EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer.
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Date
2017-12-11ICR Author
Author
Oldrini, B
Hsieh, W-Y
Erdjument-Bromage, H
Codega, P
Carro, MS
Curiel-García, A
Campos, C
Pourmaleki, M
Grommes, C
Vivanco, I
Rohle, D
Bielski, CM
Taylor, BS
Hollmann, TJ
Rosenblum, M
Tempst, P
Blenis, J
Squatrito, M
Mellinghoff, IK
Type
Journal Article
Metadata
Show full item recordAbstract
Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway.
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Subject
Cells, Cultured
Cell Line, Tumor
Animals
Mice, Knockout
Humans
Mice, SCID
Glioma
Doxorubicin
ran GTP-Binding Protein
beta Karyopherins
Antibiotics, Antineoplastic
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
Active Transport, Cell Nucleus
Female
STAT3 Transcription Factor
Gene Knockdown Techniques
Feedback, Physiological
HEK293 Cells
ErbB Receptors
Research team
Molecular Addictions
Language
eng
Date accepted
2017-11-09
License start date
2017-12-11
Citation
Nature communications, 2017, 8 (1), pp. 2035 - ?
Publisher
NATURE PUBLISHING GROUP