Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice

Abstract

B-cell lymphoma-2 (Bcl-2) family members have been demonstrated to play a crucial role in the regulation of apoptosis as mediators in between the apical stimuli sensing steps and the executory mechanisms of apoptosis. Deregulation of their role may subvert the homeostasis of a given tissue and collaborate in the genesis of a myriad of diseases characterised by exacerbated or insufficient apoptosis, including diseases such as neurodegenerative diseases or cancer. Structural studies have defined homology regions shared by the members of the family that are responsible of the network of interactions established amongst the members of the family. These proteins usually form heterodimers between the so called antiapoptotic multidomain members and the proapoptotic BH3-only proteins. As a consequence, mitochondrial apoptogenic proteins are released to the cytoplasm and the apoptotic signal proceeds towards the final, execution phase of the apoptotic process. The high complexity of the family (more than 20 members have been isolated) makes the study of individual proteins difficult. Genetic approaches have revealed a high degree of redundancy in the family. Only a few proteins belonging to the antiapoptotic group have been proven to be essential for correct embryonic development. Genetic inactivation in mice shows a dramatic phenotype characterised by massive cell death in multiple tissues during embryogenesis, which leads from very early up to perinatal death. This genetic evidence proves the importance of the members of the family for the regulation of apoptosis in order to achieve the proper development and homeostasis of tissues and organs.

Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway

“…Signal transduction pathways associated with apoptosis include the mitochondrial pathway, death receptor pathway, and endoplasmic reticulum stress pathway, of which the mitochondrial pathway serves a vital function in apoptosis (26,27). The Bax/Bcl-2 ratio is the key factor that triggers the mitochondrial pathway of apoptosis, and when the ratio of Bax/Bcl-2 increases apoptosis is initiated (27)(28)(29)(30). Bcl-2 and Bax proteins are located upstream of the mitochondrial apoptosis pathway and regulate the release of Cyt c, which is an important component of the mitochondrial electron transport chain.…”

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

“…Table 1 summarizes the findings on Bid, Bim, and Puma for which knockout mouse data are available in status epilepticus, ischemia, and TBI. Description of the non-central nervous system phenotypes of mice deficient in BH3-only proteins can be found elsewhere (Roset et al, 2007;Strasser, 2005;Youle and Strasser, 2008). Figure 3 summarizes the contributions of the three BH3-only proteins to neuronal death in each model.…”

Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

“…BAX is pro-apoptotic member of the family of Bcl-2-related proteins, which has an extensive amino acid homology with Bcl-2 [85,86]. Whether the cell will live or die may depend on the level of either protein; while Bcl-2 prevents death, BAX is a death promoter [78][79][80]. Postmortem studies demonstrated the increased expression level of BAX encoding gene [87] as well as high BAX/Bcl-2 proteins ratio in the temporal cortex of patients with SCZ [88].…”

“…The ultimate vulnerability of cells to diverse apoptotic stimuli is determined by the relative ratio of various pro-apoptotic and anti-apoptotic members of the Bcl-2 family [78,79]. Bcl-2 proper and Bax are members of the Bcl-2 family proteins [80].…”