Recent studies have reported the involvement of the BH3-only factors Bim and Bmf in specific cell death processes. One of the proposed mechanisms for modulation of their pro-apoptotic functions is the release of Bim and Bmf from their sequestration sites at DLC1 and DLC2, which are tail light chains of dynein and myosin Va, respectively. Moreover, recent evidences have shown the essential role of MVa in tumor cell migration and metastasis. We have recently demonstrated that a fragment of the human myosin Va was capable to interact with both DLC 1 and DLC 2, with consequent induction of apoptosis. By interfering with apoptotic intrinsic pathway, which is the key to cancer tumor suppression, MVaf peptide may act specifically against cancer. Thus, in this project we aim to construct apoptosis-inducing peptides based on MVaf structure and its DLC-binding properties, through rational design, and then evaluate their potential as anti-tumor agents by in vitro peptide therapy of melanoma cell lines. The HIV-derived TAT, a cytoplasmic transduction peptide, will be fused with recombinant MVaf or synthetic peptides in order to internalize within the cells. Functional analyses of apoptotic cells will be performed by flow cytometry, confocal microscopy, Western blotting and immunoprecipitation. With these approaches, we expect to contribute to the development of new therapeutic strategies targeted towards key players of cytoskeletally regulated apoptosis, with potential for specific action against cancer.
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