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Statements

Subject Item
n2:RIV%2F00209805%3A_____%2F13%3A%230000417%21RIV14-GA0-00209805
rdf:type
n5:Vysledek skos:Concept
rdfs:seeAlso
http://www.nature.com/onc/journal/v32/n25/full/onc2012314a.html
dcterms:description
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-b 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. 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-b 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.
dcterms:title
C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances
skos:prefLabel
C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances
skos:notation
RIV/00209805:_____/13:#0000417!RIV14-GA0-00209805
n5:predkladatel
n8:ico%3A00209805
n3:aktivita
n10:Z n10:P n10:I
n3:aktivity
I, P(ED2.1.00/03.0101), P(GAP301/11/1678), P(GBP206/12/G151), P(NT13794), Z(MZ0MOU2005)
n3:cisloPeriodika
25
n3:dodaniDat
n19:2014
n3:domaciTvurceVysledku
n12:9637419 n12:1330586 n12:7623933 n12:5395488
n3:druhVysledku
n13:J
n3:duvernostUdaju
n21:S
n3:entitaPredkladatele
n15:predkladatel
n3:idSjednocenehoVysledku
67448
n3:idVysledku
RIV/00209805:_____/13:#0000417
n3:jazykVysledku
n18:eng
n3:klicovaSlova
Hsp70; Hsp90; CHIP; HOP; chaperone; folding
n3:klicoveSlovo
n9:CHIP n9:HOP n9:folding n9:Hsp90 n9:Hsp70 n9:chaperone
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[CA7299F29C52]
n3:nazevZdroje
Oncogene
n3:obor
n20:EB
n3:pocetDomacichTvurcuVysledku
4
n3:pocetTvurcuVysledku
6
n3:projekt
n4:NT13794 n4:GBP206%2F12%2FG151 n4:GAP301%2F11%2F1678 n4:ED2.1.00%2F03.0101
n3:rokUplatneniVysledku
n19:2013
n3:svazekPeriodika
32
n3:tvurceVysledku
Hrstka, Roman Růčková, Eva Müller, Petr Vojtěšek, Bořivoj
n3:wos
000320705700010
n3:zamer
n7:MZ0MOU2005
s:issn
0950-9232
s:numberOfPages
10
n11:doi
10.1038/onc.2012.314