Prothymosin-α1 prevents necrosis and apoptosis following stroke

Fujita, Ryosuke; Ueda, Hiroshi

doi:10.1038/sj.cdd.4402189

Cited by 37 publications

(42 citation statements)

References 18 publications

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“…29 We have also reported the ischemia-dependent transport of Myc-tagged ProTa to the brain 30 min after systemic administration (i.v.). 11 Thus, these findings suggest that damage to retinal capillary vessels by ischemic treatment allows the material to be freely transported.…”

Section: Discussionmentioning

confidence: 85%

“…More recently, we demonstrated that ProTa strongly prevents ischemia-induced damage after rat middle cerebral artery occlusion. 11 In that study, ProTa inhibited both necrotic and apoptotic cell death in vivo, in contrast with the fact that this protein caused apoptosis in a culture study. 10 However, the machineries underlying this difference remain to be determined.…”

mentioning

confidence: 78%

“…28 However, this switch in cell death mode seems to have an important role in the protection of the brain in the event of stroke, as brain has potent anti-apoptosis systems, such as neurotrophins. 11 Indeed, we have demonstrated that the concomitant addition of neurotrophins with ProTa completely inhibited neuronal death, at least for 3 days, in an in vitro culture system. 10 The present study provides in vivo evidence for the ProTainduced switch in cell death mode.…”

Section: Discussionmentioning

confidence: 99%

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Prothymosin-α plays a defensive role in retinal ischemia through necrosis and apoptosis inhibition

et al. 2008

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Prothymosin-a (ProTa) causes a switch in cell death mode from necrosis to neurotrophin-reversible apoptosis in primary cultured cortical neurons. In the present study, post-ischemic administration (3 or 24 h, intravenously) of recombinant mouse ProTa without neurotrophins completely prevented ischemia-induced retinal damage accompanying necrosis and apoptosis, as well as dysfunction assessed by electroretinogram. Treatments with anti-erythropoietin (EPO) or brain-derived neurotrophic factor (BDNF) immunoglobulin G (IgG) reversed ProTa-induced inhibition of apoptosis. ProTa upregulated retinal EPO and BDNF levels in the presence of ischemia. Moreover, intravitreous administration of anti-ProTa IgG or an antisense oligodeoxynucleotide for ProTa accelerated ischemia-induced retinal damage. We also observed that ischemia treatment caused a depletion of ProTa from retinal cells. Altogether, these results suggest that the systemic administration of ProTa switches ischemia-induced necrosis to apoptosis, which in turn is inhibited by neurotrophic factors upregulated by ProTa and ischemia. ProTa released upon ischemic stress was found to have a defensive role in retinal ischemia.

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Section: Discussionmentioning

confidence: 85%

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confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Prothymosin-α plays a defensive role in retinal ischemia through necrosis and apoptosis inhibition

et al. 2008

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“…[27][28][29] However, after stroke, endogenous neurotrophins, such as brain-derived neurotrophic factor (BDNF) or erythropoietin, have been found to inhibit the apoptosis induced by exogenously administered ProTa. 6 In Figure 6 Apoptotic stress induces re-distribution of ProTa. (a) Altered distribution of ProTa in C6 glioma cells.…”

Section: Discussionmentioning

confidence: 99%

“…6,7 This protein is extracellularly released on starving or ischemic stress, and inhibits necrosis by inducing the membrane translocation of glucose transporters, which are endocytosed under ischemic conditions, resulting in an acceleration of necrosis owing to energy crisis. 5 On the basis of pharmacological analyses, ProTainduced translocation of glucose transporters is mediated by stimulation of a putative G i/o -coupled receptor, phospholipase C, and protein kinase C (PKC) b II .…”

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confidence: 99%

Stress-induced non-vesicular release of prothymosin-α initiated by an interaction with S100A13, and its blockade by caspase-3 cleavage

Matsunaga

Ueda

2010

Cell Death Differ

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The nuclear protein prothymosin-a (ProTa), which lacks a signal peptide sequence, is released from neurons and astrocytes on ischemic stress and exerts a unique form of neuroprotection through an anti-necrotic mechanism. Ischemic stress-induced ProTa release is initiated by a nuclear release, followed by extracellular release in a non-vesicular manner, in C6 glioma cells. These processes are caused by ATP loss and elevated Ca 2 þ , respectively. S100A13, a Ca 2 þ -binding protein, was identified to be a major protein co-released with ProTa in an immunoprecipitation assay. The Ca 2 þ -dependent interaction between ProTa and S100A13 was found to require the C-terminal peptide sequences of both proteins. In C6 glioma cells expressing a D88-98 mutant of S100A13, serum deprivation caused the release of S100A13 mutant, but not of ProTa. When cells were administered apoptogenic compounds, ProTa was cleaved by caspase-3 to generate a C-terminal peptide-deficient fragment, which lacks the nuclear localization signal (NLS). However, there was no extracellular release of ProTa. All these results suggest that necrosisinducing stress induces an extacellular release of ProTa in a non-vesicular manner, whereas apoptosis-inducing stress does not, owing to the loss of its interaction with S100A13, a cargo molecule for extracellular release.

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Mitochondria as decision‐makers in cell death

Borutaitė

2010

Environ and Mol Mutagen

105

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Mitochondria play an essential role in both cell health and death. Increasing experimental evidence suggests that mitochondria are involved in active control of cell death processes at several levels including (1) mitochondrial membrane permeabilization and release of proapoptotic proteins, (2) post-cytochrome c regulation of caspase activation, and (3) supply of energy for execution of death program. The purpose of this review is to discuss the main mechanisms by which alterations in mitochondrial outer membrane permit the translocation of proapoptotic proteins into cytosol, how mitochondria "make decisions" on the mode of cell death, and how they regulate caspase activation by changing the redox state of cytosolic cytochrome c. The interventions into these processes may constitute an important strategy for the pharmacological prevention of unwanted cell death in various pathologies or, conversely, for facilitation of anticancer therapy.

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Prothymosin-α1 prevents necrosis and apoptosis following stroke

Cited by 37 publications

References 18 publications

Prothymosin-α plays a defensive role in retinal ischemia through necrosis and apoptosis inhibition

Prothymosin-α plays a defensive role in retinal ischemia through necrosis and apoptosis inhibition

Stress-induced non-vesicular release of prothymosin-α initiated by an interaction with S100A13, and its blockade by caspase-3 cleavage

Mitochondria as decision‐makers in cell death

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