Ratjadones inhibit nuclear export by blocking CRM1/exportin 1.
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.
Department of Gene Regulation and Differentiation, GBF-German Research Centre for Biotechnology, Mascheroder Weg 1, D-38124 Braunschweig, Germany.
Mario
M
Köster
Søren
S
Lykke-Andersen
Yasser A
YA
Elnakady
Klaus
K
Gerth
Peter
P
Washausen
Gerhard
G
Höfle
Florenz
F
Sasse
Jørgen
J
Kjems
Hansjörg
H
Hauser
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005057:Eukaryotic Cells / Q000187:drug effects* / Q000378:metabolism*; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D015394:Molecular Structure; D009231:Myxococcales / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021382:Protein Sorting Signals / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects* / Q000502:physiology; D011753:Pyrones / Q000737:chemistry* / Q000302:isolation & purification*; D018160:Receptors, Cytoplasmic and Nuclear; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020931:ran GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism; D000097606:Exportin 1 Protein
D028884:Karyopherins; D046911:Macromolecular Substances; D021382:Protein Sorting Signals; D011753:Pyrones; D018160:Receptors, Cytoplasmic and Nuclear; D020931:ran GTP-Binding Protein; D000097606:Exportin 1 Protein; C429103:ratjadone