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Bargagna-Mohan P, Hamza A, Kim YE, Khuan Abby Ho Y, Mor-Vaknin N, Wendschlag
N, Liu J, Evans RM, Markovitz DM, Zhan CG, Kim KB, Mohan R.
The tumor inhibitor and antiangiogenic agent withaferin A targets the
intermediate filament protein vimentin.
Chem Biol. 2007 Jun;14(6):623-34
Department of Ophthalmology and Visual Sciences, University of Kentucky,
Lexington, KY 40536, USA.
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
withanolide-based therapeutics for treating angioproliferative and malignant
diseases.
PMID: 17584610
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