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C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances
P. Muller, E. Ruckova, P. Halada, PJ. Coates, R. Hrstka, DP. Lane, B. Vojtesek
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
NS9812
MZ0
CEP - Centrální evidence projektů
NT13794
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Plný text - Článek
Zdroj
Zdroj
Open Access Digital Library od 1997-01-01
Medline Complete (EBSCOhost) od 1997-01-09 do 2015-11-26
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem
Odkazy
PubMed
22824801
DOI
10.1038/onc.2012.314
Knihovny.cz E-zdroje
- MeSH
- fosforylace MeSH
- HEK293 buňky MeSH
- kinasa 3 glykogensynthasy metabolismus MeSH
- lidé MeSH
- messenger RNA biosyntéza MeSH
- nádorové buněčné linie MeSH
- nádory prsu metabolismus MeSH
- proteiny tepelného šoku HSP70 metabolismus MeSH
- proteiny tepelného šoku HSP90 metabolismus MeSH
- proteiny tepelného šoku genetika metabolismus MeSH
- sbalování proteinů MeSH
- ubikvitinligasy metabolismus MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Heat shock proteins Hsp90 and Hsp70 facilitate protein folding but can also direct proteins for ubiquitin-mediated degradation. The mechanisms regulating these opposite activities involve Hsp binding to co-chaperones including CHIP and HOP at their C-termini. We demonstrated that the extreme C-termini of Hsp70 and Hsp90 contain phosphorylation sites targeted by kinases including CK1, CK2 and GSK3-β in vitro. The phosphorylation of Hsp90 and Hsp70 prevents binding to CHIP and thus enhances binding to HOP. Highly proliferative cells contain phosphorylated chaperones in complex with HOP and phospho-mimetic and non-phosphorylable Hsp mutant proteins show that phosphorylation is directly associated with increased proliferation rate. We also demonstrate that primary human cancers contain high levels of phosphorylated chaperones and show increased levels of HOP protein and mRNA. These data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-chaperone expression and chaperone modifications. In addition to identifying the pathway responsible for regulating chaperone-mediated protein folding/degradation balances in normal cells, the data provide novel mechanisms to account for the aberrant chaperone activities observed in human cancer cells and have implications for the application of anti-chaperone therapies in cancer treatment.
Centre for Oncology and Molecular Medicine University of Dundee Nethergate Dundee Scotland UK
Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic
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