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  • 1
    Keywords: HUMAN-BREAST ; MEDIA ; MMP-9 ; tumor microenvironment ; E ; THERAPIES ; SERUM ; PROGRESSION ; prevention ; BREAST-CANCER ; breast cancer ; culture ; BREAST ; microenvironment ; CANCER-CELLS ; SERA ; THERAPY ; human ; tumor ; CELL ; CANCER ; CANCER CELLS ; CELLS
    Type of Publication: Book chapter
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  • 2
    Keywords: ALPHA ; p53 ; CRYSTAL-STRUCTURE ; MULTIPLE SEQUENCE ALIGNMENT ; SUBSTRATE ; HEPATITIS-C-VIRUS ; GENOTYPE 1 INFECTION ; TRANSACTIVATION DOMAIN ; HOMOLOGOUS PROTEINS ; NS5A
    Abstract: ABSTRACT: BACKGROUND: Interaction of non-structural protein 5A (NS5A) of Hepatitis C virus (HCV) with human kinases namely, casein kinase 1alpha (ck1alpha) and protein kinase R (PKR) have different functional implications such as regulation of viral replication and evasion of interferon induced immune response respectively. Understanding the structural and molecular basis of interactions of the viral protein with two different human kinases can be useful in developing strategies for treatment against HCV. RESULTS: Serine 232 of NS5A is known to be phosphorylated by human ck1alpha. A structural model of NS5A peptide containing phosphoacceptor residue Serine 232 bound to ck1alpha has been generated using the known 3-D structures of kinase-peptide complexes. The substrate interacting residues in ck1alpha has been identified from the model and these are found to be conserved well in the ck1 family. ck1alpha - substrate peptide complex has also been used to understand the structural basis of association between ck1alpha and its other viral stress induced substrate, tumour suppressor p53 transactivation domain which has a crystal structure available.Interaction of NS5A with another human kinase PKR is primarily genotype specific. NS5A from genotype 1b has been shown to interact and inhibit PKR whereas NS5A from genotype 2a/3a are unable to bind and inhibit PKR efficiently. This is one of the main reasons for the varied response to interferon therapy in HCV patients across different genotypes. Using PKR crystal structure, sequence alignment and evolutionary trace analysis some of the critical residues responsible for the interaction of NS5A 1b with PKR have been identified. CONCLUSIONS: The substrate interacting residues in ck1alpha have been identified using the structural model of kinase - substrate peptide. The PKR interacting NS5A 1b residues have also been predicted using PKR crystal structure, NS5A sequence analysis along with known experimental results. Functional significance and nature of interaction of interferon sensitivity determining region and variable region 3 of NS5A in different genotypes with PKR which was experimentally shown are also supported by the findings of evolutionary trace analysis. Designing inhibitors to prevent this interaction could enable the HCV genotype 1 infected patients respond well to interferon therapy.
    Type of Publication: Journal article published
    PubMed ID: 23148689
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  • 3
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; proliferation ; SURVIVAL ; tumor ; CELL ; human ; KINASE ; PATHWAY ; PATHWAYS ; SUPPORT ; EXPOSURE ; SITE ; DIFFERENTIATION ; MONOCLONAL-ANTIBODY ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; BINDING ; PHOSPHORYLATION ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; antibodies ; MEMBRANE ; METASTASIS ; REGION ; CANCER-CELLS ; EXTRACELLULAR-MATRIX ; BETA ; ADHESION ; MIGRATION ; FACTOR-KAPPA-B ; INTEGRIN ; NF-kappa B ; RECEPTORS ; MMP ; FIBRONECTIN ; TUMOR-METASTASIS ; SERUM ; FAMILIES ; basement membrane ; cell adhesion ; GELATINASE-A ; MMP-2 ; INTEGRINS ; RGD ; NUCLEAR ; EVENTS ; ERK ; MMP-9 ; pharmacology ; MT1-MMP ; TISSUE INHIBITOR ; ENGLAND ; matrix metalloproteinase ; MATRIX-METALLOPROTEINASE ; MEDICINE ; MEDIA ; interactions ; MT1-MMP MMP-14 ; PI-3K
    Abstract: Interactions between tumour cells and the extracellular matrix (ECM) strongly influence tumour development, affecting cell survival, proliferation and migration. Many of these interactions are mediated through a family of cell surface receptors named integrins. Fibronectin and its integrin receptors play important roles in tumour development. The alpha 5 beta 1 integrin interacts with the central cell adhesive region of fibronectin and requires both the RGD and synergy sites for maximal binding. Matrix metalloproteinases (MMPs) are a family of zinc dependent endopeptidases. They are capable of digesting the different components of the ECM and basement membrane. The ECM gives structural support to cells and plays a central role in cell adhesion, differentiation, proliferation and migration. Binding of ECM to integrins modulates expression and activity of the different MMPs. Our experimental findings demonstrate that cultivation of human breast cancer cells, MCF-7, in serum free medium in the presence of fibronectin upregulates the activity of MMP-2 and MMP-9. Blocking of alpha 5 beta 1 integrin with anti-alpha 5 monoclonal antibody inhibits the fibronectin-induced MMP activation response appreciably. This strongly indicates alpha 5 beta 1 mediated signalling events in activation of MMP-2 and MMP-9. Phosphorylation of FAK and PI-3 kinase and the nuclear translocation of ERK and NF-kappa B upon fibronectin binding demonstrate possible participation of the FAK/PI-3K/ERK signalling pathways in the regulation of MMP-2 activity. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18243246
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