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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zurawska, Anna Urbanski, Jakub Matulis, Daumantas Filipek, Slawomir Klejman, Marcin P. Baraniak, Janina Bieganowski, Pawel Matuliene, Jurgita |
| Description | Author Affiliation: Zurawska A ( International Institute of Molecular and Cell Biology, Warsaw, Poland.) |
| Abstract | Hsp90 inhibitors are currently tested in clinical trials as anticancer agents. We investigated whether inhibitor resistance may arise as a result of a point mutation in Hsp90. We used yeast cells that expressed human Hsp90β to select inhibitor-resistant mutants from the randomly mutagenized library. Single amino acid substitution, I123T, in a selected mutant was sufficient to confer inhibitor resistance. Transfection of human cells with the HSP90β I123T and the corresponding HSP90α I128T yielded cell lines resistant to inhibitors of the Hsp90 ATPase. Unexpectedly, mutations did not result in diminished inhibitor binding in vitro. Similarly resistant cells were obtained after transfection with previously described A116N and T31I mutants of HSP90β that cause increase in ATPase activity in vitro. Inhibitor-resistant phenotypes of the I123T and A116N mutants depended on their increased affinity for Aha1, whereas T31I mutation did not result in increased Aha1 binding. These results show possible scenario by which resistance may arise in patients treated with Hsp90 inhibitors. Additionally, our results show that each isoform of Hsp90 can alone sustain cellular functions. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 5 |
| Volume Number | 1803 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2010-05-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Adenosine Triphosphatases Metabolism Drug Resistance HSP90 Heat-Shock Proteins Genetics Mutation Saccharomyces Cerevisiae Amino Acid Substitution Benzoquinones Pharmacology Blotting, Western Chaperonins Enzyme Inhibitors Antagonists & Inhibitors Immunoprecipitation In Vitro Techniques Kidney Embryology Lactams, Macrocyclic Models, Molecular Molecular Chaperones Protein Binding Protein Conformation Growth & Development Saccharomyces Cerevisiae Proteins Two-Hybrid System Techniques Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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