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  • 1
    Online Resource
    Online Resource
    IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 9 ( 2008-11-01), p. 3818-3826
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 9 ( 2008-11-01), p. 3818-3826
    Abstract: Follicular lymphoma (FL) is characterized by constitutive expression of Bcl-2 as a consequence of t(14;18). Evidence suggests factors in the lymph node microenvironment, related to intratumoral T cells, macrophages, and dendritic cells, play a role in the disease process. We generated proteomic cytokine profiles of FL (N = 50) and follicular hyperplasia (FH; N = 23). A total of 10 cytokines were assayed using ultrasensitive multiplex enzyme-linked immunosorbent assays: IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-13, IL-12p70, tumor necrosis factor-α, and interferon-γ. Each cytokine showed overall lower protein concentrations in FL, with the exception of IL-4, which was nearly 5 times higher in FL than FH (P = .005). Using reverse-phase protein microarrays (RPMAs), we evaluated the activation state of several intracellular signaling proteins downstream of cytokine receptors. Basal Erk phosphorylation was approximately 4 times greater in FL than FH (P 〈 .001), with similar findings for Mek; Stat-6 showed weak basal phosphorylation that was approximately twice as high in FL than in FH (P = .012). In conclusion, the FL microenvironment contains increased levels of IL-4, with prominent tumor basal phosphorylation of Erk. These findings suggest IL-4, Erk, and possibly Stat-6 may play a role in the biology of FL and may serve as targets for future therapies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-02-138933
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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    detail.hit.zdb_id: 80069-7
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  • 2
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    Novel point mutations attenuate autotaxin activity
    Springer Science and Business Media LLC ; 2009
    In:  Lipids in Health and Disease Vol. 8, No. 1 ( 2009-12)
    Details
    In: Lipids in Health and Disease, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2009-12)
    Abstract: The secreted enzyme autotaxin (ATX) stimulates tumor cell migration, tumorigenesis, angiogenesis, and metastasis. ATX hydrolyzes nucleotides, but its hydrolysis of lysophospholipids to produce lysophosphatidic acid (LPA) accounts for its biological activities. ATX has been identified only as a constitutively active enzyme, and regulation of its activity is largely unexplored. In spite of its presence in plasma along with abundant putative substrate LPC, the product LPA is found in plasma at unexpectedly low concentrations. It is plausible that the LPA-producing activity of ATX is regulated by its expression and by access to substrate(s). For this reason studying the interaction of enzyme with substrate is paramount to understanding the regulation of LPA production. Results In this study we determine ATX hydrolytic activities toward several artificial and natural substrates. Two novel point mutations near the enzyme active site (H226Q and H434Q) confer attenuated activity toward all substrates tested. The Vmax for LPC compounds depends upon chain length and saturation; but this order does not differ among wild type and mutants. However the mutant forms show disproportionately low activity toward two artificial substrates, pNpTMP and FS-3. The mutant forms did not significantly stimulate migration responses at concentrations that produced a maximum response for WT-ATX, but this defect could be rescued by inclusion of exogenous LPC. Conclusion H226Q-ATX and H434Q-ATX are the first point mutations of ATX/NPP2 demonstrated to differentially impair substrate hydrolysis, with hydrolysis of artificial substrates being disproportionately lower than that of LPC. This implies that H226 and H434 are important for substrate interaction. Assays that rely on hydrolyses of artificial substrates (FS-3 and pNpTMP), or that rely on hydrolysis of cell-derived substrate, might fail to detect certain mutated forms of ATX that are nonetheless capable of producing LPA in the presence of sufficient exogenous substrate. H420Q-ATX could not be differentiated from WT-ATX, indicating that histidine at position 420 is not required for any of the activities of ATX tested in this study.
    Type of Medium: Online Resource
    ISSN: 1476-511X
    URL: Article
    DOI: 10.1186/1476-511X-8-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
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  • 3
    Online Resource
    Online Resource
    Dynamic Profiling of the Post-translational Modifications and Interaction Partners of Epidermal Growth Factor Receptor Signaling after Stimulation by Epidermal Growth Factor Using Extended Range Proteomic Analysis (ERPA)
    Elsevier BV ; 2006
    In:  Molecular & Cellular Proteomics Vol. 5, No. 9 ( 2006-09), p. 1610-1627
    Details
    In: Molecular & Cellular Proteomics, Elsevier BV, Vol. 5, No. 9 ( 2006-09), p. 1610-1627
    Type of Medium: Online Resource
    ISSN: 1535-9476
    URL: Article
    DOI: 10.1074/mcp.M600105-MCP200
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2006
    detail.hit.zdb_id: 2071375-7
    SSG: 12
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  • 4
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    Analysis of Albumin-Associated Peptides and Proteins from Ovarian Cancer Patients
    Oxford University Press (OUP) ; 2005
    In:  Clinical Chemistry Vol. 51, No. 10 ( 2005-10-01), p. 1933-1945
    Details
    In: Clinical Chemistry, Oxford University Press (OUP), Vol. 51, No. 10 ( 2005-10-01), p. 1933-1945
    Abstract: Background: Albumin binds low–molecular-weight molecules, including proteins and peptides, which then acquire its longer half-life, thereby protecting the bound species from kidney clearance. We developed an experimental method to isolate albumin in its native state and to then identify [mass spectrometry (MS) sequencing] the corresponding bound low–molecular-weight molecules. We used this method to analyze pooled sera from a human disease study set (high-risk persons without cancer, n= 40; stage I ovarian cancer, n = 30; stage III ovarian cancer, n = 40) to demonstrate the feasibility of this approach as a discovery method. Methods: Albumin was isolated by solid-phase affinity capture under native binding and washing conditions. Captured albumin-associated proteins and peptides were separated by gel electrophoresis and subjected to iterative MS sequencing by microcapillary reversed-phase tandem MS. Selected albumin-bound protein fragments were confirmed in human sera by Western blotting and immunocompetition. Results: In total, 1208 individual protein sequences were predicted from all 3 pools. The predicted sequences were largely fragments derived from proteins with diverse biological functions. More than one third of these fragments were identified by multiple peptide sequences, and more than one half of the identified species were in vivo cleavage products of parent proteins. An estimated 700 serum peptides or proteins were predicted that had not been reported in previous serum databases. Several proteolytic fragments of larger molecules that may be cancer-related were confirmed immunologically in blood by Western blotting and peptide immunocompetition. BRCA2, a 390-kDa low-abundance nuclear protein linked to cancer susceptibility, was represented in sera as a series of specific fragments bound to albumin. Conclusion: Carrier-protein harvesting provides a rich source of candidate peptides and proteins with potential diverse tissue and cellular origins that may reflect important disease-related information.
    Type of Medium: Online Resource
    ISSN: 0009-9147 , 1530-8561
    URL: Article
    DOI: 10.1373/clinchem.2005.052944
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2005
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  • 5
    Online Resource
    Online Resource
    L-histidine inhibits production of lysophosphatidic acid by the tumor-associated cytokine, autotaxin
    Springer Science and Business Media LLC ; 2005
    In:  Lipids in Health and Disease Vol. 4, No. 1 ( 2005-12)
    Details
    In: Lipids in Health and Disease, Springer Science and Business Media LLC, Vol. 4, No. 1 ( 2005-12)
    Abstract: Autotaxin (ATX, NPP-2), originally purified as a potent tumor cell motility factor, is now known to be the long-sought plasma lysophospholipase D (LPLD). The integrity of the enzymatic active site, including three crucial histidine moieties, is required for motility stimulation, as well as LPLD and 5'nucleotide phosphodiesterase (PDE) activities. Except for relatively non-specific chelation agents, there are no known inhibitors of the ATX LPLD activity. Results We show that millimolar concentrations of L-histidine inhibit ATX-stimulated but not LPA-stimulated motility in two tumor cell lines, as well as inhibiting enzymatic activities. Inhibition is reversed by 20-fold lower concentrations of zinc salt. L-histidine has no significant effect on the Km of LPLD, but reduces the Vmax by greater than 50%, acting as a non-competitive inhibitor. Several histidine analogs also inhibit the LPLD activity of ATX; however, none has greater potency than L-histidine and all decrease cell viability or adhesion. Conclusion L-histidine inhibition of LPLD is not a simple stoichiometric chelation of metal ions but is more likely a complex interaction with a variety of moieties, including the metal cation, at or near the active site. The inhibitory effect of L-histidine requires all three major functional groups of histidine: the alpha amino group, the alpha carboxyl group, and the metal-binding imidazole side chain. Because of LPA's involvement in pathological processes, regulation of its formation by ATX may give insight into possible novel therapeutic approaches.
    Type of Medium: Online Resource
    ISSN: 1476-511X
    URL: Article
    DOI: 10.1186/1476-511X-4-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2005
    detail.hit.zdb_id: 2091381-3
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  • 6
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    Drosophila screening model for metastasis: Semaphorin 5c is required for l(2)gl cancer phenotype
    Proceedings of the National Academy of Sciences ; 2003
    In:  Proceedings of the National Academy of Sciences Vol. 100, No. 20 ( 2003-09-30), p. 11463-11468
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 100, No. 20 ( 2003-09-30), p. 11463-11468
    Abstract: Cancer metastasis is a complex process involving many genes and pathways. This complexity hinders the identification of molecules functionally required for this process. We have developed and used a Drosophila screening system to identify genes that are functionally important for tumorigenicity and metastasis. Deletion of Drosophila lethal giant larvae ( l(2)gl ) leads to highly invasive and widely metastatic tumors on transplantation into adult flies. Random homozygous P element insertions were screened for the ability to modulate the l(2)gl phenotype. Analysis of metastasis patterns of the lines containing P element insertions and lacking wild-type l(2)gl expression identified three homozygous mutations that dramatically alter tumorigenesis and/or metastasis. Semaphorin 5c ( Sema 5c ) is required for tumorigenicity, apontic overexpression suppresses metastasis but not tumorigenicity, and pointed up-regulation accelerates lethality of l(2)gl tumors. Furthermore, class 5 semaphorins are shown to be expressed in cancer cells and localized to the membrane. Drosophila Sema-5c and the mammalian homologs are transmembrane proteins with extracellular thrombospondin type I (TspI) repeats. TspI repeats are known in some proteins to bind and activate transforming growth factor (TGF)-β ligand. Phospho-Mad and the downstream target gene vestigial were elevated in l(2)gl tumors, thus linking Drosophila neoplasia to the Dpp (TGF-β-like) signal pathway. The activation of the Dpp pathway in l(2)gl tumors occurred only in the presence of Sema-5c. This study demonstrates that the power of Drosophila genetics can be applied to screen, identify, and characterize molecules that are functionally required for invasion and metastasis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2031202100
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2003
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
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    Online Resource
    Sphingosine-1-phosphate initiates rapid retraction of pseudopodia by localized RhoA activation
    Elsevier BV ; 2007
    In:  Cellular Signalling Vol. 19, No. 6 ( 2007-06), p. 1328-1338
    Details
    In: Cellular Signalling, Elsevier BV, Vol. 19, No. 6 ( 2007-06), p. 1328-1338
    Type of Medium: Online Resource
    ISSN: 0898-6568
    URL: Article
    DOI: 10.1016/j.cellsig.2007.01.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
    detail.hit.zdb_id: 1496718-2
    SSG: 12
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  • 8
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    Online Resource
    Thrombospondin-1 regulates blood pressure and cardiac response
    Elsevier BV ; 2008
    In:  Matrix Biology Vol. 27 ( 2008-12), p. 32-
    Details
    In: Matrix Biology, Elsevier BV, Vol. 27 ( 2008-12), p. 32-
    Type of Medium: Online Resource
    ISSN: 0945-053X
    URL: Article
    DOI: 10.1016/j.matbio.2008.09.310
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 2005263-7
    SSG: 12
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  • 9
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    Online Resource
    Global Regulation of Promoter Melting in Naive Lymphocytes
    Elsevier BV ; 2013
    In:  Cell Vol. 153, No. 5 ( 2013-05), p. 988-999
    Details
    In: Cell, Elsevier BV, Vol. 153, No. 5 ( 2013-05), p. 988-999
    Type of Medium: Online Resource
    ISSN: 0092-8674
    URL: Article
    DOI: 10.1016/j.cell.2013.04.033
    RVK:
    XA 36269
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 187009-9
    detail.hit.zdb_id: 2001951-8
    SSG: 12
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  • 10
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    Positive Feedback between Vascular Endothelial Growth Factor-A and Autotaxin in Ovarian Cancer Cells
    American Association for Cancer Research (AACR) ; 2008
    In:  Molecular Cancer Research Vol. 6, No. 3 ( 2008-03-01), p. 352-363
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 6, No. 3 ( 2008-03-01), p. 352-363
    Abstract: Tumor cell migration, invasion, and angiogenesis are important determinants of tumor aggressiveness, and these traits have been associated with the motility stimulating protein autotaxin (ATX). This protein is a member of the ectonucleotide pyrophosphatase and phosphodiesterase family of enzymes, but unlike other members of this group, ATX possesses lysophospholipase D activity. This enzymatic activity hydrolyzes lysophosphatidylcholine to generate the potent tumor growth factor and motogen lysophosphatidic acid (LPA). In the current study, we show a link between ATX expression, LPA, and vascular endothelial growth factor (VEGF) signaling in ovarian cancer cell lines. Exogenous addition of VEGF-A to cultured cells induces ATX expression and secretion, resulting in increased extracellular LPA production. This elevated LPA, acting through LPA4, modulates VEGF responsiveness by inducing VEGF receptor (VEGFR)-2 expression. Down-regulation of ATX secretion in SKOV3 cells using antisense morpholino oligomers significantly attenuates cell motility responses to VEGF, ATX, LPA, and lysophosphatidylcholine. These effects are accompanied by decreased LPA4 and VEGFR2 expression as well as by increased release of soluble VEGFR1. Because LPA was previously shown to increase VEGF expression in ovarian cancer, our data suggest a positive feedback loop involving VEGF, ATX, and its product LPA that could affect tumor progression in ovarian cancer cells. (Mol Cancer Res 2008;6(3):352–63)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-07-0143
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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