A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells

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 demo...

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Bibliographic Details
Published in:Cell death & disease 2013-03, Vol.4 (3), p.e547
Main Authors: Izidoro-Toledo, T C, Borges, A C, Araújo, D D, Mazzi, D P S Leitão, Nascimento Júnior, F O, Sousa, J F, Alves, C P, Paiva, A P B, Trindade, D M, Patussi, E V, Peixoto, P M, Kinnally, K W, Espreafico, E M
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
Apoptosis - drug effects
Apoptosis Regulatory Proteins - deficiency
Apoptosis Regulatory Proteins - genetics
bcl-2 Homologous Antagonist-Killer Protein - deficiency
bcl-2 Homologous Antagonist-Killer Protein - genetics
Bcl-2-Like Protein 11
Cell Line, Tumor
Cytoplasmic Dyneins - genetics
Cytoplasmic Dyneins - metabolism
DNA Fragmentation - drug effects
Fibroblasts - metabolism
Fibroblasts - pathology
Gene Expression Regulation, Neoplastic - drug effects
Humans
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Membrane Proteins - deficiency
Membrane Proteins - genetics
Mice
Mice, Knockout
Myosin Heavy Chains - genetics
Myosin Heavy Chains - metabolism
Myosin Type V - genetics
Myosin Type V - metabolism
Neoplasm Transplantation
Original
Peptide Fragments - genetics
Peptide Fragments - metabolism
Peptide Fragments - pharmacology
Protein Binding
Proto-Oncogene Proteins - deficiency
Proto-Oncogene Proteins - genetics
Signal Transduction - drug effects
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
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Summary: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.
ISSN:2041-4889
DOI:10.1038/cddis.2013.45