Ratjadones inhibit nuclear export by blocking CRM1/exportin 1

Mario Köster; Søren Lykke-Andersen; Yasser A Elnakady; Klaus Gerth; Peter Washausen; Gerhard Höfle; Florenz Sasse; Jørgen Kjems; Hansjörg Hauser

doi:10.1016/s0014-4827(03)00100-9

Ratjadones inhibit nuclear export by blocking CRM1/exportin 1

Exp Cell Res. 2003 Jun 10;286(2):321-31. doi: 10.1016/s0014-4827(03)00100-9.

Authors

Mario Köster¹, Søren Lykke-Andersen, Yasser A Elnakady, Klaus Gerth, Peter Washausen, Gerhard Höfle, Florenz Sasse, Jørgen Kjems, Hansjörg Hauser

Affiliation

¹ Department of Gene Regulation and Differentiation, GBF-German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany.

PMID: 12749860
DOI: 10.1016/s0014-4827(03)00100-9

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Active Transport, Cell Nucleus / drug effects*
Active Transport, Cell Nucleus / physiology
Animals
Cell Division / drug effects
Cell Division / physiology
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cell Size / drug effects
Cell Size / physiology
Dose-Response Relationship, Drug
Eukaryotic Cells / drug effects*
Eukaryotic Cells / metabolism*
Exportin 1 Protein
Karyopherins / antagonists & inhibitors
Karyopherins / metabolism
Macromolecular Substances
Mice
Molecular Structure
Myxococcales / chemistry*
Protein Binding / drug effects
Protein Binding / physiology
Protein Sorting Signals / drug effects
Protein Sorting Signals / physiology
Protein Transport / drug effects*
Protein Transport / physiology
Pyrones / chemistry*
Pyrones / isolation & purification*
Receptors, Cytoplasmic and Nuclear*
Signal Transduction / drug effects
Signal Transduction / physiology
ran GTP-Binding Protein / drug effects
ran GTP-Binding Protein / metabolism

Substances

Karyopherins
Macromolecular Substances
Protein Sorting Signals
Pyrones
Receptors, Cytoplasmic and Nuclear
ratjadone
ran GTP-Binding Protein