The Bcl2 family: regulators of the cellular life-or-death switch

Abstract

Tissue homeostasis is regulated by apoptosis, the cell-suicide programme that is executed by proteases called caspases. The Bcl2 family of intracellular proteins is the central regulator of caspase activation, and its opposing factions of anti- and pro-apoptotic members arbitrate the life-or-death decision. Apoptosis is often impaired in cancer and can limit conventional therapy. A better understanding of how the Bcl2 family controls caspase activation should result in new, more effective therapeutic approaches.

Dissection of transcriptional and non-transcriptional p53 activities in the response to genotoxic stress

“…We therefore investigated whether intrinsically generated high cytosolic p53 Dissection of p53 apoptotic activities D Speidel et al levels in 100 J/m 2 UV-irradiated NIH3T3 cells are coupled to activation of Bax. Activation of Bax involves a translocation of the protein to mitochondria and insertion into the OMM, which causes membrane permeabilization and initializes the cascade of mitochondria-mediated apoptosis leading to activation of caspase 3 (Cory and Adams, 2002). We monitored Baxactivation by confocal microscopy and studied the distribution of endogenous Bax with respect to a mitochondrial localization.…”

“…Here, permeabilization of the outer mitochondrial membrane (OMM) is the key event that initializes the apoptotic cascade. The Bcl-2 protein family, consisting of pro-apoptotic and anti-apoptotic members, controls permeability of the OMM (Cory and Adams, 2002). Acting as a transcription factor, p53 upregulates a large and still increasing number of proapoptotic genes (Vousden and Lu, 2002;Fridman and Lowe, 2003), including the pro-apoptotic Bcl-2 family members Bax (Miyashita and Reed, 1995) and Puma (Nakano and Vousden, 2001;Yu et al, 2001), and genes of other apoptosis-promoting factors, for example, PIG3 .…”

BH3-only proteins and their roles in programmed cell death

“…Indeed, release of cytochrome c from the mitochondrial intermembrane space is required for the activation of the initiator caspase-9 by the apoptotic protease-activating factor-1. Proteins of the Bcl-2 family control the integrity of the mitochondrial membrane in healthy cells, and its permeabilization in response to apoptotic stimuli (Cory and Adams, 2002).…”

Regulation of survivin expression by IGF-1/mTOR signaling

“…Restoration of apoptotic pathways is being explored for rational cancer therapy (Reed, 2003), and targeting survival proteins of the Bcl-2 (Cory and Adams, 2002), or inhibitor of apoptosis (IAP) (Salvesen and Duckett, 2002) gene family has been associated with tumor cell death, and in some cases, promising clinical responses (Reed, 2003). Survivin (Ambrosini et al, 1997) has attracted attention as a unique IAP member (Salvesen and Duckett, 2002) for its differential expression in tumors as opposed to normal tissues (Ambrosini et al, 1997), and a role in multiple pathways of tumor cell maintenance, including protection from apoptosis, cell division, the cellular stress response and p53-dependent checkpoints (Altieri, 2003).…”