title: GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis.
abstract: The ribosomal protein L11 (RPL11) binds and inhibits the MDM2 ubiquitin ligase, thereby promoting p53 stability. Thus, RPL11 acts as a tumor suppressor. Here, we show that GRWD1 (glutamate-rich WD40 repeat containing 1) physically and functionally interacts with RPL11. GRWD1 is localized to nucleoli and is released into the nucleoplasm upon nucleolar stress. Silencing of GRWD1 increases p53 induction by nucleolar stress, whereas overexpression of GRWD1 reduces p53 induction. Furthermore, GRWD1 overexpression competitively inhibits the RPL11-MDM2 interaction and alleviates RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53. These effects are mediated by the N-terminal region of GRWD1, including the acidic domain. Finally, we show that GRWD1 overexpression in combination with HPV16 E7 and activated KRAS confers anchorage-independent growth and tumorigenic capacity on normal human fibroblasts. Consistent with this, GRWD1 overexpression is associated with poor prognosis in cancer patients. Taken together, our results suggest that GRWD1 is a novel negative regulator of p53 and a potential oncogene.
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Kayama
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Takafuji
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Hironaka
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Division of Refractory and Advancer Cancer, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Enari
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Kouya
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan mfujita@phar.kyushu-u.ac.jp.
authors.forename: Masatoshi
authors.identifier: 0000-0001-6617-2452
authors.initials: M
authors.lastname: Fujita
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D002472:Cell Transformation, Viral; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D011905:Genes, ras; D064593:Heterografts; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C504316:GRWD1 protein, human; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D051736:Proto-Oncogene Proteins c-mdm2
keywords: GRWD1; nucleolar stress; p53/RPL11; tumorigenesis