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

作者：Izidoro Toledo T C; Borges A C; Araujo D D; Leitao Mazzi D P S; Nascimento Junior 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^*

来源：Cell Death & Disease, 2013, 4(3): e547.

DOI：10.1038/cddis.2013.45

• Myosin-Va
• DLC1/DLC2
• apoptosis
• melanoma
• Bmf

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. Cell Death and Disease (2013) 4, e547; doi:10.1038/cddis.2013.45; published online 21 March 2013 Subject Category: Cancer

• 出版日期2013-3