Human embryonic stem cells

Despite intense investigation on apoptosis pathways, exactly how apoptosis is regulated in various primary cells remains understudied and continues to reveal unexpected mechanisms. While a strict regulation of apoptosis is critical for the long-term survival of postmitotic cells, mitotic cells need to maintain their ability to activate apoptosis rapidly, as they can be at continual risk of becoming cancerous. Therefore, cells must efficiently balance the need for having a primed apoptotic pathway vs. the risks associated with inadvertent cell death. This balance is particularly important during embryogenesis, where human embryonic stem (hES) cells proliferate rapidly and differentiate, leading to the development of an entire organism. While optimal hES cell survival is necessary for development, the ability of these cells to respond rapidly to DNA damage by apoptosis and maintain genomic integrity is also critical to prevent propagation of mutations in the developing embryo. Indeed, hES cells are known to be highly sensitive to DNA damage, and our recent results have uncovered a novel mechanism by which these cells are primed for rapid apoptosis. An essential mediator of apoptosis in mammalian cells is Bax, a proapoptotic member of the Bcl-2 family. In healthy cells, Bax is predominantly cytosolic and present in an inactive conformation. Apoptotic stimuli, such as DNA damage, result in the induction of BH3-only family proteins that promote Bax activation by conformational changes. Activated Bax then translocates to the mitochondria, where it inserts into the mitochondrial outer membrane, promoting the release of cytochrome c and resulting in caspase activation. Thus, Bax activation is a Human embryonic stem cells Living on the edge