title: Nuclear trafficking of Pten after brain injury leads to neuron survival not death.
abstract: There is controversy whether accumulation of the tumor suppressor PTEN protein in the cell nucleus under stress conditions such as trauma and stroke causes cell death. A number of in vitro studies have reported enhanced apoptosis in neurons possessing nuclear PTEN, with the interpretation that its nuclear phosphatase activity leads to reduction of the survival protein phospho-Akt. However, there have been no in vivo studies to show that nuclear PTEN in neurons under stress is detrimental. Using a mouse model of injury, we demonstrate here that brain trauma altered the nucleo-cytoplasmic distribution of Pten, resulting in increased nuclear Pten but only in surviving neurons near the lesion. This event was driven by Ndfip1, an adaptor and activator of protein ubiquitination by Nedd4 E3 ligases. Neurons next to the lesion with nuclear PTEN were invariably negative for TUNEL, a marker for cell death. These neurons also showed increased Ndfip1 which we previously showed to be associated with neuron survival. Biochemical assays revealed that overall levels of Pten in the affected cortex were unchanged after trauma, suggesting that Pten abundance globally had not increased but rather Pten subcellular location in affected neurons had changed. Following experimental injury, the number of neurons with nuclear Pten was reduced in heterozygous mice (Ndfip1(+/-)) although lesion volumes were increased. We conclude that nuclear trafficking of Pten following injury leads to neuron survival not death.
authors.affiliation: Brain Development and Regeneration Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
authors.forename: Choo-Peng
authors.initials: CP
authors.lastname: Goh
authors.affiliation: Brain Development and Regeneration Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Putz
authors.affiliation: Brain Development and Regeneration Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Howitt
authors.affiliation: Brain Development and Regeneration Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
authors.forename: Ley-Hian
authors.initials: LH
authors.lastname: Low
authors.affiliation: Brain Development and Regeneration Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Gunnersen
authors.affiliation: National Trauma Research Institute, Alfred Hospital, Monash University, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bye
authors.affiliation: National Trauma Research Institute, Alfred Hospital, Monash University, Australia.
authors.forename: Cristina
authors.initials: C
authors.lastname: Morganti-Kossmann
authors.affiliation: Brain Development and Regeneration Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia. Electronic address: stan@florey.edu.au.
authors.forename: Seong-Seng
authors.initials: SS
authors.lastname: Tan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D003593:Cytoplasm; D004195:Disease Models, Animal; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000502:physiology*; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Ndfip1; Nedd4; Neuroprotection; Pten; Traumatic brain injury; Ubiquitination