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Construction of a yeast system to recapitulate human HSP27 suppression of programmed cell death


Apoptosis is a highly organized active process of cell death that participates in organogenesis and tissue remodeling during embryonic development. In the immune system, apoptosis is involved in the negative selection of lymphoid lineage cells; it eliminates neoplastic cells and those infected by virus, after the action of cytotoxic T lymphocytes and natural killer cells. Alterations in the mechanisms that induce or inhibit apoptosis are causes of diseases such as neurodegeneration, autoimmunity, and cancer. In mammalian cells, HSP27 is a chaperone involved in remodeling of protein aggregates and increases cell´s survival. Its cytoprotective function is related to the suppression of apoptosis pathways by interaction with pro-apoptotic proteins such as Bax, Bad, and tBid, and also to apoptogenic factors such as cytochrome c and initiator caspases. In some neoplasias, HSP27 is overexpressed and inhibits tumor cell apoptosis leading to oncogenesis and resistance to chemotherapy. This project aims to construct a yeast system that recapitulates human HSP27 suppression of programmed cell death. Hydrogen peroxide or acetic acid will be used as apoptosis inducers, and a time course will be performed to measure cell´s viability, release of cytochrome c from mitochondria, phosphatidylserine exposure in the exoplasmic face of the plasma membrane, Yca1p metacaspase activity, and HSP27 death suppression phenotype when pro-apoptotic factors are simultaneously expressed with the chaperone. Validating this system is an important step for a future strategy to screen for small molecules that could inhibit the suppression of apoptosis by HSP27, and potentially work against neoplasias. (AU)

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