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

Emma Vincent, J. Saxton, C. Baker-Glenn, I. Moal, J. D. Hirst, G. Pattenden, P. E. Shaw*

*Corresponding author for this work

    Research output: Contribution to journalArticle (Academic Journal)peer-review

    11 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)487-497
    Number of pages11
    JournalCellular and Molecular Life Sciences
    Volume64
    Issue number4
    DOIs
    Publication statusPublished - Feb 2007

    Keywords

    • Actin cytoskeleton
    • Immediate early genes
    • Serum response factor
    • Toxins
    • Transcription

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