Nuclear transport surveillance of p53 by nuclear pores in glioblastoma
Dini Kurnia Ikliptikawati,
Nozomi Hirai,
Kei Makiyama,
Hemragul Sabit,
Masashi Kinoshita,
Koki Matsumoto,
Keesiang Lim,
Makiko Meguro-Horike,
Shin-ichi Horike,
Masaharu Hazawa,
Mitsutoshi Nakada,
Richard W. Wong
Affiliations
Dini Kurnia Ikliptikawati
Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan; Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 9201192, Japan
Nozomi Hirai
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 9208641, Japan; Department of Neurosurgery, Toho University Ohashi Medical Center, Tokyo 1538515, Japan
Kei Makiyama
Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan
Hemragul Sabit
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 9208641, Japan
Masashi Kinoshita
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 9208641, Japan
Koki Matsumoto
Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan
Keesiang Lim
WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 9201192, Japan
Makiko Meguro-Horike
Advanced Science Research Center, Institute for Gene Research, Kanazawa University, Kanazawa, Ishikawa, Japan
Shin-ichi Horike
Advanced Science Research Center, Institute for Gene Research, Kanazawa University, Kanazawa, Ishikawa, Japan
Masaharu Hazawa
Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan; Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 9201192, Japan; Corresponding author
Mitsutoshi Nakada
Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 9208641, Japan; Corresponding author
Richard W. Wong
Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan; Laboratory of Molecular Cell Biology, Division of Transdisciplinary Sciences, Graduate School of Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa 9201192, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 9201192, Japan; Corresponding author
Summary: Nuclear pore complexes (NPCs) are the central apparatus of nucleocytoplasmic transport. Disease-specific alterations of NPCs contribute to the pathogenesis of many cancers; however, the roles of NPCs in glioblastoma (GBM) are unknown. In this study, we report genomic amplification of NUP107, a component of NPCs, in GBM and show that NUP107 is overexpressed simultaneously with MDM2, a critical E3 ligase that mediates p53 degradation. Depletion of NUP107 inhibits the growth of GBM cell lines through p53 protein stabilization. Mechanistically, NPCs establish a p53 degradation platform via an export pathway coupled with 26S proteasome tethering. NUP107 is the keystone for NPC assembly; the loss of NUP107 affects the integrity of the NPC structure, and thus the proportion of 26S proteasome in the vicinity of nuclear pores significantly decreases. Together, our findings establish roles of NPCs in transport surveillance and provide insights into p53 inactivation in GBM.
