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  1. Article ; Online: Caffeine inhibits PI3K and mTORC2 in Dictyostelium and differentially affects multiple other cAMP chemoattractant signaling effectors.

    Tariqul Islam, A F M / Scavello, Margarethakay / Lotfi, Pouya / Daniel, Dustin / Haldeman, Pearce / Charest, Pascale G

    Molecular and cellular biochemistry

    2019  Volume 457, Issue 1-2, Page(s) 157–168

    Abstract: Caffeine is commonly used in Dictyostelium to inhibit the synthesis of the chemoattractant cAMP and, therefore, its secretion and the autocrine stimulation of cells, in order to prevent its interference with the study of chemoattractant-induced responses. ...

    Abstract Caffeine is commonly used in Dictyostelium to inhibit the synthesis of the chemoattractant cAMP and, therefore, its secretion and the autocrine stimulation of cells, in order to prevent its interference with the study of chemoattractant-induced responses. However, the mechanism through which caffeine inhibits cAMP synthesis in Dictyostelium has not been characterized. Here, we report the effects of caffeine on the cAMP chemoattractant signaling network. We found that caffeine inhibits phosphatidylinositol 3-kinase (PI3K) and mechanistic target of rapamycin complex 2 (mTORC2). Both PI3K and mTORC2 are essential for the chemoattractant-stimulated cAMP production, thereby providing a mechanism for the caffeine-mediated inhibition of cAMP synthesis. Our results also reveal that caffeine treatment of cells leads to an increase in cAMP-induced RasG and Rap1 activation, and inhibition of the PKA, cGMP, MyoII, and ERK1 responses. Finally, we observed that caffeine has opposite effects on F-actin and ERK2 depending on the assay and Dictyostelium strain used, respectively. Altogether, our findings reveal that caffeine considerably affects the cAMP-induced chemotactic signaling pathways in Dictyostelium, most likely acting through multiple targets that include PI3K and mTORC2.
    MeSH term(s) Caffeine/pharmacology ; Chemotaxis/drug effects ; Cyclic AMP/metabolism ; Dictyostelium/metabolism ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protozoan Proteins/metabolism ; Second Messenger Systems/drug effects
    Chemical Substances Protozoan Proteins ; Caffeine (3G6A5W338E) ; Cyclic AMP (E0399OZS9N) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1)
    Language English
    Publishing date 2019-03-16
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 184833-1
    ISSN 1573-4919 ; 0300-8177
    ISSN (online) 1573-4919
    ISSN 0300-8177
    DOI 10.1007/s11010-019-03520-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 892: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Protein kinase A regulates the Ras, Rap1 and TORC2 pathways in response to the chemoattractant cAMP in

    Scavello, Margarethakay / Petlick, Alexandra R / Ramesh, Ramya / Thompson, Valery F / Lotfi, Pouya / Charest, Pascale G

    Journal of cell science

    2017  Volume 130, Issue 9, Page(s) 1545–1558

    Abstract: Efficient directed migration requires tight regulation of chemoattractant signal transduction pathways in both space and time, but the mechanisms involved in such regulation are not well understood. Here, we investigated the role of protein kinase A (PKA) ...

    Abstract Efficient directed migration requires tight regulation of chemoattractant signal transduction pathways in both space and time, but the mechanisms involved in such regulation are not well understood. Here, we investigated the role of protein kinase A (PKA) in controlling signaling of the chemoattractant cAMP in
    MeSH term(s) Actins/metabolism ; Chemotactic Factors/pharmacology ; Chemotaxis ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Dictyostelium/cytology ; Dictyostelium/drug effects ; Dictyostelium/metabolism ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Models, Biological ; Myosins/metabolism ; Phenotype ; Protozoan Proteins/metabolism ; Signal Transduction/drug effects ; Time Factors ; rap1 GTP-Binding Proteins/metabolism ; ras Proteins/metabolism
    Chemical Substances Actins ; Chemotactic Factors ; Protozoan Proteins ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Myosins (EC 3.6.4.1) ; rap1 GTP-Binding Proteins (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2017-03-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.177170
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1200: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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    Zs.MG 14: Show issues

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  3. Article ; Online: The cAMP-induced G protein subunits dissociation monitored in live Dictyostelium cells by BRET reveals two activation rates, a positive effect of caffeine and potential role of microtubules.

    Tariqul Islam, A F M / Yue, Haicen / Scavello, Margarethakay / Haldeman, Pearce / Rappel, Wouter-Jan / Charest, Pascale G

    Cellular signalling

    2018  Volume 48, Page(s) 25–37

    Abstract: To study the dynamics and mechanisms controlling activation of the heterotrimeric G protein Gα2βγ in Dictyostelium in response to stimulation by the chemoattractant cyclic AMP (cAMP), we monitored the G protein subunit interaction in live cells using ... ...

    Abstract To study the dynamics and mechanisms controlling activation of the heterotrimeric G protein Gα2βγ in Dictyostelium in response to stimulation by the chemoattractant cyclic AMP (cAMP), we monitored the G protein subunit interaction in live cells using bioluminescence resonance energy transfer (BRET). We found that cAMP induces the cAR1-mediated dissociation of the G protein subunits to a similar extent in both undifferentiated and differentiated cells, suggesting that only a small number of cAR1 (as expressed in undifferentiated cells) is necessary to induce the full activation of Gα2βγ. In addition, we found that treating cells with caffeine increases the potency of cAMP-induced Gα2βγ activation; and that disrupting the microtubule network but not F-actin inhibits the cAMP-induced dissociation of Gα2βγ. Thus, microtubules are necessary for efficient cAR1-mediated activation of the heterotrimeric G protein. Finally, kinetics analyses of Gα2βγ subunit dissociation induced by different cAMP concentrations indicate that there are two distinct rates at which the heterotrimeric G protein subunits dissociate when cells are stimulated with cAMP concentrations above 500 nM versus only one rate at lower cAMP concentrations. Quantitative modeling suggests that the kinetics profile of Gα2βγ subunit dissociation results from the presence of both uncoupled and G protein pre-coupled cAR1 that have differential affinities for cAMP and, consequently, induce G protein subunit dissociation through different rates. We suggest that these different signaling kinetic profiles may play an important role in initial chemoattractant gradient sensing.
    MeSH term(s) Bioluminescence Resonance Energy Transfer Techniques ; Caffeine/pharmacology ; Chemotactic Factors/pharmacology ; Chemotaxis/physiology ; Cyclic AMP/metabolism ; Dictyostelium/metabolism ; Heterotrimeric GTP-Binding Proteins/metabolism ; Microtubules/metabolism ; Signal Transduction
    Chemical Substances Chemotactic Factors ; Caffeine (3G6A5W338E) ; Cyclic AMP (E0399OZS9N) ; Heterotrimeric GTP-Binding Proteins (EC 3.6.5.1)
    Language English
    Publishing date 2018-04-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 1002702-6
    ISSN 1873-3913 ; 0898-6568
    ISSN (online) 1873-3913
    ISSN 0898-6568
    DOI 10.1016/j.cellsig.2018.04.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2579: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Belinostat and vincristine demonstrate mutually synergistic cytotoxicity associated with mitotic arrest and inhibition of polyploidy in a preclinical model of aggressive diffuse large B cell lymphoma.

    Havas, Aaron P / Rodrigues, Kameron B / Bhakta, Anvi / Demirjian, Joseph A / Hahn, Seongmin / Tran, Jack / Scavello, Margarethakay / Tula-Sanchez, Ana A / Zeng, Yi / Schmelz, Monika / Smith, Catharine L

    Cancer biology & therapy

    2016  Volume 17, Issue 12, Page(s) 1240–1252

    Abstract: Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in ... ...

    Abstract Diffuse Large B-cell lymphoma (DLBCL) is an aggressive malignancy that has a 60 percent 5-year survival rate, highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics being clinically-evaluated in combination with a variety of other drugs. However, rational selection of companion therapeutics for HDACi is difficult due to their poorly-understood, cell-type specific mechanisms of action. To address this, we developed a pre-clinical model system of sensitivity and resistance to the HDACi belinostat using DLBCL cell lines. In the current study, we demonstrate that cell lines sensitive to the cytotoxic effects of HDACi undergo early mitotic arrest prior to apoptosis. In contrast, HDACi-resistant cell lines complete mitosis after a short delay and arrest in G1. To force mitotic arrest in HDACi-resistant cell lines, we used low dose vincristine or paclitaxel in combination with belinostat and observed synergistic cytotoxicity. Belinostat curtails vincristine-induced mitotic arrest and triggers a strong apoptotic response associated with downregulated MCL-1 expression and upregulated BIM expression. Resistance to microtubule targeting agents (MTAs) has been associated with their propensity to induce polyploidy and thereby increase the probability of genomic instability that enables cancer progression. Co-treatment with belinostat effectively eliminated a vincristine-induced, actively cycling polyploid cell population. Our study demonstrates that vincristine sensitizes DLBCL cells to the cytotoxic effects of belinostat and that belinostat prevents polyploidy that could cause vincristine resistance. Our findings provide a rationale for using low dose MTAs in conjunction with HDACi as a potential therapeutic strategy for treatment of aggressive DLBCL.
    MeSH term(s) Apoptosis/drug effects ; Cell Line, Tumor ; Cytotoxins/pharmacology ; Drug Evaluation, Preclinical ; Drug Synergism ; G2 Phase Cell Cycle Checkpoints/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Hydroxamic Acids/pharmacology ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Mitosis/drug effects ; Models, Biological ; Paclitaxel/pharmacology ; Polyploidy ; Sulfonamides/pharmacology ; Tubulin Modulators/pharmacology ; Up-Regulation ; Vincristine/pharmacology
    Chemical Substances Cytotoxins ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Sulfonamides ; Tubulin Modulators ; Vincristine (5J49Q6B70F) ; belinostat (F4H96P17NZ) ; Paclitaxel (P88XT4IS4D)
    Language English
    Publishing date 2016-10-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2146305-0
    ISSN 1555-8576 ; 1538-4047
    ISSN (online) 1555-8576
    ISSN 1538-4047
    DOI 10.1080/15384047.2016.1250046
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5887: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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