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Although the mechanisms by which Bcl-2 family proteins control the apoptotic machinery of the cell are not fully understood, it becomes clear that the role of BH3-only proteins consists in serving as sensors or sentinels of cellular damage, transducing the apoptotic stimuli to the mitochondria. For this reason, mammalian cells have developed several strategies for their strict regulation throughout evolution. This review aims to highlight the different ways by which BH3-only proteins are controlled, including transcriptional regulation, post-translational modifications and subcellular localization.
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