Article

BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program.

Molecular Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Science (Impact Factor: 31.48). 12/2010; 330(6009):1390-3. DOI: 10.1126/science.1190217
Source: PubMed

ABSTRACT Although the proteins BAX and BAK are required for initiation of apoptosis at the mitochondria, how BAX and BAK are activated remains unsettled. We provide in vivo evidence demonstrating an essential role of the proteins BID, BIM, and PUMA in activating BAX and BAK. Bid, Bim, and Puma triple-knockout mice showed the same developmental defects that are associated with deficiency of Bax and Bak, including persistent interdigital webs and imperforate vaginas. Genetic deletion of Bid, Bim, and Puma prevented the homo-oligomerization of BAX and BAK, and thereby cytochrome c-mediated activation of caspases in response to diverse death signals in neurons and T lymphocytes, despite the presence of other BH3-only molecules. Thus, many forms of apoptosis require direct activation of BAX and BAK at the mitochondria by a member of the BID, BIM, or PUMA family of proteins.

Full-text

Available from: Osamu Takeuchi, Aug 12, 2014
0 Followers
 · 
115 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 11/2014; 284C:824-832. DOI:10.1016/j.neuroscience.2014.10.059 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: -The number of CD4(+)CD28(null) (CD28(null)) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harbouring high numbers of CD28(null) T cells have increased risk of recurrent severe acute coronary events and unfavourable prognosis. The mechanisms that govern the increase in CD28(null) T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T cell homeostasis are perturbed in CD28(null) T cells in ACS. -We found that CD28(null) T cells in ACS were resistant to apoptosis induction via Fas-ligation or ceramide. This was due to a dramatic reduction in pro-apoptotic molecules Bim, Bax and Fas in CD28(null) T cells, whilst anti-apoptotic molecules Bcl-2 and Bcl-xL were similar in CD28(null) and CD28(+) T cells. We also show that Bim is phosphorylated in CD28(null) T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28(null) T cells in ACS. -We show that CD28(null) T cells in ACS harbour marked defects in molecules that regulate T cell apoptosis, which tips the balance in favour of anti-apoptotic signals and endows these cells with resistance to apoptosis. We demonstrate that inhibition of proteasomal activity allows CD28(null) T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control apoptosis sensitivity of CD28(null) T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients.
    Circulation 12/2014; DOI:10.1161/CIRCULATIONAHA.114.013710 · 14.95 Impact Factor
  • 06/2013; 2(3):238-43. DOI:10.3978/j.issn.2218-6751.2013.01.03