Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

Abstract

Bcl-2-family proteins are central regulators of cell life and death. At least three major classes of Bcl-2-family proteins have been delineated, including proapoptotic proteins that contain several conserved regions of sequence similarity (termed 'multidomain'). In mammals, the multidomain proteins (MDPs) of the Bcl-2 family include Bax, Bak, and Bok. The founding member of the MDP group of Bcl-2-family proteins was discovered by Stanley Korsmeyer and co-workers, initiating an exciting area of cell death research. The status of current knowledge about the mechanisms and functions of MDPs is reviewed here, and some areas for future research are outlined. Therapeutic opportunities emerging from a growing understanding of MDPs with respect to their threedimensional structures, biochemical actions, and roles in disease raise hopes that the foundation of basic research laid by Korsmeyer and others will eventually be translated into clinical benefits, leaving a legacy that benefits the world for many decades.

The signalling axis mediating neuronal apoptosis in response to [Pt(O,O′-acac)(γ-acac)(DMS)]

“…4). The crucial role of Bax/Bcl-2 in mitochondrial permeability and ΔΨm loss has been well established [27,28]. The downregulation of the Bcl-2 protein level observed in many different models of apoptosis, neuronal and non-neuronal, decreases its capacity to form heterodimers with the related pro-apoptotic protein Bax, or to link with specific molecules, thus of Bcl-2, thus preventing its anti-apoptotic activity [29][30][31].…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Exploiting the endogenous cell death machinery to reactivate the apoptotic cell death pathway may be achieved by antagonizing prosurvival Bcl2 family members directly or by inhibiting apoptosis downstream of Bcl2 induction. Modulation of Bcl2 family members using small-molecule drugs in tumor cells, which may carry one or more such dysregulated signaling pathways, may present an effective way to sensitize tumor cells to combination therapies (Labi et al, 2006;Walensky, 2006;Zinkel et al, 2006;Reed, 2006b). Small-molecule inhibitors targeting Bcl2 family proteins such as the BH3-only peptidomimetic drugs (for example, ABT-737) are under evaluation in pre-clinical and clinical trials with the promise of single-agent activity against numerous cancers (Adams and Cory, 2007;Zhang et al, 2007;Cragg et al, 2009).…”

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

“…Additional positive and negative regulators of cell death with homology to Bcl-2 followed with identification of Bax and Bcl-xL, respectively (Boise et al, 1993;Oltvai et al, 1993). The Bcl-2 family emerged on the basis of BH domains (Reed, 2006). Antiapoptotic members all share four BH domains and include Bcl-2, Bcl-xL, Bcl-w, and Mcl-1 (Youle and Strasser, 2008).…”