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Søren Lykke-Andersen

Ratjadones inhibit nuclear export by blocking CRM1/exportin 1

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  • Mario Köster, Department of Gene Regulation and Differentiation, GBF—German Research Centre for Biotechnology, Braunschweig, Tyskland
  • Søren Lykke-Andersen
  • Yasser A Elnakady, Department of Natural Products, GBF—German Research Centre for Biotechnology, Braunschweig, Tyskland
  • Klaus Gerth, Department of Natural Products, GBF—German Research Centre for Biotechnology, Braunschweig, Tyskland
  • Peter Washausen, Department of Natural Products, GBF—German Research Centre for Biotechnology, Braunschweig, Tyskland
  • Gerhard Höfle, Department of Natural Products, GBF—German Research Centre for Biotechnology, Braunschweig, Tyskland
  • Florenz Sasse, Department of Natural Products, GBF—German Research Centre for Biotechnology, Braunschweig, Tyskland
  • Jørgen Kjems
  • Hansjörg Hauser
In addition to previously isolated ratjadone A we describe three new members of this family, ratjadones B, C, and D, from another strain of the myxobacterium Sorangium cellulosum. We have investigated the properties of these ratjadones with respect to their activity on mammalian cell lines. We found IC(50) values in the picomolar range and a significant increase in the size of nuclei. A further examination showed that they inhibit the export of the leucine-rich nuclear export signal (LR-NES) containing proteins in different cell lines. Ratjadones are able to inhibit the formation of the nuclear export complex composed of the CRM1, RanGTP, and the cargo protein, as shown by two different in vitro assays. Finally, the binding of ratjadone C to CRM1 was demonstrated. These ratjadone activities are in the same concentration range as described for the polyketide leptomycin B (LMB) from Streptomyces sp. Like LMB, it seems that the ratjadones covalently bind to CRM1, inhibit cargo protein binding via LR-NES, and thereby block nuclear export. Thus, the ratjadones represent a new class of natural compounds which inhibit proliferation in eukaryotes by blocking nuclear export.
OriginalsprogEngelsk
TidsskriftExperimental Cell Research
Vol/bind286
Nummer2
Sider (fra-til)321-331
Antal sider11
ISSN0014-4827
DOI
StatusUdgivet - 2003

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