Glomerulonefrite/patologia
Células HL-60
Seres Humanos
Glomérulos Renais/patologia
Camundongos
Camundongos Knockout
Neutrófilos/patologia
Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-abl/genética
Proteínas Proto-Oncogênicas c-abl/imunologia
Receptores de IgG/genética
Quinases da Família src/antagonistas & inibidores
Quinases da Família src/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (FCGR2A protein, human); 0 (Immunoglobulin G); 0 (Nitriles); 0 (Quinolines); 0 (Receptors, IgG); 5018V4AEZ0 (bosutinib); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE


  7 / 1413 MEDLINE  
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[PMID]:28842482
[Au] Autor:Li C; Park S; Zhang X; Eisenberg LM; Zhao H; Darzynkiewicz Z; Xu D
[Ad] Endereço:From the Department of Pathology.
[Ti] Título:Nuclear Gene 33/Mig6 regulates the DNA damage response through an ATM serine/threonine kinase-dependent mechanism.
[So] Source:J Biol Chem;292(40):16746-16759, 2017 Oct 06.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gene 33 (Mig6, ERRFI1) is an adaptor protein with multiple cellular functions. We recently linked Gene 33 to the DNA damage response (DDR) induced by hexavalent chromium (Cr(VI)), but the molecular mechanism remains unknown. Here we show that ectopic expression of Gene 33 triggers DDR in an ATM serine/threonine kinase (ATM)-dependent fashion and through pathways dependent or not dependent on ABL proto-oncogene 1 non-receptor tyrosine kinase (c-Abl). We observed the clear presence of Gene 33 in the nucleus and chromatin fractions of the cell. We also found that the nuclear localization of Gene 33 is regulated by its 14-3-3-binding domain and that the chromatin localization of Gene 33 is partially dependent on its ErbB-binding domain. Our data further indicated that Gene 33 may regulate the targeting of c-Abl to chromatin. Moreover, we observed a clear association of Gene 33 with histone H2AX and that ectopic expression of Gene 33 promotes the interaction between ATM and histone H2AX without triggering DNA damage. In summary, our results reveal nuclear functions of Gene 33 that regulate DDR. The nuclear localization of Gene 33 also provides a spatial explanation of the previously reported regulation of apoptosis by Gene 33 via the c-Abl/p73 pathway. On the basis of these findings and our previous studies, we propose that Gene 33 is a proximal regulator of DDR that promotes DNA repair.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/biossíntese
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo
Dano ao DNA/fisiologia
Regulação da Expressão Gênica/fisiologia
Histonas/metabolismo
Proteínas Supressoras de Tumor/biossíntese
[Mh] Termos MeSH secundário: Células A549
Proteínas Adaptadoras de Transdução de Sinal/genética
Proteínas Mutadas de Ataxia Telangiectasia/genética
Histonas/genética
Seres Humanos
Domínios Proteicos
Proteínas Proto-Oncogênicas c-abl/genética
Proteínas Proto-Oncogênicas c-abl/metabolismo
Receptor do Fator de Crescimento Epidérmico/genética
Receptor do Fator de Crescimento Epidérmico/metabolismo
Proteína Tumoral p73/genética
Proteína Tumoral p73/metabolismo
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Histones); 0 (MIG-6 protein, human); 0 (Tumor Protein p73); 0 (Tumor Suppressor Proteins); 0 (p73 protein, human); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl); EC 2.7.11.1 (ATM protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.803338


  8 / 1413 MEDLINE  
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[PMID]:28727765
[Au] Autor:O'Connell EM; Kamenyeva O; Lustigman S; Bell A; Nutman TB
[Ad] Endereço:Laboratory of Parasitic Diseases, Helminth Immunology Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America.
[Ti] Título:Defining the target and the effect of imatinib on the filarial c-Abl homologue.
[So] Source:PLoS Negl Trop Dis;11(7):e0005690, 2017 Jul.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Previously we demonstrated the micro- and macrofilaricidal properties of imatinib in vitro. Here we use electron and multiphoton microscopy to define the target of imatinib in the adult and microfilarial stages of Brugia malayi and assess the effects of pharmacologically relevant levels of imatinib on the adult parasites. METHODS: After fixation of adult B. malayi males and females, sections were stained with polyclonal rabbit anti-c-Abl antibody (or isotype control) and imaged with multiphoton fluorescent microscopy. Microfilariae were fixed and labeled with rabbit anti-c-Abl IgG primary antibody followed by anti-rabbit gold conjugated secondary antibody and imaged using transmission electron microscopy (TEM; immunoEM). In addition, adult B. malayi males and females were exposed to 0 or 10µM of imatinib for 7 days following which they were prepared for transmission electron microscopy (TEM) to assess the drug's effect on filarial ultrastructure. RESULTS: Fluorescent localization of anti-c-Abl antibody demonstrated widespread uptake in the adult filariae, but the most intense signal was seen in the reproductive organs, muscle, and intestine of both male and female worms. Fluorescence was significantly more intense in the early microfilarial stage (i.e. early morula) compared with later development stages (i.e. pretzel). Anti-c-Abl antibody in the microfilariae localized to the nuclei. Based on TEM assessment following imatinib exposure, imatinib appeared to be detrimental to embryogenesis in the adult female B. malayi. CONCLUSIONS: At pharmacologically achievable concentrations of imatinib, embryogenesis is impaired and possibly halted in adult filariae. Imatinib is likely a slow microfilaricide due to interference in intra-nuclear processes, which are slowly detrimental to the parasite and not immediately lethal, and thus may be used to lower the levels of L. loa microfilariae before they are treated within the context of conventional mass drug administration.
[Mh] Termos MeSH primário: Anti-Helmínticos/metabolismo
Antígenos de Helmintos/metabolismo
Brugia Malayi/efeitos dos fármacos
Mesilato de Imatinib/metabolismo
Inibidores de Proteínas Quinases/metabolismo
Proteínas Proto-Oncogênicas c-abl/metabolismo
[Mh] Termos MeSH secundário: Animais
Brugia Malayi/química
Brugia Malayi/crescimento & desenvolvimento
Brugia Malayi/ultraestrutura
Feminino
Masculino
Microscopia de Fluorescência
Microscopia Imunoeletrônica
Coelhos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Antigens, Helminth); 0 (Protein Kinase Inhibitors); 8A1O1M485B (Imatinib Mesylate); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005690


  9 / 1413 MEDLINE  
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[PMID]:28689759
[Au] Autor:Yoon J; Kim SB; Ahmed G; Shay JW; Terman JR
[Ad] Endereço:Departments of Neuroscience and Pharmacology, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
[Ti] Título:Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling.
[So] Source:Dev Cell;42(2):117-129.e8, 2017 Jul 24.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Extracellular cues that regulate cellular shape, motility, and navigation are generally classified as growth promoting (i.e., growth factors/chemoattractants and attractive guidance cues) or growth preventing (i.e., repellents and inhibitors). Yet, these designations are often based on complex assays and undefined signaling pathways and thus may misrepresent direct roles of specific cues. Here, we find that a recognized growth-promoting signaling pathway amplifies the F-actin disassembly and repulsive effects of a growth-preventing pathway. Focusing on Semaphorin/Plexin repulsion, we identified an interaction between the F-actin-disassembly enzyme Mical and the Abl tyrosine kinase. Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly. Genetic assays revealed that Abl allows growth factors and Semaphorin/Plexin repellents to combinatorially increase Mical-mediated F-actin disassembly, cellular remodeling, and repulsive axon guidance. Similar roles for Mical in growth factor/Abl-related cancer cell behaviors further revealed contexts in which characterized positive effectors of growth/guidance stimulate such negative cellular effects as F-actin disassembly/repulsion.
[Mh] Termos MeSH primário: Actinas/metabolismo
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Orientação de Axônios/efeitos dos fármacos
Biocatálise/efeitos dos fármacos
Fenômenos Biomecânicos
Moléculas de Adesão Celular/metabolismo
Proliferação Celular/efeitos dos fármacos
Drosophila melanogaster/embriologia
Drosophila melanogaster/metabolismo
Seres Humanos
Mesilato de Imatinib/farmacologia
Camundongos Nus
Oxigenases de Função Mista/química
Oxigenases de Função Mista/metabolismo
Modelos Biológicos
Neoplasias/patologia
Proteínas do Tecido Nervoso/metabolismo
Oxirredução
Fosforilação/efeitos dos fármacos
Ligação Proteica/efeitos dos fármacos
Domínios Proteicos
Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-abl/metabolismo
Semaforinas/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Cell Adhesion Molecules); 0 (Intercellular Signaling Peptides and Proteins); 0 (Nerve Tissue Proteins); 0 (Semaphorins); 0 (plexin); 8A1O1M485B (Imatinib Mesylate); EC 1.- (Mixed Function Oxygenases); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170711
[St] Status:MEDLINE


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[PMID]:28667884
[Au] Autor:Kim T; Tyndel MS; Zhang Z; Ahn J; Choi S; Szardenings M; Lipton JH; Kim HJ; Kim Dong Hwan D
[Ad] Endereço:Department of Computer Science, University of Toronto, Toronto, ON, Canada; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
[Ti] Título:Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy.
[So] Source:Leuk Res;59:142-148, 2017 Aug.
[Is] ISSN:1873-5835
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with ABL1 kinase domain (KD) mutations, but only around half of TKI non-responders have detectable ABL1 KD mutations. METHOD: We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without ABL1 KD mutations using whole-exome sequencing. RESULTS: In 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, and TP63. We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as DNMT3A and ASXL1 seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of ABL1 KD mutations. CONCLUSION: This study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking ABL1 KD mutations.
[Mh] Termos MeSH primário: DNA (Citosina-5-)-Metiltransferases/genética
Exoma/genética
Variação Genética
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética
Proteínas Repressoras/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos de Coortes
Progressão da Doença
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Seres Humanos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia
Masculino
Meia-Idade
Mutação
Inibidores de Proteínas Quinases/uso terapêutico
Proteínas Proto-Oncogênicas c-abl/genética
Análise de Sequência de DNA
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ASXL1 protein, human); 0 (Protein Kinase Inhibitors); 0 (Repressor Proteins); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); EC 2.1.1.37 (DNA methyltransferase 3A); EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170702
[St] Status:MEDLINE



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