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PMID: 14532117 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

CHIP activates HSF1 and confers protection against apoptosis and cellular stress.

The EMBO journal ·Vol. 22 ·No. 20 ·2003-10-15 ·Pages 5446-58

Dai Q, Zhang C, Wu Y, McDonough H, Whaley RA, Godfrey V, Li HH, Madamanchi N, Xu W, Neckers L, Cyr D, Patterson C

Abstract

Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory control by molecular chaperones Hsp70 and Hsp90. In metazoan species, the chaperone system also provides protection against apoptosis. We demonstrate that the dual function co-chaperone/ubiquitin ligase CHIP (C-terminus of Hsp70-interacting protein) regulates activation of the stress-chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress-induced apoptosis in murine fibroblasts. The consequences of this function are demonstrated by the phenotype of mice lacking CHIP, which develop normally but are temperature-sensitive and develop apoptosis in multiple organs after environmental challenge. CHIP exerts a central and unique role in tuning the response to stress at multiple levels by regulation of protein quality control and transcriptional activation of stress response signaling.

MeSH Terms
Amino Acid Substitution Animals Apoptosis/physiology COS Cells Cells, Cultured Chlorocebus aethiops DNA-Binding Proteins/deficiency,genetics,physiology Fibroblasts/cytology,physiology Gene Expression Regulation HSP70 Heat-Shock Proteins/genetics Heat Shock Transcription Factors Hot Temperature Mice Mice, Knockout Mutagenesis, Site-Directed Promoter Regions, Genetic Recombinant Proteins/metabolism Stress, Mechanical Transcription Factors Transcriptional Activation Ubiquitin-Protein Ligases/deficiency,genetics,metabolism
Chemicals
DNA-Binding Proteins HSF1 protein, human HSP70 Heat-Shock Proteins Heat Shock Transcription Factors Recombinant Proteins Transcription Factors STUB1 protein, human Ubiquitin-Protein Ligases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Dai Qian
Carolina Cardiovascular Biology Center, and Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
Zhang Chunlian
Wu Yaxu
McDonough Holly
Whaley Ryan A
Godfrey Virginia
Li Hui-Hua
Madamanchi Nageswara
Xu Wanping
Neckers Len
Cyr Douglas
Patterson Cam
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg529
Published
2003-10-15
Pages
5446-58
Language
English
Region
England
NLM ID
8208664
PMCID
PMC213783
Subset
IM
Grants
NHLBI NIH HHS · HL65619 · United States
NHLBI NIH HHS · R01 HL065619 · United States
NIGMS NIH HHS · R01 GM061728 · United States
NHLBI NIH HHS · R37 HL065619 · United States
NIGMS NIH HHS · R01 GM056981 · United States
NIGMS NIH HHS · GM61728 · United States
NIGMS NIH HHS · GM56981 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdg529 PMC Full Text View journal details
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