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Effects of ulapualide A and synthetic macrolide analogues on actin dynamics and gene regulation

  • E. Vincent
  • J. Saxton
  • C. Baker-Glenn
  • I. Moal
  • J. D. Hirst
  • G. Pattenden
  • P. E. Shaw
Research Article

Abstract.

Several marine macrolide toxins act as potent and specific actin-severing molecules. Recent elucidation of their stereochemistries and modes of interaction with actin has allowed the syntheses of bioactive analogues. Here we used synthetic analogues in a structure-function analysis of ulapualide A, a trisoxazole-based macrolide. Ulapualide A harboured potent actin-depolymerising activity both in cells and in vitro. Its synthetic diastereoisomer was three orders of magnitude less active than the natural toxin and synthetic macrolide fragments lacked actin-capping/ severing activity altogether. Modulation of serum response factor (SRF)-dependent gene expression, as described for other actin-binding toxins, was also examined. Specific changes in response to ulapualide A were not observed, primarily due to its profound effects on cytoskeletal integrity and cell adhesion. Several synthetic fragments of ulapualide A also had no effect on SRF-dependent gene expression. However, inhibition was observed with a molecule corresponding to the extended aliphatic side chain of halichondramide, a structurally related macrolide. These findings indicate that side-chain derivatives of trisoxazole-based macrolides may serve to uncouple gene-regulatory events from actin dynamics.

Keywords.

Actin cytoskeleton immediate early genes toxins transcription serum response factor 

Copyright information

© Birkhäuser Verlag, Basel 2007

Authors and Affiliations

  • E. Vincent
    • 1
    • 3
  • J. Saxton
    • 1
  • C. Baker-Glenn
    • 2
  • I. Moal
    • 2
  • J. D. Hirst
    • 2
  • G. Pattenden
    • 2
  • P. E. Shaw
    • 1
  1. 1.Centre for Biochemistry and Cell Biology, School of Biomedical SciencesUniversity of Nottingham, Queen’s Medical CentreNottinghamUK
  2. 2.School of ChemistryUniversity ParkNottinghamUK
  3. 3.Department of BiochemistryUniversity of BristolBristolUK

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