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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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Autores principales: Izidoro-Toledo, T C, Borges, A C, Araújo, D D, Leitão Mazzi, D P S, Nascimento, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613824/
https://www.ncbi.nlm.nih.gov/pubmed/23519116
http://dx.doi.org/10.1038/cddis.2013.45
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author Izidoro-Toledo, T C
Borges, A C
Araújo, D D
Leitão Mazzi, D P S
Nascimento, 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
author_facet Izidoro-Toledo, T C
Borges, A C
Araújo, D D
Leitão Mazzi, D P S
Nascimento, 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
author_sort Izidoro-Toledo, T C
collection PubMed
description 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.
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spelling pubmed-36138242013-04-11 A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells Izidoro-Toledo, T C Borges, A C Araújo, D D Leitão Mazzi, D P S Nascimento, 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 Cell Death Dis Original Article 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. Nature Publishing Group 2013-03 2013-03-21 /pmc/articles/PMC3613824/ /pubmed/23519116 http://dx.doi.org/10.1038/cddis.2013.45 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Izidoro-Toledo, T C
Borges, A C
Araújo, D D
Leitão Mazzi, D P S
Nascimento, 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
A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
title A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
title_full A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
title_fullStr A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
title_full_unstemmed A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
title_short A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
title_sort myosin-va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613824/
https://www.ncbi.nlm.nih.gov/pubmed/23519116
http://dx.doi.org/10.1038/cddis.2013.45
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