Homodimerization antagonizes nuclear export of survivin.
Survivin plays separate roles during different phases of the cell cycle. In mitosis, Survivin is a key regulator of cell division, while in interphase, Survivin is able to protect cells from apoptosis. Survivin shuttles between nucleus and cytoplasm under the influence of one or more nuclear export signals (NESs). Paradoxically, our data show that Survivin poorly binds CRM1 in vitro because hydrophobic residues of the NES are occupied in homodimer contacts. We show that NES-preserving dimerization mutants behave as monomers in solution, show dramatically increased CRM1 binding and are more efficiently exported in vivo than wild-type Survivin. These data indicate that Survivin contains a monomer-specific NES and that dimerization modulates cytoplasmic access of the protein. Our findings have implications for both the mitotic and interphase roles of survivin.
Engelsma
Dieuwke
D
Department of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Rodriguez
Jose A
JA
Fish
Alexander
A
Giaccone
Giuseppe
G
Fornerod
Maarten
M
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008027:Light; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000502:physiology*; D008938:Mitosis; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D049790:Nuclear Export Signals; D012542:Scattering, Radiation; D000077022:Survivin
C107489:BIRC5 protein, human; D005231:Fatty Acids, Unsaturated; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D049790:Nuclear Export Signals; D000077022:Survivin; C038753:leptomycin B