title: GADD34 induces cell death through inactivation of Akt following traumatic brain injury.
abstract: Neuronal cell death contributes significantly to the pathology of traumatic brain injury (TBI) irrespective of the mode or severity of the injury. Activation of a pro-survival protein, Akt, is known to be regulated by an E3 ligase TRAF6 through a process of ubiquitination-coupled phosphorylation at its T308 residue. Here we show that upregulation of a pro-apototic protein, GADD34, attenuates TRAF6-mediated Akt activation in a controlled cortical impact model of TBI in mice. TBI induces the expression of GADD34 by stimulating binding of a stress inducible transcription factor, ATF4, to the GADD34 promoter. GADD34 then binds with TRAF6 and prevents its interaction with Akt. This event leads to retention of Akt in the cytosol and prevents phosphorylation at the T308 position. Finally, in vivo depletion of GADD34 using a lentiviral knockdown approach leads to a rescue of Akt activation and markedly attenuates TBI-induced cell death.
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Farook
authors.forename: J
authors.initials: J
authors.lastname: Shields
authors.forename: A
authors.initials: A
authors.lastname: Tawfik
authors.forename: S
authors.initials: S
authors.lastname: Markand
authors.forename: T
authors.initials: T
authors.lastname: Sen
authors.forename: S B
authors.initials: SB
authors.lastname: Smith
authors.forename: D
authors.initials: D
authors.lastname: Brann
authors.forename: K M
authors.initials: KM
authors.lastname: Dhandapani
authors.forename: N
authors.initials: N
authors.lastname: Sen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001930:Brain Injuries / Q000201:enzymology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D015533:Transcriptional Activation; D054875:Ubiquitination
chemical_list: C081452:Atf4 protein, mouse; D018690:Excitatory Amino Acid Agonists; D017382:Reactive Oxygen Species; D048029:TNF Receptor-Associated Factor 6; D051701:Activating Transcription Factor 4; D016202:N-Methylaspartate; D051057:Proto-Oncogene Proteins c-akt; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1
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