Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If You Use a Screen Reader

This content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.

The Dual Mode of Action of Bistramide A Entails Severing of Filamentous Actin and Covalent Protein Modification

Syed Alipayam Rizvi, David S. Courson, Valerie A. Keller, Ronald S. Rock and Sergey A. Kozmin
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 11 (Mar. 18, 2008), pp. 4088-4092
Stable URL: http://www.jstor.org/stable/25461375
Page Count: 5
  • Read Online (Free)
  • Subscribe ($19.50)
  • Cite this Item
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
The Dual Mode of Action of Bistramide A Entails Severing of Filamentous Actin and Covalent Protein Modification
Preview not available

Abstract

This study provides comprehensive characterization of the mode of action of bistramide A and identifies structural requirements of bistramide-based compounds that are responsible for severing actin filaments and inhibiting growth of cancer cells in vitro and in vivo. We rationally designed and assembled a series of structural analogs of the natural product, including a fluorescently labeled conjugate. We used TIRF microscopy to directly observe actin filament severing by this series of small molecules, which established that the combination of the spiroketal and the amide subunits was sufficient to enable rapid actin filament disassembly in vitro. In addition, we demonstrated that the enone subunit of bistramide A is responsible for covalent modification of the protein in vitro and in A549 cells, resulting in further increase in the cytotoxicity of the natural product. Our results demonstrate that bistramide A elicits its potent antiproliferative activity by a dual mechanism of action, which entails both severing of actin filaments and covalent sequestration of monomeric actin in the cell.

Page Thumbnails

  • Thumbnail: Page 
4088
    4088
  • Thumbnail: Page 
4089
    4089
  • Thumbnail: Page 
4090
    4090
  • Thumbnail: Page 
4091
    4091
  • Thumbnail: Page 
4092
    4092