Buckley, CD and Pilling, D and Henriquez, NV and Parsonage, G and Threlfall, K and Scheel-Toellner, D and Simmons, DL and Akbar, AN and Lord, JM and Salmon, M (1999) RGD peptides induce apoptosis by direct caspase-3 activation. 534 - 539.
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|Title:||RGD peptides induce apoptosis by direct caspase-3 activation|
|Additional information:||Buckley, C D Pilling, D Henriquez, N V Parsonage, G Threlfall, K Scheel-Toellner, D Simmons, D L Akbar, A N Lord, J M Salmon, M Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England Nature Nature. 1999 Feb 11;397(6719):534-9. Synthetic peptides containing the arginine-glycine-aspartate (RGD) motif have been used extensively as inhibitors of integrin-ligand interactions in studies of cell adhesion, migration, growth and differentiation, because the RGD motif is an integrin-recognition motif found in many ligands. Here we report that RGD-containing peptides are able to directly induce apoptosis without any requirement for integrin-mediated cell clustering or signals. We show that RGD-containing peptides enter cells and directly induce autoprocessing and enzymatic activity of procaspase-3, a pro-apoptotic protein. Using the breast carcinoma cell line MCF-7, which has a functional deletion of the caspase-3 gene, we confirm that caspase-3 is required for RGD-mediated cell death. In addition to an RGD motif, pro-caspase-3 also contains a potential RGD-binding motif, aspartate-aspartate-methionine (DDM), near the site of processing to produce the p12 and p17 subunits. On the basis of the ability of RGD-DDX interactions to trigger integrin activation, we suggest that RGD peptides induce apoptosis by triggering conformational changes that promote pro-caspase-3 autoprocessing and activation. These findings provide an alternative molecular explanation for the potent proapoptotic properties of RGD peptides in models of angiogenesis, inflammation and cancer metastasis.|
|Keywords:||Amino Acid Sequence *Apoptosis Caspase 3 Caspases/genetics/*metabolism Cell Line Enzyme Activation Enzyme Precursors/metabolism Humans Integrins/metabolism Jurkat Cells Lymphocytes/cytology/drug effects Molecular Sequence Data Oligopeptides/*pharmacology Protein Processing, Post-Translational Tumor Cells, Cultured|
|UCL classification:||UCL > VP Enterprise|
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