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  • 1
    Keywords: APOPTOSIS ; PROTEIN ; INDUCTION ; ASSOCIATION ; CERVICAL-CANCER ; p53 ; POSITIVE CANCER-CELLS ; NUCLEAR-LOCALIZATION ; E6-MEDIATED DEGRADATION ; AGGRESOMES
    Abstract: Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer and other malignancies in humans. The HPV E6 oncoprotein is considered to be an attractive therapeutic target since its inhibition can lead to the apoptotic cell death of HPV-positive cancer cells. The HPV type 16 (HPV16) E6-binding peptide pep11, and variants thereof, induce cell death specifically in HPV16-positive cancer cells. Although they do not encompass the LxxLL binding motif found in cellular HPV16 E6 interaction partners, such as E6AP, the pep11 variants strongly bind to HPV16 E6 by contacting the recently identified E6AP binding pocket. Thus, these peptides can serve as prototype E6-inhibitory molecules which target the E6AP pocket. We here analyzed their intracellular interaction with HPV16 E6. By comprehensive intracellular binding studies and GST pull-down assays, we show that E6-binding competent pep11 variants induce the formation of a trimeric complex, consisting of pep11, HPV16 E6 and p53. These findings indicate that peptides, which do not contain the LxxLL motif, can reshape E6 to enable its interaction with p53. The formation of the trimeric HPV16 E6 / peptide / p53 complex was associated with an increase of endogenous HPV16 E6 protein amounts. Yet, total cellular p53 amounts were also increased, indicating that the E6 / E6AP-mediated degradation of p53 is blocked. These findings suggest that inhibition of oncogenic activities by targeting the E6AP pocket on HPV16 E6 could be a strategy for therapeutic intervention.
    Type of Publication: Journal article published
    PubMed ID: 26151636
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  • 2
    Keywords: tumor ; SYSTEM ; ANTIGEN ; METASTATIC MELANOMA ; VACCINE ; PERIPHERAL-BLOOD ; CARCINOMA PATIENTS ; DOSE INTERLEUKIN-2 ; CLINICAL CANCER STAGE ; IV-MELANOMA
    Abstract: PURPOSE: To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen-specific T cells in patients with melanoma with distant metastasis. EXPERIMENTAL DESIGN: The percentage of CD14(+)CD11b(+)HLA-DR(-/low) MDSCs, CD4(+)CD25(+)FoxP3(+) Tregs, and the presence of NY-ESO-1- or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan-Meier and log-rank tests. Multivariate analyses were performed using Cox regression models. RESULTS: NY-ESO-1-specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of 〉11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P 〈 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs. CONCLUSIONS: Circulating CD14(+)CD11b(+)HLA-DR(-/low) MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches. Clin Cancer Res; 20(6); 1601-9. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 24323899
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  • 3
    Abstract: The HPV E6 oncoprotein maintains the malignant phenotype of HPV-positive cancer cells and represents an attractive therapeutic target. E6 forms a complex with the cellular E6AP ubiquitin ligase, ultimately leading to p53 degradation. The recently elucidated x-ray structure of a HPV16 E6/E6AP complex showed that HPV16 E6 forms a distinct binding pocket for E6AP. This discovery raises the question whether the E6AP binding pocket is druggable, i. e. whether it provides a docking site for functional E6 inhibitors. To address these issues, we performed a detailed analysis of the HPV16 E6 interactions with two small peptides: (i) E6APpep, corresponding to the E6 binding domain of E6AP, and (ii) pep11**, a peptide that binds to HPV16 E6 and, in contrast to E6APpep, induces apoptosis, specifically in HPV16-positive cancer cells. Surface plasmon resonance, NMR chemical shift perturbation, and mammalian two-hybrid analyses coupled to mutagenesis indicate that E6APpep contacts HPV16 E6 amino acid residues within the E6AP pocket, both in vitro and intracellularly. Many of these amino acids were also important for binding to pep11**, suggesting that the binding sites for the two peptides on HPV16 E6 overlap. Yet, few E6 amino acids were differentially involved which may contribute to the higher binding affinity of pep11**. Data from the HPV16 E6/pep11** interaction allowed the rational design of single amino acid exchanges in HPV18 and HPV31 E6 that enabled their binding to pep11**. Taken together, these results suggest that E6 molecular surfaces mediating E6APpep binding can also accommodate pro-apoptotic peptides that belong to different sequence families. As proof of concept, this study provides the first experimental evidence that the E6AP binding pocket is druggable, opening new possibilities for rational, structure-based drug design.
    Type of Publication: Journal article published
    PubMed ID: 25383876
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  • 4
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 62 (1993), S. 964-966 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The shift in the final state emission energy, resulting from selective pair luminescence in an applied magnetic field in GaAs, is very small. Any shift that is observed is toward lower energy. The relatively constant emission energy in the presence of an applied magnetic field is realized because the increase in band-gap energy, which would shift the emission toward higher energies, is offset by an increase in the donor binding energy which shifts the emission toward lower energies. The acceptor binding energy is essentially constant with applied field while the change in the Coulomb term, due to a change in the pair separation in a magnetic field, is quite small. As a result, the same acceptor excited states are identified in the presence of an applied magnetic field, as in zero field for the same pump energy. The results of this experiment are limited to applied fields ≤36 kG.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 62 (1993), S. 2608-2610 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We report the effects of heat treatment on sharp-line photoluminescence spectra from GaAs layers grown by low-temperature molecular beam epitaxy. The photoluminescence consists of no-phonon lines of three different centers and associated phonon sidebands of both lattice and localized vibrational modes. By considering the calculated values of local phonon modes, the photoluminescence features, and layer growth conditions, we attribute the three no-phonon lines to the nearest neighbor C3v-type arsenic interstitial complexes: Asin-VGa, Asin-CAs and Asin-AsGa. Heat treatments at 300–500 °C considerably increase the concentration of Asin, and thereby, of Asin-CAs and Asin-AsGa.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 61 (1992), S. 2317-2319 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Photoluminescence measurements were made at 2–300 K on GaSbAs-InAlAs single quantum wells lattice matched to InP grown by molecular beam epitaxy. The experimental exciton transition energy from the first electron subband to the first heavy hole subband was analyzed with calculated values obtained from the envelope function method. The quantum well exciton transition energy for well widths of 10–300 A(ring) is fitted to a large valence-band offset (ΔEv) of 0.93 ΔEg. The exciton linewidth increases with decreasing well width. The two dominant exciton line broadening mechanisms were found to be monolayer fluctuations of the well width and the band filling of electron.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 60 (1992), S. 2377-2379 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: The localized vibrational modes (LVMs) of silicon donor (SiGa) and aluminum isovalent (AlGa) impurities in molecular beam epitaxial GaAs layers grown at various temperatures are studied using the infrared absorption technique. It is found that the total integrated absorption of these impurities LVMs is decreased as the growth temperature decreases. This finding suggests a nonsubstitutional incorporation of Si and Al in GaAs layers grown at 200 °C. On the other hand, a subtitutional incorporation is obtained in GaAs layers grown at temperatures higher than 350 °C. A recovery of the SiGa LVMs in GaAs layers grown at 200 °C has not been achieved by thermal annealing.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 57 (1990), S. 2570-2572 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Previous attempts to passivate the n-type (100)GaAs surface have significantly reduced only the surface recombination centers, but not the surface acceptors which pin the Fermi level. Here we show that a 100 A(ring) molecular beam epitaxial layer grown at 200 °C reduces the effective surface potential energy − eφs from 0.70 to 0.17 eV, nearly eliminates light sensitivity, and permits nonalloyed ohmic contacts. After a 10 min, 450 °C anneal, − eφs increases only to 0.22 eV.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Molecular beam epitaxial GaAs layers of electron concentration 1.69×1017 cm−3, and various thicknesses d=0.25, 0.50, 1.00, and 2.00 μm, have been grown on semi-insulating GaAs substrates and characterized by the Hall effect and capacitance-voltage (C-V) techniques. A plot of sheet Hall concentration ns vs d gives accurate values of (ND−NA) and (ws+wi), the sum of the surface and interface free-carrier depletion widths, respectively. The C-V measurements verify the value of ND−NA, and also give a good estimate of wi. By comparing the value of wi with depletion theory, it is shown unambiguously that the interface depletion is mainly due to interface states, of concentration 1.2×1012 cm−2 (below midgap). This result has important technological implications.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Photocurrent spectra of InxGa1−xAs/GaAs multiple quantum well structures grown by molecular beam epitaxy are studied in the presence of electric fields perpendicular to the heterointerface. Several Δn=0 allowed and Δn≠0 forbidden excitonic transitions are observed. Both negative and positive shifts of exciton transitions are found. Good agreement is found between the photocurrent observations and calculations using a multiband effective-mass approach, taking into account the strain-induced splitting.
    Type of Medium: Electronic Resource
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