Induction and redistribution of XAF1, a new antagonist of XIAP in the rat brain after transient focal ischemia

Siegelin, Markus D.; Touzani, Omar; Toutain, Jérôme; Liston, Peter; Rami, Abdelhaq

doi:10.1016/j.nbd.2005.04.006

Cited by 24 publications

(16 citation statements)

References 39 publications

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“…Protein signals were analyzed semiquantitatively using a computer-assisted image analysis system and the NIH gel analysis software. 4 The sum of gray values of all pixels and the sum of densities were determined for each individual band (26). To normalize the means of sum of density values from different experiments, each value was given as the percentage of the control value.…”

Section: Methodsmentioning

confidence: 99%

The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin

Siegelin

Reuß

Habel

et al. 2008

Molecular Cancer Therapeutics

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Resistance to tumor necrosis factor -related apoptosisinducing ligand (TRAIL/Apo2L) limits its potential as a drug for cancer therapy. Here, we report that kaempferol, a bioactive plant flavonoid, sensitizes U251 and U87 glioma cells to TRAIL-mediated apoptosis. In contrast, U373 cells are not affected by kaempferol treatment. Treatment of kaempferol alone for 24 h did not induce apoptosis in the cell lines. We provide evidence that TRAIL-induced apoptosis is partially driven by kaempferol-mediated reduction of survivin protein levels. On kaempferol treatment, proteasomal degradation of survivin was observed. Inhibition of proteasomal degradation with MG132 in kaempferol-treated cells restored survivin protein levels in both glial cell lines. Consequently, overexpression of survivin attenuated TRAIL-kaempferol -induced apoptosis. In addition, we show that kaempferol mediates down-regulation of phosphorylated Akt, thereby further reducing survivin protein level. Furthermore, the blockage of the serine/threonine kinase Akt activity by kaempferol is important for inhibition of survivin because active phosphorylated Akt enhances the stability of survivin. However, we also show that the combined treatment of TRAIL and kaempferol induces cleavage (activation) of caspase-8, thereby exerting a proapoptotic effect independent of survivin known not to inhibit caspase-8 activation. Other effects induced by kaempferol were suppression of X-linked inhibitor of apoptosis proteins as the antiapoptotic members of the Bcl-2 family, Bcl-2, Bcl-xL, and Mcl-1 in a concentrationdependent manner. In summary, we showed that suppression of survivin is an essential mechanism in TRAIL-kaempferol -mediated apoptosis. [Mol Cancer Ther 2008;7(11):3566 -74]

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Section: Methodsmentioning

confidence: 99%

The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin

Siegelin

Reuß

Habel

et al. 2008

Molecular Cancer Therapeutics

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“…In the present study, the PFT-mediated shift of transcriptional activities of p53 (blocked) and NF-kB (enhanced) resulted in reduced protein levels of the p53-target Bax and increased expression of the NF-kB-target XIAP in vitro and in vivo (Figure 11). Similar to other members of the inhibitory of apoptosis protein family, XIAP prevents cell death by various mechanisms [28][29][30] and was attributed a critical role for neuronal cell death in various disease models, for example cerebral ischemia, 13,31,32 neonatal hypoxia, 14 retinal ischemia 33 or epileptic seizures. 34 In line with the observed reduction of NF-kB transcriptional activity, protein levels of full-length XIAP declined after TBI in injured brain tissue.…”

Section: 12mentioning

confidence: 99%

Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity

Plesnila¹,

Baumgarten²,

Retiounskaia³

et al. 2007

Cell Death Differ

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Acute and chronic neurodegeneration, for example, following brain injury or Alzheimer's disease, is characterized by programmed death of neuronal cells. The present study addresses the role and interaction of p53-and NF-jB-dependent mechanisms in delayed neurodegeneration following traumatic brain injury (TBI). After experimental TBI in mice p53 rapidly accumulated in the injured brain tissue and translocated to the nucleus of damaged neurons, whereas NF-jB transcriptional activity simultaneously declined. Post-traumatic neurodegeneration correlated with the increase in p53 levels and was significantly reduced by the selective p53 inhibitor pifithrin-a (PFT). Strikingly, this protective effect was observed even when PFT treatment was delayed up to 6 h after trauma. Inhibition of p53 activity resulted in the concomitant increase in NF-jB transcriptional activity and upregulation of NF-jB-target proteins, for example X-chromosomal-linked inhibitor of apoptosis (XIAP). It is interesting to note that inhibition of XIAP abolished the neuroprotective effects of PFT in cultured neurons exposed to camptothecin, glutamate, or oxygen glucose deprivation. In conclusion, delayed neuronal cell death after brain trauma is mediated by p53-dependent mechanisms that involve inhibition of NF-jB transcriptional activity. Hence, p53 inhibition provides a promising approach for the treatment of acute brain injury, since it blocks apoptotic pathways and concomitantly triggers survival signaling with a therapeutic window relevant for clinical applications.

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“…Studies in cultured cells and isolated mitochondria have demonstrated that besides cytochrome c and pro-caspases, mitochondria contain a number of other proapoptotic molecules that are released during apoptosis [3,4]. Among them, Smac/DIABLO, the second mitochondria-derived activator of caspases (Smac) or direct inhibitor of apoptosis-binding protein with low pi (DIABLO) has been shown to play a critical regulatory role in apoptosis [5][6][7]. In mammals, Smac/DIABLO binds to XIAP and induces thereby a caspase-dependent apoptosis [3,8].…”

Section: Introductionmentioning

confidence: 99%

Translocation of the Serine Protease Omi/HtrA2 from Mitochondria into the Cytosol Upon Seizure-Induced Hippocampal Injury in the Neonatal Rat Brain

2010

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Omi/HtrA2 is a pro-apoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death upon various brain injuries. However, the role of Omi/HtrA2 in neuronal death induced by status epilepticus (SE) in the immature brain has not been reported. In this study, we analyzed the contribution of serine protease Omi/HtrA2, its substrate X-linked inhibitor of apoptosis protein (XIAP) and the caspase-3 activation to damage of hippocamplal CA1 cells following lithium-pilocarpine SE in P14 rat pups. Status epilepticus in the immature brain significantly induced translocation of Omi/HtrA2 from mitochondria into the cytosol, increased cytosolic accumulation of Omi/HtrA2, induced appearance of XIAP-breakdown products and enhanced caspase-3 activity in the selectively vulnerable hippocampal CA1-subfield. Taken together, these results demonstrate for the first time that SE in the immature brain results in Omi/HtrA2 accumulation in the cytosol, where it probably promotes neuronal death by neutralizing and cleaving XIAP, one of the most potent endogenous inhibitors of apoptosis.

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Induction and redistribution of XAF1, a new antagonist of XIAP in the rat brain after transient focal ischemia

Cited by 24 publications

References 39 publications

The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin

The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin

Delayed neuronal death after brain trauma involves p53-dependent inhibition of NF-κB transcriptional activity

Translocation of the Serine Protease Omi/HtrA2 from Mitochondria into the Cytosol Upon Seizure-Induced Hippocampal Injury in the Neonatal Rat Brain

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