Mitochondrial signaling in cell death via the Bcl-2 family

Abstract

Apoptosis is a critical process for the maintenance of tissue homeostasis and prevention of tumorigenesis. The members of the Bcl-2 family of proteins are the central regulators of the intrinsic apoptotic pathway. Within the Bcl-2 family, the BH3-only subfamily of proteins is tasked with sensing a broad range of apoptotic stimuli and transmitting this signal to other Bcl-2 proteins to initiate programmed cell death. This family of proteins is highly regulated at both transcriptional and post-translational levels, as well as by prominent protein-protein interactions among the family members. Bcl-2 family proteins are often deregulated in cancer, with overexpression of anti-apoptotic members, as well as mutations or defects in pro-apoptotic members. These proteins have been the subject of intensive study for many years and the complex relationships between their regulation and tumorigenesis have spawned a new thinking about cancer treatment. New generations of small molecule Bcl-2 family inhibitors and BH3 and SMAC mimetics have brought new optimism to the pursuit of more individualized and effective cancer therapies.