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  • 1
    Keywords: CELLS ; CELL ; Germany ; INHIBITION ; PROTEIN ; PROTEINS ; COMPLEX ; MECHANISM ; DOMAIN ; FORM ; PARTICLES ; DEGRADATION ; ANTIVIRAL ACTIVITY ; HIV-1 VIF ; LEUKEMIA-VIRUS ; VIF ; 2 DISTINCT ; ANTIRETROVIRAL DEFENSE ; CYTIDINE DEAMINASES ; EDITING ENZYME APOBEC3G ; MURINE APOBEC3 ; SOCS-BOX ; TYPE-1 VIF
    Abstract: The APOBEC3 cytidine deaminases are part of the intrinsic defense of cells against retroviruses. Lentiviruses and spumaviruses have evolved essential accessory proteins, Vif and Bet, respectively, which counteract the APOBEC3 proteins. We show here that Bet of the Prototype foamy virus inhibits the antiviral APOBEC3C activity by a mechanism distinct to Vif: Bet forms a complex with APOBEC3C without inducing its degradation. Bet abolished APOBEC3C dimerization as shown by co-immunoprecipitation and cross-linking experiments. These findings implicate a physical interaction between Bet and the APOBEC3C. Subsequently, we identified the Bet interaction domain in human APOBEC3C in the predicted APOBEC3C dimerization site. Taken together, these data support the hypothesis that Bet inhibits incorporation of APOBEC3Cs into retroviral particles. Bet likely achieves this by trapping APOBEC3C protein in complexes rendering them unavailable for newly generated viruses due to direct immobilization
    Type of Publication: Journal article published
    PubMed ID: 19074429
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  • 2
    Keywords: APOPTOSIS ; CELLS ; INHIBITOR ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; SUPPORT ; POPULATION ; PROTEIN ; PROTEINS ; ACTIVATION ; mechanisms ; BINDING ; ANTITUMOR-ACTIVITY ; ACID ; LYMPHOMA ; resistance ; BAX ; specificity ; HISTONE DEACETYLASE ; INHIBITORS ; LEUKEMIC-CELLS ; AGENT ; SINGLE ; TUMORIGENESIS ; HISTONE DEACETYLASE INHIBITORS ; valproic acid ; MCL-1 ; BCL-2 FAMILY-MEMBERS ; BH3 MIMETIC ABT-737 ; therapeutic
    Abstract: The apoptotic and therapeutic activities of the histone deacetylase inhibitor (HDACi) vorinostat are blocked by overexpresssion of Bcl-2 or Bcl-X-L. Herein, we used the small molecule inhibitor ABT-737 to restore sensitivity of E mu-myc lymphomas overexpressing Bcl-2 or Bcl-X-L to vorinostat and valproic acid (VPA). Combining low-dose ABT-737 with vorinostat or VPA resulted in synergistic apoptosis of these cells. ABT-737 was ineffective against E mu-myc/Mcl-1 and E mu-myc/A1 cells either as a single agent or in combination with HDACi. However, in contrast to the reported binding specificity data, E mu-myc/Bcl-w lymphomas were insensitive to ABT-737 used alone or in combination with HDACi, indicating that the regulatory activity of ABT-737 is restricted to Bcl-2 and Bcl-X-L. E mu-myc lymphomas that expressed Bcl-2 throughout the tumorigenesis process were especially sensitive to ABT-737, while those forced to overexpress Mcl-1 were not. This supports the notion that tumor cells "addicted" to ABT-737 target proteins (ie, Bcl-2 or Bcl-X-L) are likely to be the most sensitive target cell population. Our studies provide important preclinical data on the binding specificity of ABT-737 and its usefulness against primary hematologic malignancies when used as a single agent and in combination with HDACi. (Blood. 2009; 113: 1982-1991)
    Type of Publication: Journal article published
    PubMed ID: 19060243
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  • 3
    Keywords: RECEPTOR ; CELLS ; IN-VITRO ; CELL ; Germany ; MICROSCOPY ; VITRO ; imaging ; screening ; TOOL ; VISUALIZATION ; GENE ; GENOME ; PROTEIN ; PROTEINS ; LINES ; TRANSDUCTION ; gene transfer ; GENE-TRANSFER ; DOMAIN ; CONTRAST ; BINDING ; CELL-LINES ; CYCLE ; GLYCOPROTEIN ; PARTICLES ; TARGET ; virus ; IDENTIFICATION ; VECTOR ; PLASMA ; MEMBRANE ; CELL-LINE ; LINE ; REPLICATION ; INFECTIVITY ; GAG PROTEIN ; cell lines ; MEMBRANES ; ORIGIN ; FEATURES ; DETERMINANTS ; assembly ; plasma membrane ; TERMINUS ; RANGE ; COEXPRESSION ; Lead ; Type ; FAK ; RED FLUORESCENT PROTEIN ; TAG
    Abstract: Background: The foamy virus (FV) replication cycle displays several unique features, which set them apart from orthoretroviruses. First, like other B/D type orthoretroviruses, FV capsids preassemble at the centrosome, but more similar to hepadnaviruses, FV budding is strictly dependent on cognate viral glycoprotein coexpression. Second, the unusually broad host range of FV is thought to be due to use of a very common entry receptor present on host cell plasma membranes, because all cell lines tested in vitro so far are permissive. Results: In order to take advantage of modern fluorescent microscopy techniques to study FV replication, we have created FV Gag proteins bearing a variety of protein tags and evaluated these for their ability to support various steps of FV replication. Addition of even small N-terminal HA-tags to FV Gag severely impaired FV particle release. For example, release was completely abrogated by an N-terminal autofluorescent protein (AFP) fusion, despite apparently normal intracellular capsid assembly. In contrast, C-terminal Gag-tags had only minor effects on particle assembly, egress and particle morphogenesis. The infectivity of C-terminal capsid-tagged FV vector particles was reduced up to 100-fold in comparison to wild type; however, infectivity was rescued by coexpression of wild type Gag and assembly of mixed particles. Specific dose-dependent binding of fluorescent FV particles to target cells was demonstrated in an Env-dependent manner, but not binding to target cell-extracted- or synthetic-lipids. Screening of target cells of various origins resulted in the identification of two cell lines, a human erythroid precursor- and a zebrafish- cell line, resistant to FV Env-mediated FV- and HIV-vector transduction. Conclusions: We have established functional, autofluorescent foamy viral particles as a valuable new tool to study FV host cell interactions using modern fluorescent imaging techniques. Furthermore, we succeeded for the first time in identifying two cell lines resistant to Prototype Foamy Virus Env-mediated gene transfer. Interestingly, both cell lines still displayed FV Env-dependent attachment of fluorescent retroviral particles, implying a post-binding block potentially due to lack of putative FV entry cofactors. These cell lines might ultimately lead to the identification of the currently unknown ubiquitous cellular entry receptor(s) of FVs
    Type of Publication: Journal article published
    PubMed ID: 20478027
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; AGENTS ; CELL ; CLINICAL-TRIAL ; MODEL ; PATHWAYS ; SUPPORT ; DEATH ; GENE ; GENES ; PROTEIN ; PROTEINS ; DRUG ; RESPONSES ; T cell ; T-CELL ; ACID ; TARGET ; MOUSE ; TRIAL ; TRIALS ; LYMPHOMA ; MALIGNANCIES ; DIFFERENCE ; CELL-DEATH ; NUMBER ; CLINICAL-TRIALS ; MOUSE MODEL ; OVEREXPRESSION ; CANCER-THERAPY ; B-CELL LYMPHOMA ; Bcl-2 ; INHIBITORS ; AGENT ; molecular ; ONCOLOGY ; RE ; T-CELL LYMPHOMA ; USA ; DRUGS ; cancer research ; B-CELL ; clinical trial ; DEPSIPEPTIDE ; HUMAN LEUKEMIA-CELLS
    Abstract: Histone deacetylase inhibitors (HDACi) are compounds that target the epigenome and cause tumor cell-selective apoptosis. A large number of these agents that have different chemical structures and can target multiple HDACs are being testing in clinical trials and vorinostat is now an approved drug for the treatment of cutaneous T-cell lymphoma. Although these agents are showing promise for the treatment of hematologic malignancies, it is possible that different drugs may have different mechanistic, biological, and therapeutic activities. When comparing an HDACi belonging to the hydroxamic acid class of compounds (vorinostat) with a cyclic tetrapeptide (romidepsin), we showed that these agents regulate the expression of a common set of cellular genes, but certain genes specifically responded to each agent. Using the E mu-myc mouse model of B-cell lymphoma, we showed previously that overexpression of the prosurvival proteins Bcl-2 and Bcl-X-L inhibited the apoptotic and therapeutic activities of the vorinostat. Herein, we compared and contrasted the apoptotic-inducing activities of the hydroxamic acid oxamflatin with romidepsin. Like vorinostat, oxamflatin was unable to kill lymphomas overexpressing Bcl-2 and Bcl-X-L, indicating that these proteins can generally protect cells against this class of HDACi. In contrast, romidepsin was able to induce apoptosis in lymphomas overexpressing Bcl-2 with delayed kinetics of cell death and could mediate therapeutic responses against these lymphomas. However, romidepsin was inactive when Bcl-X-L was overexpressed. These data provide strong support that HDACi of different chemical classes may have subtle yet potentially important differences in their molecular and biological activities
    Type of Publication: Journal article published
    PubMed ID: 18483296
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