A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
| Autor: | Daniel M. Trindade, Kathleen W. Kinnally, F O Nascimento Júnior, Antonio Carlos Borges, Enilza Maria Espreáfico, J F Sousa, Ana Paiva, Pablo M. Peixoto, D P S Leitão Mazzi, Cleidson de Pádua Alves, T C Izidoro-Toledo, E V Patussi, Daniela Dover de Araújo |
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| Rok vydání: | 2013 |
| Předmět: |
Cytoplasmic Dyneins
Cancer Research Skin Neoplasms Myosin Type V Immunology Dynein DLC1/DLC2 Apoptosis DNA Fragmentation Biology Mice Cellular and Molecular Neuroscience Cell Line Tumor Proto-Oncogene Proteins Bmf Myosin melanoma Animals Humans Myosin-Va Cytoskeleton Adaptor Proteins Signal Transducing Mice Knockout Bcl-2-Like Protein 11 Myosin Heavy Chains Activator (genetics) NEOPLASIAS CUTÂNEAS Membrane Proteins Cell Biology Fibroblasts Actin cytoskeleton Molecular biology Peptide Fragments Cell biology Gene Expression Regulation Neoplastic bcl-2 Homologous Antagonist-Killer Protein DNA fragmentation Original Article DLC1 Apoptosis Regulatory Proteins Neoplasm Transplantation Protein Binding Signal Transduction |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Cell Death & Disease |
| Popis: | Previous studies proposed that myosin-Va regulates apoptosis by sequestering pro-apoptotic Bmf to the actin cytoskeleton through dynein light chain-2 (DLC2). Adhesion loss or other cytoskeletal perturbations would unleash Bmf, allowing it to bind and inhibit pro-survival Bcl2 proteins. Here, we demonstrated that overexpression of a myosin-Va medial tail fragment (MVaf) harboring the binding site for DLC2 dramatically decreased melanoma cell viability. Morphological and molecular changes, including surface blebbing, mitochondrial outer membrane permeabilization, cytochrome-c and Smac release, as well as caspase-9/-3 activation and DNA fragmentation indicated that melanoma cells died of apoptosis. Immobilized MVaf interacted directly with DLCs, but complexed MVaf/DLCs did not interact with Bmf. Overexpression of DLC2 attenuated MVaf-induced apoptosis. Thus, we suggest that, MVaf induces apoptosis by sequestering DLC2 and DLC1, thereby unleashing the pair of sensitizer and activator BH3-only proteins Bmf and Bim. Murine embryonic fibroblasts (MEFs) lacking Bim and Bmf or Bax and Bak were less sensitive to apoptosis caused by MVaf expression than wild-type MEFs, strengthening the putative role of the intrinsic apoptotic pathway in this response. Finally, MVaf expression attenuated B16-F10 solid tumor growth in mice, suggesting that this peptide may be useful as an apoptosis-inducing tool for basic and translational studies. |
| Databáze: | OpenAIRE |
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