Document Detail

Stress-dependent Daxx-CHIP interaction suppresses the p53 apoptotic program.
MedLine Citation:
PMID:  19465479     Owner:  NLM     Status:  MEDLINE    
Our previous studies have implicated CHIP (carboxyl terminus of Hsp70-interacting protein) as a co-chaperone/ubiquitin ligase whose activities yield protection against stress-induced apoptotic events. In this report, we demonstrate a stress-dependent interaction between CHIP and Daxx (death domain-associated protein). This interaction interferes with the stress-dependent association of HIPK2 with Daxx, blocking phosphorylation of serine 46 in p53 and inhibiting the p53-dependent apoptotic program. Microarray analysis confirmed suppression of the p53-dependent transcriptional portrait in CHIP(+/+) but not in CHIP(-/-) heat shocked mouse embryonic fibroblasts. The interaction between CHIP and Daxx results in ubiquitination of Daxx, which is then partitioned to an insoluble compartment of the cell. In vitro ubiquitination of Daxx by CHIP revealed that ubiquitin chain formation utilizes non-canonical lysine linkages associated with resistance to proteasomal degradation. The ubiquitination of Daxx by CHIP utilizes lysines 630 and 631 and competes with the sumoylation machinery of the cell at these residues. These studies implicate CHIP as a stress-dependent regulator of Daxx that counters the pro-apoptotic influence of Daxx in the cell. By abrogating p53-dependent apoptotic pathways and by ubiquitination competitive with Daxx sumoylation, CHIP integrates the proteotoxic stress response of the cell with cell cycle pathways that influence cell survival.
Holly McDonough; Peter C Charles; Eleanor G Hilliard; Shu-Bing Qian; Jin-Na Min; Andrea Portbury; Douglas M Cyr; Cam Patterson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-05-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-27     Completed Date:  2009-10-14     Revised Date:  2010-09-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20649-59     Citation Subset:  IM    
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599-7126, USA.
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MeSH Terms
Carrier Proteins / chemistry,  metabolism*
Cell Line
Cell Nucleus / metabolism
Embryo, Mammalian / cytology
Fibroblasts / metabolism
Gene Expression Profiling
Heat-Shock Response
Intracellular Signaling Peptides and Proteins / chemistry,  metabolism*
Lysine / metabolism
Molecular Sequence Data
Nuclear Proteins / chemistry,  metabolism*
Protein Binding
Protein Interaction Mapping
Protein Structure, Tertiary
Protein Transport
Protein-Serine-Threonine Kinases / metabolism
Small Ubiquitin-Related Modifier Proteins / metabolism
Stress, Physiological*
Substrate Specificity
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin-Protein Ligases / chemistry,  metabolism*
Up-Regulation / genetics
Grant Support
Reg. No./Substance:
0/Carrier Proteins; 0/Daxx protein, mouse; 0/Intracellular Signaling Peptides and Proteins; 0/Nuclear Proteins; 0/Small Ubiquitin-Related Modifier Proteins; 0/Tumor Suppressor Protein p53; 56-87-1/Lysine; EC 2.7.1.-/Hipk2 protein, mouse; EC Kinases; EC protein, mouse; EC Ligases

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