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Title: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics

Authors:
; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1337464
Grant/Contract Number:
AC02-05CH11231
Resource Type:
Journal Article: Published Article
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 8; Related Information: CHORUS Timestamp: 2017-06-24 16:37:21; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science (PLoS)
Country of Publication:
United States
Language:
English

Citation Formats

Waight, Andrew B., Bargsten, Katja, Doronina, Svetlana, Steinmetz, Michel O., Sussman, Django, Prota, Andrea E., and Komarova, ed., Yulia. Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0160890.
Waight, Andrew B., Bargsten, Katja, Doronina, Svetlana, Steinmetz, Michel O., Sussman, Django, Prota, Andrea E., & Komarova, ed., Yulia. Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics. United States. doi:10.1371/journal.pone.0160890.
Waight, Andrew B., Bargsten, Katja, Doronina, Svetlana, Steinmetz, Michel O., Sussman, Django, Prota, Andrea E., and Komarova, ed., Yulia. 2016. "Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics". United States. doi:10.1371/journal.pone.0160890.
@article{osti_1337464,
title = {Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics},
author = {Waight, Andrew B. and Bargsten, Katja and Doronina, Svetlana and Steinmetz, Michel O. and Sussman, Django and Prota, Andrea E. and Komarova, ed., Yulia},
abstractNote = {},
doi = {10.1371/journal.pone.0160890},
journal = {PLoS ONE},
number = 8,
volume = 11,
place = {United States},
year = 2016,
month = 8
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1371/journal.pone.0160890

Citation Metrics:
Cited by: 2works
Citation information provided by
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  • Highlights: • COH-203 exhibits anti-hepatoma effects in vitro and in vivo with low toxicity. • COH-203 inhibits tubulin polymerization. • COH-203 induces mitotic arrest followed by mitotic slippage in BEL-7402 cells. • COH-203 induces p53-dependent senescence in BEL-7402 cells. - Abstract: 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1, 2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal livermore » cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14{sup Arf}–p53–p21 and p16{sup INK4α}–Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.« less
  • No abstract prepared.
  • Plus-end tracking proteins, such as EB1 and the dynein/dynactin complex, regulate microtubule dynamics. These proteins are thought to stabilize microtubules by forming a plus-end complex at microtubule growing ends with ill-defined mechanisms. Here we report the crystal structure of two plus-end complex components, the carboxy-terminal dimerization domain of EB1 and the microtubule binding (CAP-Gly) domain of the dynactin subunit p150{sup Glued}. Each molecule of the EB1 dimer contains two helices forming a conserved four-helix bundle, while also providing p150{sup Glued} binding sites in its flexible tail region. Combining crystallography, NMR, and mutational analyses, our studies reveal the critical interacting elementsmore » of both EB1 and p150{sup Glued}, whose mutation alters microtubule polymerization activity. Moreover, removal of the key flexible tail from EB1 activates microtubule assembly by EB1 alone, suggesting that the flexible tail negatively regulates EB1 activity. We, therefore, propose that EB1 possesses an autoinhibited conformation, which is relieved by p150{sup Glued} as an allosteric activator.« less
  • No abstract prepared.