GADD34 induces cell death through inactivation of Akt following traumatic brain injury

J. M. Farook, J. Shields, Amany Mohamed Tawfik, S. Markand, T. Sen, Sylvia B Smith, Darrell W Brann, Krishnan Michael Dhandapani, Nilkantha Sen

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere754
JournalCell Death and Disease
Volume4
Issue number8
DOIs
StatePublished - Jan 1 2013

Fingerprint

TNF Receptor-Associated Factor 6
Cell Death
Activating Transcription Factor 4
Phosphorylation
Ubiquitin-Protein Ligases
Ubiquitination
Cytosol
Proteins
Up-Regulation
Pathology
Traumatic Brain Injury
Wounds and Injuries

Keywords

  • Akt
  • Cell death
  • GADD34
  • TBI
  • TRAF6

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

GADD34 induces cell death through inactivation of Akt following traumatic brain injury. / Farook, J. M.; Shields, J.; Tawfik, Amany Mohamed; Markand, S.; Sen, T.; Smith, Sylvia B; Brann, Darrell W; Dhandapani, Krishnan Michael; Sen, Nilkantha.

In: Cell Death and Disease, Vol. 4, No. 8, e754, 01.01.2013.

Research output: Contribution to journalArticle

@article{50d55910112a4d4c8afc8d95e4ce07fb,
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.",
keywords = "Akt, Cell death, GADD34, TBI, TRAF6",
author = "Farook, {J. M.} and J. Shields and Tawfik, {Amany Mohamed} and S. Markand and T. Sen and Smith, {Sylvia B} and Brann, {Darrell W} and Dhandapani, {Krishnan Michael} and Nilkantha Sen",
year = "2013",
month = "1",
day = "1",
doi = "10.1038/cddis.2013.280",
language = "English (US)",
volume = "4",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - GADD34 induces cell death through inactivation of Akt following traumatic brain injury

AU - Farook, J. M.

AU - Shields, J.

AU - Tawfik, Amany Mohamed

AU - Markand, S.

AU - Sen, T.

AU - Smith, Sylvia B

AU - Brann, Darrell W

AU - Dhandapani, Krishnan Michael

AU - Sen, Nilkantha

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - Akt

KW - Cell death

KW - GADD34

KW - TBI

KW - TRAF6

UR - http://www.scopus.com/inward/record.url?scp=84882585205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84882585205&partnerID=8YFLogxK

U2 - 10.1038/cddis.2013.280

DO - 10.1038/cddis.2013.280

M3 - Article

VL - 4

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 8

M1 - e754

ER -