Hsp90 is essential for restoring cellular functions of temperature-sensitive p53 mutant protein but not for stabilization and activation of wild-type p53: implications for cancer therapy
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
15613472
DOI
10.1074/jbc.m412767200
PII: S0021-9258(19)62783-3
Knihovny.cz E-zdroje
- MeSH
- genetická transkripce MeSH
- jaderné proteiny genetika MeSH
- konformace proteinů MeSH
- lidé MeSH
- mutace * MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 genetika metabolismus fyziologie MeSH
- nádory patologie MeSH
- proteiny tepelného šoku HSP90 metabolismus fyziologie MeSH
- protoonkogenní proteiny c-mdm2 MeSH
- protoonkogenní proteiny genetika MeSH
- regulace genové exprese u nádorů MeSH
- teplota * MeSH
- zpětná vazba fyziologická MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- jaderné proteiny MeSH
- MDM2 protein, human MeSH Prohlížeč
- nádorový supresorový protein p53 MeSH
- proteiny tepelného šoku HSP90 MeSH
- protoonkogenní proteiny c-mdm2 MeSH
- protoonkogenní proteiny MeSH
Several signaling pathways that monitor the dynamic state of the cell converge on the tumor suppressor p53. The ability of p53 to process these signals and exert a dynamic downstream response in the form of cell cycle arrest and/or apoptosis is crucial for preventing tumor development. This p53 function is abrogated by p53 gene mutations leading to alteration of protein conformation. Hsp90 has been implicated in regulating both wild-type and mutant p53 conformations, and Hsp90 antagonists are effective for the therapy of some human tumors. Using cell lines that contain human tumor-derived temperature-sensitive p53 mutants we show that Hsp90 is required for both stabilization and reactivation of mutated p53 at the permissive temperature. A temperature decrease to 32 degrees C causes conversion to a protein conformation that is capable of inducing expression of MDM2, leading to reduction of reactivated p53 levels by negative feedback. Mutant reactivation is enhanced by simultaneous treatment with agents that stabilize the reactivated protein and is blocked by geldanamycin, a specific inhibitor of Hsp90 activity, indicating that Hsp90 antagonist therapy and therapies that act to reactivate mutant p53 will be incompatible. In contrast, Hsp90 is not required for maintaining wild-type p53 or for stabilizing wild-type p53 after treatment with chemotherapeutic agents, indicating that Hsp90 therapy might synergize with conventional therapies in patients with wild-type p53. Our data demonstrate the importance of the precise characterization of the interaction between p53 mutants and stress proteins, which may shed valuable information for fighting cancer via the p53 tumor suppressor pathway.
Citace poskytuje Crossref.org