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Control of cellular GADD34 levels by the 26S proteasome.

Publication ,  Journal Article
Brush, MH; Shenolikar, S
Published in: Mol Cell Biol
December 2008

GADD34, the product of a growth arrest and DNA damage-inducible gene, is expressed at low levels in unstressed cells. In response to stress, the cellular content of GADD34 protein increases and, on termination of stress, rapidly declines. We investigated the mechanisms that control GADD34 levels in human cells. GADD34 proteins containing either an internal FLAG or a C-terminal green fluorescent protein epitope were degraded at rates similar to endogenous GADD34. However, the addition of epitopes at the N terminus or deletion of N-terminal sequences stabilized GADD34. N-terminal peptides of GADD34, either alone or fused to heterologous proteins, exhibited rapid degradation similar to wild-type GADD34, thereby identifying an N-terminal degron. Deletion of internal PEST repeats had no impact on GADD34 stability but modulated the binding and activity of protein phosphatase 1. Proteasomal but not lysosomal inhibitors enhanced GADD34 stability and eukaryotic initiation factor 2alpha (eIF-2alpha) dephosphorylation, a finding consistent with GADD34's role in assembling an eIF-2alpha phosphatase. GADD34 was polyubiquitinated, and this modification enhanced its turnover in cells. A stabilized form of GADD34 promoted the accumulation and aggregation of the mutant cystic fibrosis transmembrane conductance regulator (CFTRDeltaF508), highlighting the physiological importance of GADD34 turnover in protein processing in the endoplasmic reticulum and the potential impact of prolonged GADD34 expression in human disease.

Duke Scholars

Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

December 2008

Volume

28

Issue

23

Start / End Page

6989 / 7000

Location

United States

Related Subject Headings

  • Ubiquitination
  • Tumor Cells, Cultured
  • Protein Stability
  • Protein Phosphatase 1
  • Proteasome Endopeptidase Complex
  • Humans
  • Eukaryotic Initiation Factor-2
  • Endoplasmic Reticulum
  • Developmental Biology
  • Cystic Fibrosis Transmembrane Conductance Regulator
 

Citation

APA
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ICMJE
MLA
NLM
Brush, M. H., & Shenolikar, S. (2008). Control of cellular GADD34 levels by the 26S proteasome. Mol Cell Biol, 28(23), 6989–7000. https://doi.org/10.1128/MCB.00724-08
Brush, Matthew H., and Shirish Shenolikar. “Control of cellular GADD34 levels by the 26S proteasome.Mol Cell Biol 28, no. 23 (December 2008): 6989–7000. https://doi.org/10.1128/MCB.00724-08.
Brush MH, Shenolikar S. Control of cellular GADD34 levels by the 26S proteasome. Mol Cell Biol. 2008 Dec;28(23):6989–7000.
Brush, Matthew H., and Shirish Shenolikar. “Control of cellular GADD34 levels by the 26S proteasome.Mol Cell Biol, vol. 28, no. 23, Dec. 2008, pp. 6989–7000. Pubmed, doi:10.1128/MCB.00724-08.
Brush MH, Shenolikar S. Control of cellular GADD34 levels by the 26S proteasome. Mol Cell Biol. 2008 Dec;28(23):6989–7000.

Published In

Mol Cell Biol

DOI

EISSN

1098-5549

Publication Date

December 2008

Volume

28

Issue

23

Start / End Page

6989 / 7000

Location

United States

Related Subject Headings

  • Ubiquitination
  • Tumor Cells, Cultured
  • Protein Stability
  • Protein Phosphatase 1
  • Proteasome Endopeptidase Complex
  • Humans
  • Eukaryotic Initiation Factor-2
  • Endoplasmic Reticulum
  • Developmental Biology
  • Cystic Fibrosis Transmembrane Conductance Regulator