title: Critical role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries.
abstract: Stroke is the leading cause of disability in developed countries. However, no treatment is available beyond 3 h post-ictus. Here, we report that nuclear translocation of PTEN (phosphatase and tensin homolog deleted on chromosome TEN) is a delayed step causatively leading to excitotoxic (in vitro) and ischemic (in vivo) neuronal injuries. We found that excitotoxic stimulation of N-methyl-d-aspartate (NMDA) resulted in PTEN nuclear translocation in cultured neurons, a process requiring mono-ubiquitination at the lysine 13 residue (K13), as the translocation was prevented by mutation of K13 or a short interfering peptide (Tat-K13) that flanks the K13 residue. More importantly, using a rat model of focal ischemia, we demonstrated that systemic application of Tat-K13, even 6 h after stroke, not only reduced ischemia-induced PTEN nuclear translocation, but also strongly protected against ischemic brain damage. Our study suggests that inhibition of PTEN nuclear translocation may represent a novel after stroke therapy.
authors: Brain Research Centre and Department of Medicine, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, V6T2B5, Canada.
authors: Shu
authors: S
authors: Zhang
authors: Changiz
authors: C
authors: Taghibiglou
authors: Kimberly
authors: K
authors: Girling
authors: Zhifang
authors: Z
authors: Dong
authors: Shinn-Zong
authors: SZ
authors: Lin
authors: Wei
authors: W
authors: Lee
authors: Woei-cherng
authors: WC
authors: Shyu
authors: Yu Tian
authors: YT
authors: Wang
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002545:Brain Ischemia / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D019788:Fluorodeoxyglucose F18; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000633:toxicity; D009422:Nervous System Diseases / Q000209:etiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011247:Pregnancy; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018690:Excitatory Amino Acid Agonists; D019913:Nuclear Localization Signals; D010455:Peptides; C485184:enhanced green fluorescent protein; D019788:Fluorodeoxyglucose F18; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D051059:PTEN Phosphohydrolase
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