EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer

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 nor...

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Detalles Bibliográficos
Autores: Oldrini, Barbara, Hsieh, Wan-Ying, Erdjument-Bromage, Hediye, Codega, Paolo, Carro, Maria Stella, Curiel-García, Alvaro, Campos, Carl, Pourmaleki, Maryam, Grommes, Christian, Vivanco, Igor, Rohle, Daniel, Bielski, Craig M, Taylor, Barry S, Hollmann, Travis J, Rosenblum, Marc, Tempst, Paul, Blenis, John, Squatrito, Massimo, Mellinghoff, Ingo K
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/6884
Acceso en línea:http://hdl.handle.net/20.500.12105/6884
Access Level:acceso abierto
Palabra clave:Active Transport, Cell Nucleus
Animals
Antibiotics, Antineoplastic
Cell Line, Tumor
Cells, Cultured
Doxorubicin
ErbB Receptors
Feedback, Physiological
Female
Gene Knockdown Techniques
Glioma
HEK293 Cells
Humans
Mice, Knockout
Mice, SCID
STAT3 Transcription Factor
Xenograft Model Antitumor Assays
beta Karyopherins
ran GTP-Binding Protein
Gene Expression Regulation, Neoplastic
Descripción
Sumario: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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