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)
JournalCell Death and Disease
Volume4
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

Dyneins
Myosins
Tail
Melanoma
Apoptosis
Fibroblasts
Caspase 9
Mitochondrial Membranes
DNA Fragmentation
Blister
Cytochromes c
Actin Cytoskeleton
Caspase 3
Cell Survival
Proteins
Binding Sites
Peptides
Growth
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Izidoro-Toledo, T. C., Borges, A. C., Araujo, D. D., Leitão Mazzi, D. P. S., Junior, F. O. N., Sousa, J. F., ... 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). https://doi.org/10.1038/cddis.2013.45

A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells. / Izidoro-Toledo, T. C.; Borges, A. C.; Araujo, D. D.; Leitão Mazzi, D. P S; Junior, F. O Nascimento; 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.

In: Cell Death and Disease, Vol. 4, No. 3, 03.2013.

Research output: Contribution to journalArticle

Izidoro-Toledo, TC, Borges, AC, Araujo, DD, Leitão Mazzi, DPS, Junior, FON, Sousa, JF, Alves, CP, Paiva, APB, Trindade, DM, Patussi, EV, Peixoto, PM, Kinnally, KW & Espreafico, EM 2013, 'A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells', Cell Death and Disease, vol. 4, no. 3. https://doi.org/10.1038/cddis.2013.45
Izidoro-Toledo TC, Borges AC, Araujo DD, Leitão Mazzi DPS, Junior FON, Sousa JF et al. A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells. Cell Death and Disease. 2013 Mar;4(3). https://doi.org/10.1038/cddis.2013.45
Izidoro-Toledo, T. C. ; Borges, A. C. ; Araujo, D. D. ; Leitão Mazzi, D. P S ; Junior, F. O Nascimento ; 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. In: Cell Death and Disease. 2013 ; Vol. 4, No. 3.
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AU - Trindade, D. M.

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