Bax and other pro-apoptotic Bcl-2 family "killer-proteins" and their victim the mitochondrion

Abstract

Two major intracellular apoptosis signaling cascades have been characterized, the mitochondrial pathway and the death receptor pathway. The mitochondrial pathway is regulated by members of the Bcl-2 protein family. The members of this family can be subdivided into anti- and pro-apoptotic proteins. The pro-apoptotic members are further divided into two groups, the multidomain and the 'BH3 domain only' proteins. When cells are exposed to apoptotic stimulation, pro-apoptotic proteins are activated through post-translational modifications or changes in their conformation. The main site of action of the multidomain proteins are the mitochondria, where these proteins induce permeabilization of the outer membrane resulting in the release of proteins, including cytochrome c, from the intermembrane space. In the cytosol cytochrome c activates caspase cascades ultimately leading to cell death. Mounting evidence indicates that apoptosis is involved in a wide range of pathological conditions. Recent studies suggest that the mitochondrial signaling pathway is involved in several diseases. Although, so far, with the exception of C. elegans, most studies on apoptosis have been performed in mammalian systems, recently homologues to the Bcl-2 family members, including pro-apoptotic members, have been identified in Drosophila and zebrafish. Here the structure and function of the various pro-apoptotic Bcl-2 family members, their effects on mitochondria, and their involvement in diseases are discussed.

Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma

“…It has been well documented that Bax acts on the mitochondria to induce mitochondrial permeability transition, and thereby regulating the cytoplasmic release of cytochrome c (Antonsson, 2001). Neuroblastoma cell lines that we examined in this study carry wildtype p53.…”

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

“…Additional BH3-only proteins may be important in neomycin-induced toxicity, perhaps by preventing binding of Bcl2 to Bax, which could explain the lack of protection seen in the Bcl2 overexpression fish. This conjecture requires further exploration of BH3-only proteins such as Bim and Noxa that modulate Bcl2 interactions with other protein targets (Antonsson 2001;Han et al 2010).…”

Low Expression of the bcl2 Gene in Gastric Adenocarcinomas in Mazandaran Province of Iran

“…The Bcl-2 gene codes for a 25KDa protein. The C terminal 21 aminoacids encode a stretch of hydrophobic aminoacids that are important in membrane docking: Bcl-2 resides on the cytoplasmic face of the mitochondrial outer membrane, the nuclear envelope, and the endoplasmic reticulum (Antonsson et al, 2001). Assessment of apoptosis and individual components of the apoptosis pathway might therefore be relevant in determining the prognosis in an individual patient.…”