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

T. C. Izidoro-Toledo, A. C. Borges, D. D. Araujo, D. P.S. Leitão Mazzi, F. O.Nascimento Junior, J. F. Sousa, C. P. Alves, A. P.B. Paiva, D. M. Trindade, E. V. Patussi, P. M. Peixoto, K. W. Kinnally, E. M. Espreafico

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)e547
JournalCell Death and Disease
Volume4
Issue number3
DOIs
StatePublished - Mar 2013

Keywords

  • Apoptosis
  • Bmf
  • DLC1/DLC2
  • Melanoma
  • Myosin-Va

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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  • Cite this

    Izidoro-Toledo, T. C., Borges, A. C., Araujo, D. D., Leitão Mazzi, D. P. S., Junior, F. O. N., 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. (2013). A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells. Cell Death and Disease, 4(3), e547. https://doi.org/10.1038/cddis.2013.45