RGD Reference Report - Nuclear translocation of X-linked inhibitor of apoptosis (XIAP) determines cell fate after hypoxia ischemia in neonatal brain. - Rat Genome Database

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Nuclear translocation of X-linked inhibitor of apoptosis (XIAP) determines cell fate after hypoxia ischemia in neonatal brain.

Authors: Russell, JC  Whiting, H  Szuflita, N  Hossain, MA 
Citation: Russell JC, etal., J Neurochem. 2008 Aug;106(3):1357-70. Epub 2008 May 13.
RGD ID: 2314399
Pubmed: PMID:18485100   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2008.05482.x   (Journal Full-text)

The inhibitors of apoptosis (IAPs) are emerging as key proteins in the control of cell death. In this study, we evaluated the expression and subcellular distribution of the antiapoptotic protein X-linked IAP (XIAP), and its interactions with the XIAP-associated factor 1 (XAF1) in neonatal rat brain following hypoxia-ischemia (HI). HI triggered the mitochondrial release of cytochrome c, Smac/DIABLO, and caspase 3 activation. Confocal microscopy detected XIAP-specific immunofluorescence in the cytoplasm under normal condition, which exhibited a diffuse distribution at 6 h post-HI and by 12 h the majority of XIAP was redistributed into the nucleus. XIAP nuclear translocation was confirmed by subcellular fractionations and by expressing FLAG-tagged XIAP in primary cortical neurons. Over-expression of XIAP significantly reduced, whereas XIAP gene silencing further enhanced cell death, demonstrating a specific requirement of cytoplasmic XIAP for cell survival. An elevated level of cytosolic XIAP was also evident under the conditions of neuroprotection by fibroblast growth factor-1. XAF1 expression was increased temporally and there was increased nuclear co-localization with XIAP in hypoxic-ischemic cells. XIAP co-immunoprecipitated > 9-fold XAF1 protein concurrent with decreased association with caspases 9 and 3. This is evidenced by the enhanced caspase 3 activity and neuronal death. Our findings implicate XIAP nuclear translocation in neuronal death and point to a novel mechanism in the regulation of hypoxic-ischemic brain injury.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XiapRatnegative regulation of neuron apoptotic process  IMP  RGD 
Xaf1Ratnegative regulation of protein-containing complex assembly  IDA  RGD 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
XiapRatperinuclear region of cytoplasm  IDA  RGD 

Molecular Function

  

Objects Annotated

Genes (Rattus norvegicus)
Casp3  (caspase 3)
Casp9  (caspase 9)
Xaf1  (XIAP associated factor 1)
Xiap  (X-linked inhibitor of apoptosis)

Objects referenced in this article
Gene Cycs cytochrome c, somatic Rattus norvegicus
Gene Diablo diablo, IAP-binding mitochondrial protein Rattus norvegicus

Additional Information