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PMID:15678128

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Citation

Saito, A, Hayashi, T, Okuno, S, Nishi, T and Chan, PH (2005) Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitin-proteasome system during reperfusion after stroke: role of oxidative stress. J. Cereb. Blood Flow Metab. 25:267-80

Abstract

The tumor suppressor gene p53 plays an important role in the regulation of apoptosis through transcriptional activation of cell cycle control. Degradation of p53 hinders its role in apoptosis regulation. Recent studies have shown that MDM2-mediated ubiquitylation and the ubiquitin-proteasome system are critical regulating systems of p53 ubiquitylation. However, the mechanism regulating p53-mediated neuronal apoptosis after cerebral ischemia remains unknown. We examined the MDM2 pathway and the ubiquitin-proteasome system using a transient focal cerebral ischemia (tFCI) model and analyzed the interaction between p53 regulation and superoxide using copper/zinc superoxide dismutase (SOD1) transgenic mice after tFCI. p53 degradation and ubiquitylation were detected after tFCI. The accumulation of ubiquitylated p53 was inhibited and p53 degradation was facilitated by SOD1. Nuclear translocation and MDM2/Akt interaction were detected after tFCI and were inhibited by phosphatidylinositol 3-kinase inhibition and promoted by SOD1. Cytosolic translocation of the p53/MDM2 complex was detected after tFCI and was promoted by SOD1. Moreover, accumulation of multiubiquitin chains and direct oxidative injury to a proteasome were detected and inhibited by SOD1 after tFCI. These results suggest that SOD1 promotes the MDM2 pathway and the ubiquitin-proteasome system after tFCI and that production of reactive oxygen species after tFCI prevents p53 degradation by inhibiting both systems.

Links

PubMed Online version:10.1038/sj.jcbfm.9600028

Keywords

Animals; Apoptosis/physiology; Blotting, Western; Enzyme Inhibitors/pharmacology; Female; Fluorescent Antibody Technique; Humans; Immunoprecipitation; Mice; Mice, Transgenic; Nuclear Proteins/metabolism; Oxidative Stress/physiology; Phosphatidylinositol 3-Kinases/drug effects; Phosphatidylinositol 3-Kinases/metabolism; Proteasome Endopeptidase Complex/metabolism; Protein Transport/physiology; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-mdm2; Reperfusion Injury/etiology; Reperfusion Injury/metabolism; Reperfusion Injury/physiopathology; Stroke/complications; Stroke/metabolism; Stroke/physiopathology; Superoxide Dismutase/metabolism; Tumor Suppressor Protein p53/metabolism; Ubiquitin/metabolism

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


See also

References

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