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Structural basis for depletion of heat shock protein 90 client proteins by deguelin

Authors
Oh, SHWoo, JKYazici, YDMyers, JNKim, WYJin, QHong, SSPark, HJSuh, YGKim, KWHong, WKLee, HY
Issue Date
Jun-2007
Publisher
OXFORD UNIV PRESS INC
Citation
JOURNAL OF THE NATIONAL CANCER INSTITUTE, v.99, no.12, pp 949 - 961
Pages
13
Journal Title
JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume
99
Number
12
Start Page
949
End Page
961
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/148416
DOI
10.1093/jnci/djm007
ISSN
0027-8874
1460-2105
Abstract
Background The molecular chaperone heat shock protein 90 (Hsp90) participates in preserving the expression and activity of various oncoproteins, including hypoxia-inducible factor la (HIF-1 alpha) and Akt. Deguelin is a rotenoid with antitumor activities. We investigated whether the antitumor activities of deguelin involve the functional inhibition of Hsp90. Method Human xenograft tumors were generated in mice from H1299 (n = 6 per group) and A549 (n = 4 per group) non-small-cell lung cancer cells, UMSCC38 (n = 5 per group) head and neck cancer cells, MKN45 (n = 5 per group) stomach cancer cells, and PC-3 (n = 3 per group) prostate cancer cells. Tumor-bearing mice were treated with deguelin at 4 or 8 mg/kg or with vehicle (as a control) twice a day by oral gavage for 15-28 days. Protein expression was assessed by western blot analysis. Akt and Hsp90 were assessed by use of adenoviral vectors expressing constitutively active Akt or Hsp90. Binding of deguelin to Hsp90 was examined by docking analysis and by competition binding experiments with ATP-Sepharose beads. The proteasome inhibitor MG132 was used to investigate deguelin's effect on the induction of ubiquitin-mediated proteasomal degradation of HIF-1a. All statistical tests were two-sided. Results Deguelin bound to the ATP-binding pocket of Hsp90 and disrupt
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