GRWD 1 negatively regulates p53 via the RPL 11– MDM 2 pathway and promotes tumorigenesis

• DOI: 10.15252/embr.201642444
• Publication Date: 2016-11-18T02:50:22Z
• Authors: Kota Kayama; Shinya Watanabe; Takuya Takafuji; Takahiro Tsuji; Kensuke Hironaka; Masaki Matsumoto; Keiichi I Nakayama; Masato Enari; Takashi Kohno; Kouya Shiraishi; Tohru Kiyono; Kazumasa Yoshida; Nozomi Sugimoto; Masatoshi Fujita
• Keywords: 0303 health sciences; Protein Stability; Gene Expression; Proto-Oncogene Proteins c-mdm2; Cell Transformation, Viral; Prognosis; 3. Good health; Gene Expression Regulation, Neoplastic; Disease Models, Animal; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Genes, ras; Cell Line, Tumor; Neoplasms; Animals; Heterografts; Humans; Female; Protein Interaction Domains and Motifs; Gene Silencing; Carrier Proteins; Protein Binding

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.