Bax Involvement in p53-Mediated Neuronal Cell Death

Abstract

The tumor suppressor gene p53 has been implicated in the loss of neuronal viability, but the signaling events associated with p53-mediated cell death in cortical and hippocampal neurons are not understood. Previous work has shown that adenovirus-mediated delivery of the p53 gene causes cortical and hippocampal neuronal cell death with some features typical of apoptosis. In the present study we determined whether p53-initiated changes in neuronal viability were dependent on members of the Bcl-2 family of cell death regulators. Primary cultures of cortical neurons were derived from animals containing Bax (+/+ and +/-) or those deficient in Bax (-/-). Cell damage was assessed by direct cell counting and by measurements of MTT activity. Neurons containing at least one copy of the Bax gene were damaged severely by exposure to excitotoxins or by the induction of DNA damage. In contrast, Bax-deficient neurons (-/-) exhibited significant protection from both types of injury. Bax protein expression was elevated significantly by glutamate exposure, but not by camptothecin-induced DNA damage in wild-type neurons. The glutamate-induced increase in Bax protein was dependent on the presence of the p53 gene. However, increased p53 expression, using adenovirus-mediated transduction, was not sufficient by itself to elevate Bax protein levels. These results demonstrate that Bax is required for neuronal cell death in response to some forms of cytotoxic injury and further support the key role for p53 activation in response to excitotoxic and genotoxic injury.

Involment of p53, Bax, and Bcl‐2 pathway in microcystins‐induced apoptosis in rat testis

“…Induction of p53 is associated with a rapid increase in its levels and with an increased ability to bind DNA and mediate transcriptional activation (Lakin and Jackson, 1999). The products encoded by p53 can regulate the expression of Bax, which may mediate p53-dependent cell apoptosis (Xiang et al, 1998;Chen et al, 2005a,b). It was reported that p53 might lead to apoptosis indirectly by down-regulating expression of bcl-2 (Miyashita et al, 1994).…”

Neural precursor cells possess multiple p53-dependent apoptotic pathways

“…36 Of the proapoptotic members of the Bcl-2 family, Bax is considered to be the most significant mediator of mitochondria-dependent apoptosis in neurons. 29,30 The contribution of Bak to neuronal apoptosis depends on the cell type and apoptotic stimulus. 28 Bax deficiency alone partially protects primary telencephalic NPCs against DNA damage-induced death; however, dual Bax and Bak deficiency provides an even greater protective effect against this apoptotic stimulus.…”

“…The proapoptotic molecules Bax and Bak play overlapping functions in the regulation of apoptosis, and it appears that the significance of either molecule is highly dependent on cell type. 11,[28][29][30] We reasoned that either Bax or Bak might be critical for the activation of the intrinsic apoptotic pathway in NPCs. To test this hypothesis, we crossed mice that were heterozygous for both bax and bak and prepared FGF2-expanded NPCs from E13 embryos.…”

AMP kinase–mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis

“…The transcriptional induction and/or the posttranslational activation of Bcl-2 homology domain 3 (BH3)-only proteins is believed to be essential for Bax/Bak activation and downstream signaling events. Previous studies have demonstrated that apoptotic excitotoxic injury is inhibited by loss of Bax or Bcl-2 overexpression (Xiang et al, 1998;Wang et al, 2004;Dietz et al, 2007;Semenova et al, 2007). In this study, we demonstrate that, in contrast to currently held views, ATP depletion and energy stress signaling are not only responsible for the activation of necrotic but also for the activation of apoptotic excitotoxic injury and that this occurs via the activation of an AMP-activated protein kinase (AMPK), culminating in the activation of the BH3-only protein Bim.…”