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

Abstract:

: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.

journal_name

J Neurochem

authors

Russell JC,Whiting H,Szuflita N,Hossain MA

doi

10.1111/j.1471-4159.2008.05482.x

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

1357-70

issue

3

eissn

0022-3042

issn

1471-4159

pii

JNC5482

journal_volume

106

pub_type

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