http://www.cnr.it/ontology/cnr/individuo/prodotto/ID21337
RET is a heat shock protein 90 (HSP90) client protein and is knocked down upon HSP90 pharmacological block. (Articolo in rivista)
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- RET is a heat shock protein 90 (HSP90) client protein and is knocked down upon HSP90 pharmacological block. (Articolo in rivista) (literal)
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- 2010-01-01T00:00:00+01:00 (literal)
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Alfano L, Guida T, Provitera L, Vecchio G, Billaud M, Santoro M, Carlomagno F. (2010)
RET is a heat shock protein 90 (HSP90) client protein and is knocked down upon HSP90 pharmacological block.
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- Alfano L, Guida T, Provitera L, Vecchio G, Billaud M, Santoro M, Carlomagno F. (literal)
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- ISI Web of Science (WOS) (literal)
- Titolo
- RET is a heat shock protein 90 (HSP90) client protein and is knocked down upon HSP90 pharmacological block. (literal)
- Abstract
- CONTEXT: Mutations of the RET receptor tyrosine kinase are associated to multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinoma (MTC). The heat shock protein (HSP) 90 chaperone is required for folding and stability of several kinases. HSP90 is specifically inhibited by 17-allyl-amino-17-demethoxygeldanamycin (17-AAG).
OBJECTIVE: Our aim was to investigate whether RET protein half-life depends on HSP90 and to dissect the molecular pathway responsible for the degradation of RET upon HSP90 inhibition by 17-AAG.
DESIGN: 17-AAG effects were studied in RAT1 fibroblasts exogenously expressing MEN2-associated RET mutants and human MTC-derived cell lines.
RESULTS: 17-AAG induced a 26S proteasome-dependent degradation of wild-type RET and MEN2-associated RET mutants. The compound hampered HSP90/RET interaction and stabilized RET binding to HSP70, leading to the recruitment of the HSP70-associated E3 ligase C-terminus of Hsc70-interacting protein. In turn, C-terminus of Hsc70-interacting protein polyubiquitinated RET, promoting its proteasomal degradation. 17-AAG blocked RET downstream effectors and RET-dependent transcriptional activation of gene promoters. In human MTC cells carrying oncogenic RET mutants, HSP90 inhibition induced receptor degradation and signaling hindrance leading to cell cycle arrest.
CONCLUSION: RET and MEN2-associated RET mutants rely on HSP90 for protein stability, and HSP90 blockade by 17-AAG promotes RET degradation. (literal)
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