Importin-β/karyopherin-β1 modulates mitotic microtubule function and taxane sensitivity in cancer cells via its nucleoporin-binding region.
Bridged-Ring Compounds
/ pharmacology
Drug Synergism
Gene Expression Regulation, Neoplastic
/ drug effects
HeLa Cells
Humans
Microtubules
/ drug effects
Mitosis
/ drug effects
Nuclear Pore Complex Proteins
/ metabolism
Paclitaxel
/ pharmacology
Protein Binding
Taxoids
/ pharmacology
beta Karyopherins
/ chemistry
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
02
09
2018
accepted:
25
04
2019
revised:
27
02
2019
pubmed:
8
9
2019
medline:
17
4
2020
entrez:
8
9
2019
Statut:
ppublish
Résumé
The nuclear transport receptor importin-β/karyopherin-β1 is overexpressed in cancers that display genomic instability. It is regarded as a promising cancer target and inhibitors are being developed. In addition to its role in nucleo-cytoplasmic transport, importin-β regulates mitosis, but the programmes and pathways in which it operates are defined only in part. To unravel importin-β's mitotic functions we have developed cell lines expressing either wild-type or a mutant importin-β form in characterised residues required for nucleoporin binding. Both forms similarly disrupted spindle pole organisation, while only wild-type importin-β affected microtubule plus-end function and microtubule stability. A proteome-wide search for differential interactors identified a set of spindle regulators sensitive to mutations in the nucleoporin-binding region. Among those, HURP (hepatoma up-regulated protein) is an importin-β interactor and a microtubule-stabilising factor. We found that induction of wild type, but not mutant importin-β, under the same conditions that destabilise mitotic microtubules, delocalised HURP, indicating that the spatial distribution of HURP along the spindle requires importin-β's nucleoporin-binding residues. Concomitantly, importin-β overexpression sensitises cells to taxanes and synergistically increases mitotic cell death. Thus, the nucleoporin-binding domain is dispensable for importin-β function in spindle pole organisation, but regulates microtubule stability, at least in part via HURP, and renders cells vulnerable to certain microtubule-targeting drugs.
Identifiants
pubmed: 31492900
doi: 10.1038/s41388-019-0989-x
pii: 10.1038/s41388-019-0989-x
doi:
Substances chimiques
Bridged-Ring Compounds
0
KPNB1 protein, human
0
Nuclear Pore Complex Proteins
0
Taxoids
0
beta Karyopherins
0
taxane
1605-68-1
Paclitaxel
P88XT4IS4D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
454-468Références
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