期刊
CHEMISTRY & BIOLOGY
卷 14, 期 6, 页码 623-634出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2007.04.010
关键词
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资金
- NEI NIH HHS [R01 EY016782-01A2, R01 EY016782-03, R01 EY016782-05, R01 EY016782-02, R01 EY016782, R01 EY016782-04] Funding Source: Medline
The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved alpha-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolidebased therapeutics for treating angioproliferative and malignant diseases.
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