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  1. Article ; Online: TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer.

    Hai, Josephine / Zhu, Chang-Qi / Wang, Tao / Organ, Shawna L / Shepherd, Frances A / Tsao, Ming-Sound

    Scientific reports

    2017  Volume 7, Page(s) 39692

    Abstract: Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for ... ...

    Abstract Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC. Little is known about the function of TRIM14 protein in normal or disease states. We investigated the functional and prognostic role of TRIM14 in NSCLC using in vitro and in vivo perturbation model systems. Firstly, a pooled RNAi screen identified TRIM14 to effect cell proliferation/survival in NSCLC cells. Secondly, silencing of TRIM14 expression significantly enhanced tumor growth in NSCLC xenograft mouse models, while exogenous TRIM14 expression attenuated tumorigenesis. In addition, differences in apoptotic activity between TRIM14-deficient and control tumors suggests that TRIM14 tumor suppressor activity may depend on cell death signaling pathways. TRIM14-deficient cell lines showed both resistance to hypoxia-induced cell death and attenuation of interferon response via STAT1 signaling. Consistent with these phenotypes, multivariate analyses on published mRNA expression datasets of over 600 primary NSCLCs demonstrated that low TRIM14 mRNA levels are significantly associated with poorer prognosis in early stage NSCLC patients. Our functional data therefore establish a novel tumor suppressive role for TRIM14 in NSCLC progression.
    MeSH term(s) Animals ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/immunology ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carrier Proteins/immunology ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Humans ; Immunity, Innate ; Mice, SCID ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; STAT1 Transcription Factor/metabolism ; Signal Transduction ; Xenograft Model Antitumor Assays
    Chemical Substances Carrier Proteins ; STAT1 Transcription Factor ; STAT1 protein, human ; TRIM14 protein, human ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2017-01-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/srep39692
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Quantitative phospho-proteomic profiling of hepatocyte growth factor (HGF)-MET signaling in colorectal cancer.

    Organ, Shawna L / Tong, Jiefei / Taylor, Paul / St-Germain, Jonathan R / Navab, Roya / Moran, Michael F / Tsao, Ming-Sound

    Journal of proteome research

    2011  Volume 10, Issue 7, Page(s) 3200–3211

    Abstract: Colorectal cancer (CRC) is the second leading cause of death from cancer. The MET receptor tyrosine kinase and/or its ligand HGF are frequently amplified or overexpressed in CRC. It is known that tyrosine phosphorylated proteins are involved in ... ...

    Abstract Colorectal cancer (CRC) is the second leading cause of death from cancer. The MET receptor tyrosine kinase and/or its ligand HGF are frequently amplified or overexpressed in CRC. It is known that tyrosine phosphorylated proteins are involved in progression and metastasis of colorectal cancer; however, little is known about the MET phospho-proteome in CRC. High resolution mass spectrometry was used to characterize immunoaffinity-purified, phosphotyrosine (pY)-containing tryptic peptides of the MET-expressing CRC cell model, DLD1. A total of 266 unambiguously identified pY sites spanning 168 proteins were identified. Quantification of mass spectrometry ion currents identified 161 pY sites, including many not previously linked to MET signaling, that were modulated in abundance by HGF stimulation. Overlay of these data with protein-protein interaction data sets suggested that many of the identified HGF-modulated phospho-proteins may be directly or indirectly associated with MET. Analysis of pY sequence motifs indicated a prevalence of Src family kinase consensus sequences, and reciprocal signaling between Src and MET was confirmed by using selective small molecule inhibitors of these kinases. Therefore, using quantitative phospho-proteomics profiling, kinase modulation by ligand and inhibitors, and data integration, an outline of the MET signaling network was generated for the CRC model.
    MeSH term(s) Blotting, Western ; Cell Line, Tumor ; Chromatography, Liquid ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Gene Expression ; Gene Expression Profiling ; Hepatocyte Growth Factor/pharmacology ; Humans ; Immunoprecipitation ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Phosphotyrosine/genetics ; Phosphotyrosine/metabolism ; Protein Binding/genetics ; Protein Interaction Mapping/methods ; Protein Kinase Inhibitors/pharmacology ; Proteome/genetics ; Proteome/metabolism ; Proteomics/methods ; Proto-Oncogene Proteins c-met/genetics ; Proto-Oncogene Proteins c-met/metabolism ; Signal Transduction/genetics ; Tandem Mass Spectrometry ; src-Family Kinases/genetics ; src-Family Kinases/metabolism
    Chemical Substances Phosphoproteins ; Protein Kinase Inhibitors ; Proteome ; Phosphotyrosine (21820-51-9) ; Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2011-07-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078618-9
    ISSN 1535-3907 ; 1535-3893
    ISSN (online) 1535-3907
    ISSN 1535-3893
    DOI 10.1021/pr200238t
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6189: Show issues Location:
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  3. Article ; Online: p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line.

    Organ, Shawna L / Hai, Josephine / Radulovich, Nikolina / Marshall, Christopher B / Leung, Lisa / Sasazuki, Takehiko / Shirasawa, Senji / Zhu, Chang-Qi / Navab, Roya / Ikura, Mitsuhiko / Tsao, Ming-Sound

    PloS one

    2014  Volume 9, Issue 1, Page(s) e86103

    Abstract: KRAS is mutated in ∼40% of colorectal cancer (CRC), and there are limited effective treatments for advanced KRAS mutant CRC. Therefore, it is crucial that downstream mediators of oncogenic KRAS continue to be studied. We identified p190RhoGAP as being ... ...

    Abstract KRAS is mutated in ∼40% of colorectal cancer (CRC), and there are limited effective treatments for advanced KRAS mutant CRC. Therefore, it is crucial that downstream mediators of oncogenic KRAS continue to be studied. We identified p190RhoGAP as being phosphorylated in the DLD1 CRC cell line, which expresses a heterozygous KRAS G13D allele, and not in DKO4 in which the mutant allele has been deleted by somatic recombination. We found that a ubiquitous binding partner of p190RhoGAP, p120RasGAP (RasGAP), is expressed in much lower levels in DKO4 cells compared to DLD1, and this expression is regulated by KRAS. Rescue of RasGAP expression in DKO4 rescued Rho pathway activation and partially rescued tumorigenicity in DKO4 cells, indicating that the combination of mutant KRAS and RasGAP expression is crucial to these phenotypes. We conclude that RasGAP is an important effector of mutant KRAS in CRC.
    MeSH term(s) Base Sequence ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Gene Expression Regulation, Neoplastic ; Guanine Nucleotide Exchange Factors/metabolism ; Humans ; Models, Biological ; Molecular Sequence Data ; Mutant Proteins/metabolism ; Mutation/genetics ; Phenotype ; Phosphorylation ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins p21(ras) ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Repressor Proteins/metabolism ; Signal Transduction ; Stress Fibers/metabolism ; p120 GTPase Activating Protein/genetics ; p120 GTPase Activating Protein/metabolism ; ras Proteins/genetics
    Chemical Substances ARHGAP35 protein, human ; Guanine Nucleotide Exchange Factors ; KRAS protein, human ; Mutant Proteins ; Proto-Oncogene Proteins ; RASA1 protein, human ; RNA, Messenger ; Repressor Proteins ; p120 GTPase Activating Protein ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2014-01-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0086103
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  4. Article ; Online: Discovery of a chemical probe for PRDM9.

    Allali-Hassani, Abdellah / Szewczyk, Magdalena M / Ivanochko, Danton / Organ, Shawna L / Bok, Jabez / Ho, Jessica Sook Yuin / Gay, Florence P H / Li, Fengling / Blazer, Levi / Eram, Mohammad S / Halabelian, Levon / Dilworth, David / Luciani, Genna M / Lima-Fernandes, Evelyne / Wu, Qin / Loppnau, Peter / Palmer, Nathan / Talib, S Zakiah A / Brown, Peter J /
    Schapira, Matthieu / Kaldis, Philipp / O'Hagan, Ronan C / Guccione, Ernesto / Barsyte-Lovejoy, Dalia / Arrowsmith, Cheryl H / Sanders, John M / Kattar, Solomon D / Bennett, D Jonathan / Nicholson, Benjamin / Vedadi, Masoud

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 5759

    Abstract: PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded ... ...

    Abstract PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC
    MeSH term(s) Crystallography, X-Ray ; DNA Methylation/drug effects ; Drug Discovery/methods ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HEK293 Cells ; Histone-Lysine N-Methyltransferase/antagonists & inhibitors ; Histone-Lysine N-Methyltransferase/metabolism ; Histone-Lysine N-Methyltransferase/ultrastructure ; Histones/metabolism ; Humans ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Molecular Probes/chemistry ; Molecular Probes/pharmacology ; Protein Domains ; S-Adenosylmethionine/metabolism
    Chemical Substances Enzyme Inhibitors ; Histones ; Molecular Probes ; histone H3 trimethyl Lys4 ; S-Adenosylmethionine (7LP2MPO46S) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; PRDM9 protein, human (EC 2.1.1.43)
    Language English
    Publishing date 2019-12-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-13652-x
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  5. Article ; Online: Src and FAK mediate cell-matrix adhesion-dependent activation of Met during transformation of breast epithelial cells.

    Hui, Angela Y / Meens, Jalna A / Schick, Colleen / Organ, Shawna L / Qiao, Hui / Tremblay, Eric A / Schaeffer, Erik / Uniyal, Shashi / Chan, Bosco M C / Elliott, Bruce E

    Journal of cellular biochemistry

    2009  Volume 107, Issue 6, Page(s) 1168–1181

    Abstract: Cell-matrix adhesion has been shown to promote activation of the hepatocyte growth factor receptor, Met, in a ligand-independent manner. This process has been linked to transformation and tumorigenesis in a variety of cancer types. In the present report, ...

    Abstract Cell-matrix adhesion has been shown to promote activation of the hepatocyte growth factor receptor, Met, in a ligand-independent manner. This process has been linked to transformation and tumorigenesis in a variety of cancer types. In the present report, we describe a key role of integrin signaling via the Src/FAK axis in the activation of Met in breast epithelial and carcinoma cells. Expression of an activated Src mutant in non-neoplastic breast epithelial cells or in carcinoma cells was found to increase phosphorylation of Met at regulatory tyrosines in the auto-activation loop domain, correlating with increased cell spreading and filopodia extensions. Furthermore, phosphorylated Met is complexed with beta1 integrins and is co-localized with vinculin and FAK at focal adhesions in epithelial cells expressing activated Src. Conversely, genetic or pharmacological inhibition of Src abrogates constitutive Met phosphorylation in carcinoma cells or epithelial cells expressing activated Src, and inhibits filopodia formation. Interestingly, Src-dependent phosphorylation of Met requires cell-matrix adhesion, as well as actin stress fiber assembly. Phosphorylation of FAK by Src is also required for Src-induced Met phosphorylation, emphasizing the importance of the Src/FAK signaling pathway. However, stimulation of Met phosphorylation by addition of exogenous HGF in epithelial cells is refractory to inhibition of Src family kinases, indicating that HGF-dependent and Src/integrin-dependent Met activation occur via distinct mechanisms. Together these findings demonstrate a novel mechanism by which the Src/FAK axis links signals from the integrin adhesion complex to promote Met activation in breast epithelial cells.
    MeSH term(s) Animals ; Cell Adhesion ; Cell Line, Tumor ; Cell Shape ; Cell Transformation, Neoplastic ; Epithelial Cells/pathology ; Female ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Integrins ; Mammary Neoplasms, Animal/pathology ; Mice ; Phosphorylation ; Proto-Oncogene Proteins c-met/metabolism ; Pseudopodia ; src-Family Kinases/metabolism
    Chemical Substances Integrins ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Focal Adhesion Protein-Tyrosine Kinases (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2009-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.22219
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