The Proapoptotic BH3-Only, Bcl-2 Family Member, Puma Is Critical for Acute Ethanol-Induced Neuronal Apoptosis

Ghosh, Arindam; Walls, Ken C.; Klocke, Barbara J.; Toms, Rune; Strasser, Andreas; Roth, Kevin A.

doi:10.1097/nen.0b013e3181a9d524

Cited by 33 publications

(41 citation statements)

References 71 publications

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“…Quantification of FJB-positive staining revealed WT mice had significant ND in all brain regions in comparison with saline-treated mice and ethanol-treated tPA −/− mice ( Fig. 2 I and J Apoptotic ND induced by ethanol at P7 is mediated by Bax, requires the release of cytochrome c, and culminates with the activation of caspase-3 (7,14,17,18). To determine if activation of ethanol-induced apoptosis after ethanol exposure is tPA dependent, we measured cleaved caspase-3 by Western blot.…”

Section: Resultsmentioning

confidence: 99%

Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

Noel

Norris

Strickland

2011

Proc. Natl. Acad. Sci. U.S.A.

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Ethanol exposure during developmental synaptogenesis can lead to brain defects referred to as fetal alcohol syndrome (FAS), which can include mental health problems such as cognitive deficits and mental retardation. In FAS, widespread neuronal death and brain mass loss precedes behavioral and cognitive impairments in adulthood. Because tissue plasminogen activator (tPA) has been implicated in neurodegeneration, we examined whether it mediates FAS. Neonatal WT and tPA −/− mice were injected with ethanol to mimic FAS in humans. In WT mice, ethanol elicited caspase-3 activation, significant forebrain neurodegeneration, and decreased contextual fear conditioning in adults. However, tPA-deficient mice were protected from these neurotoxicities, and this protection could be abrogated by exogenous tPA. Selective pharmacological modulators of NMDA and GABA A receptor pathways revealed that the effects of tPA were mediated by the NR2B subunit of the NMDA receptor. This study identifies tPA as a critical signaling component in FAS.

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Section: Resultsmentioning

confidence: 99%

Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

Noel

Norris

Strickland

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…As a Bcl-2 homology 3 (BH3)-only family member, PUMA has been implicated as a p53-upregulated modulator of apoptosis (42). It activates Bax, which in turn initiates caspase-3 activation via the intrinsic mitochondrial apoptotic pathway, and this has been shown to be involved in neuronal apoptosis (43,44). Hence, the p53-PUMA-Bax system has been postulated to be a classic signal for the induction of cell death via apoptosis (45).…”

Section: Discussionmentioning

confidence: 99%

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

Zhang

Xie

Chen

et al. 2016

Antimicrob Agents Chemother

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Colistin is used as a last-line treatment option against multidrug-resistant (MDR) Gram-negative bacteria, which can cause life-threatening infections (1-3). However, its clinical use is limited by potential nephrotoxicity and neurotoxicity (4, 5), the mechanisms of which are still unknown. It has been discovered in a mouse model and neuroblastoma 2a cells that autophagy is involved in colistin-induced nephrotoxicity (6, 7). Apoptosis and autophagy are two common forms of cell death (8, 9). Apoptosis is a prevalent form of programmed cell death (PCD) in multicellular organisms, which is the culmination of coordinately regulated intrinsic and extrinsic pathways involving major protein families, including the Bcl-2 family and caspases (10). Autophagy is a catabolic process of degradation and recycling of dysfunctional cellular components by lysosomal systems (11-13). Autophagy participates in organelle turnover and in the bioenergetic management of starvation stresses, pathogen infection, and hypoxia in order to maintain cellular homeostasis (14,15). A number of stimuli can induce autophagy, apoptosis, or both, and recent studies suggest that autophagy delays or promotes apoptosis under certain conditions (16,17). For example, treatment of cells with pemetrexed and simvastatin promoted autophagy and inhibited apoptosis (16), while oridonin phosphate induced autophagy and enhanced apoptotic cell death (17). However, the precise mechanisms that determine autophagy, apoptosis, and their interaction remain to be elucidated.A number of studies in tumor cells (e.g., hepatocellular carcinoma and OVCAR-3 cancer cells) have shown that the p53 tumor suppressor protein, which is an important cellular stress sensor, can trigger cell cycle arrest and apoptosis and also regulate autophagy (18)(19)(20). Activation of p53 in response to a death stimulus leads to the transcription of genes involved in apoptosis, including PUMA (p53 upregulated modulator of apoptosis), AMPK (AMPactivated protein kinase), and Bax in the nucleus. These in turn activate the intrinsic mitochondrial apoptotic pathway in the cytoplasm via inhibition of the antiapoptotic proteins Bcl-2 and Bcl-X L (19,20). In addition, p53 appears to play a dual role in the control of autophagy. At basal levels, p53 has an inhibitory effect, and its activation initiates the autophagic process (21,22). Thus, p53-induced autophagy may either constitute a physiological cellular defense response (23) or contribute to cell death (24). The cellular localization of p53 appears to determine whether a cell will undergo autophagy or apoptosis. Nuclear p53 induces and regulates autophagy, while cytoplasmic p53 inhibits autophagy (22,25).

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“…Puma and Noxa have been implicated to directly and indirectly activate Bax (Bcl-2-associated X protein) and Bak (Bcl-2-antagonist/killer), resulting in permeabilization of the outer mitochondrial membrane, release of cytochrome c and induction of apoptosis [20], [21]. Although both Puma and Noxa have been shown to mediate neuronal cell death, only Puma deficiency was significantly protective against apoptosis, stressing the importance of this factor in the apoptotic cascade [22]–[24]. With respect to cerebral ischemia, work by Chan and coworkers [25] demonstrated that cerebral ischemia induced Puma upregulation in the hippocampal CA1 region was inhibited by the p53 inhibitor, PFTα, which was correlated with significant neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen

et al. 2011

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BackgroundRecent studies demonstrate that acetylation of the transcription factor, p53 on lysine373 leads to its enhanced stabilization/activity and increased susceptibility of cells to stress. However, it is not known whether acetylation of p53 is altered in the hippocampus following global cerebral ischemia (GCI) or is regulated by the hormone, 17β-estradiol (17β−E2), and thus, this study examined these issues.Methodology/Principal FindingsThe study revealed that Acetyl p53-Lysine373 levels were markedly increased in the hippocampal CA1 region after GCI at 3 h, 6 h and 24 h after reperfusion, an effect strongly attenuated by 17β−E2. 17β−E2 also enhanced interaction of p53 with the ubiquitin ligase, Mdm2, increased ubiquitination of p53, and induced its down-regulation, as well as attenuated elevation of the p53 transcriptional target, Puma. We also observed enhanced acetylation of p53 at a different lysine (Lys382) at 3 h after reperfusion, and 17β−E2 also markedly attenuated this effect. Furthermore, administration of an inhibitor of CBP/p300 acetyltransferase, which acetylates p53, was strongly neuroprotective of the CA1 region following GCI. In long-term estrogen deprived (LTED) animals, the ability of 17β−E2 to attenuate p53 acetylation was lost, and intriguingly, Acetyl p53-Lysine373 levels were markedly elevated in sham (non-ischemic) LTED animals. Finally, intracerebroventricular injections of Gp91ds-Tat, a specific NADPH oxidase (NOX2) inhibitor, but not the scrambled tat peptide control (Sc-Tat), attenuated acetylation of p53 and reduced levels of Puma following GCI.Conclusions/SignificanceThe studies demonstrate that p53 undergoes enhanced acetylation in the hippocampal CA1 region following global cerebral ischemia, and that the neuroprotective agent, 17β−E2, markedly attenuates the ischemia-induced p53 acetylation. Furthermore, following LTED, the suppressive effect of 17β−E2 on p53 acetylation is lost, and p53 acetylation increases in the hippocampus, which may explain previous reports of increased sensitivity of the hippocampus to ischemic stress following LTED.

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The Proapoptotic BH3-Only, Bcl-2 Family Member, Puma Is Critical for Acute Ethanol-Induced Neuronal Apoptosis

Cited by 33 publications

References 71 publications

Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

Tissue plasminogen activator is required for the development of fetal alcohol syndrome in mice

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

Acetylation of the Pro-Apoptotic Factor, p53 in the Hippocampus following Cerebral Ischemia and Modulation by Estrogen

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