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PMID: 12724406 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.

Molecular and cellular biology ·Vol. 23 ·No. 10 ·2003-05-00 ·Pages 3477-86

Hung WJ, Roberson RS, Taft J, Wu DY

Abstract

The cellular stress response protein GADD34 mediates growth arrest and apoptosis in response to DNA damage, negative growth signals, and protein malfolding. GADD34 binds to protein phosphatase PP1 and can attenuate the translational elongation of key transcriptional factors through dephosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha). Recently, we reported the involvement of human SNF5/INI1 (hSNF5/INI1) protein in the functions of GADD34 and showed that hSNF5/INI1 binds GADD34 and stimulates the bound PP1 phosphatase activity. To better understand the regulatory and functional mechanisms of GADD34, we undertook a yeast two-hybrid screen with full-length GADD34 as bait in order to identify additional protein partners of GADD34. We report here that human cochaperone protein BAG-1 interacts with GADD34 in vitro and in SW480 cells treated with the proteasome inhibitor z-LLL-B to induce apoptosis. Two other proteins, Hsp70/Hsc70 and PP1, associate reversibly with the GADD34-BAG-1 complex, and their dissociation is promoted by ATP. BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress.

MeSH Terms
3T3 Cells Animals Antigens, Differentiation Apoptosis Carrier Proteins/metabolism Cell Cycle Proteins Cell Line Chromosomal Proteins, Non-Histone DNA-Binding Proteins/metabolism Dose-Response Relationship, Drug Eukaryotic Initiation Factor-2/metabolism Flow Cytometry Glutathione Transferase/metabolism HSC70 Heat-Shock Proteins HSP70 Heat-Shock Proteins/metabolism Humans Mice Phosphorylation Plasmids/metabolism Precipitin Tests Protein Binding Protein Isoforms Protein Phosphatase 1 Protein Structure, Tertiary Proteins/metabolism SMARCB1 Protein Transcription Factors/metabolism Transfection Two-Hybrid System Techniques
Chemicals
Antigens, Differentiation BCL2-associated athanogene 1 protein Carrier Proteins Cell Cycle Proteins Chromosomal Proteins, Non-Histone DNA-Binding Proteins Eukaryotic Initiation Factor-2 HSC70 Heat-Shock Proteins HSP70 Heat-Shock Proteins HSPA8 protein, human Hspa8 protein, mouse Protein Isoforms Proteins SMARCB1 Protein SMARCB1 protein, human Smarcb1 protein, mouse Transcription Factors Glutathione Transferase PPP1R15A protein, human Ppp1r15a protein, mouse Protein Phosphatase 1
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Hung Wesley J
Division of Medical Oncology, Department of Medicine, Veterans Administration Puget Sound Health Care System, Seattle Division, 1660 S. Columbian Way, Seattle, WA 98108, USA.
Roberson Rachel S
Taft Jaime
Wu Daniel Y
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.10.3477-3486.2003
Published
2003-05-00
Pages
3477-86
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC164759
Subset
IM
Grants
NCI NIH HHS · 5K08 CA 71928-01 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.10.3477-3486.2003 PMC Full Text View journal details
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